Protocol of A Randomized, Double-blind, Placebo-controlled, Phase 3 Clinical Trial with Oral Recombinant Helicobacter Pylori Vaccine in Chinese Healthy Children
作者: 来源:疫苗临床评价所 日期: 2015-05-14
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Protocol Cover Page

 

Protocol Title:

 

A Randomized, Double-blind, Placebo-controlled, Phase 3 Clinical Trial with Oral Recombinant Helicobacter Pylori Vaccine in Chinese Healthy Children Aged from 6 to 15 Years Old

Protocol Number:

 

TMMUHP03

Protocol Date:

 

November 20, 2007

Version:

 

Version 1.2 (final)

Phase:

 

Phase 3

Sponsor:

 

Chongqing Kangwei biological technology Co., Ltd (renamed as Wuhu Kangwei biological technology Co., Ltd. in 2011)

Protocol Authors

 

Ming Zeng, National Institute for Food and Drug Control, China

Feng-Cai Zhu, Jiangsu Provincial Center for Diseases Control and Prevention

Xu-Hu Mao, Third Military Medical University

Quan-Ming Zou, Third Military Medical University

 

 

 


Document History

Document

Version Date

Summary of Changes

Version1.0

December 1, 2004

N/A

Version 1.1

November 15, 2006

Extended follow-up at month 24 after the third dose

Version 1.2

November 20, 2007

Extended follow-up at month 36 after the third dose

 

 


 

CLINICAL TRIAL CONTACT LIST

Sponsor

 

 

Chongqing Kangwei biological technology Co., Ltd (renamed as Wuhu Kangwei biological technology Co., Ltd. in 2011)

Yan Yu Yuan B-7-5

Du Shi Hua Yuan, Gaotanyan Street

Chongqing 400038, People's Republic of China

 

Tel:

Fax:

E-mail:

+86-10-65718923, 86-10-65756778

+86-10-65718923, 86-10-65756778

li0809@yahoo.cnchqh76@163.com

Principal Investigator

 

Ming Zeng

National Institute for Food and Drug Control

No.2,Tiantanxili, Beijing 100050,

People's Republic of China

E-mail:

Tel:

Fax:

zemingng@nifdc.org.cn

+86-10-67058402

+86-10-67058402

Co-Principal Investigator

 

Feng-Cai Zhu

Jiangsu Provincial Center for Diseases Control and Prevention

No. 172, Jiangsu Road,

Nanjing 210009, Jiangsu Province,

People's Republic of China

 

E-mail:

Tel:

Fax:

 jszfc@vip.sina.com

+86-25-83759418

+86-25-83759409

Serious Adverse Event

Contact Sponsor:

 

Wen-De Tong

Wen-De Tong

 

E-mail:

Tel:

Fax:

Mob. Phone:

twd8958@sina.com

86-23-68771017

86-23-68752377

13508389118

Clinical Laboratory:

 

Bing Wang

National Institute for Food and Drug Control

No.2,Tiantanxili, Beijing 100050,

People's Republic of China

 

E-mail:

Tel:

Fax:

Mob. Phone:

binwang@nifdc.org.cn

86-10-67095418

86-10-67058402

13611039871

           

PROTOCOL SUMMARY

Sponsor:

Name of Study Vaccine:

Active Ingredient(s):

Chongqing Kangwei biological technology Co., Ltd (renamed as Wuhu Kangwei biological technology Co., Ltd. in 2011)

Oral Recombinant Helicobacter Pylori Vaccine

Each dose contains 15mg of purified genetically engineered expressed fusion protein of H. pylori urease B subunit and immune adjuvant Escherichia coli LT toxin B subunit

Placebo:

Placebo contains 0U of fusion protein of H. pylori urease B subunit and immune adjuvant Escherichia coli LT toxin B subunit

Title of the trial:

A Phase 3 Clinical Trial for Efficacy, Immunogenicity, Safety of Oral Recombinant Helicobacter Pylori Vaccine in Chinese Children Aged from 6 to 15 Years Old.

Trial Centers and Investigators:

Site: Ganyu County, in Jiangsu Province

De-Lin Wu

Tel:  86-518-86995266         e-mail:  WDLCDC@126.com

Da-Han Li

Tel86-518-86013271;        e-mail: Lidahangy@126.com

Trial Duration:

Trial Phase:

40 months 

Phase 3

Objectives:

Primary Objectives:

To investigate the occurrence of Helicobacter pylori infection in subjects (aged from 6 to15 years old) within one year after three-dose vaccination.

 

Secondary Objectives:

To evaluate the safety of H. pylori vaccine in children (aged 6 to 15 years old).

To evaluate the immunogenicity of H. pylori vaccine in children (aged 6 to15 years old).

To evaluate the persistence of antibody elicited by H. pylori vaccine in children (aged 6 to 15 years old) within one year.

 

Exploratory Objectives:

To explore the relationship between antigen-specific antibody levels one month after third-dose vaccination and protection efficiency.

To investigate the efficacy of Helicobacter pylori vaccine against H. pylori infection in subjects within two years after the third dose vaccination.

To investigate the occurrence of Helicobacter pylori infection in subjects within three years after the third dose vaccination.

To evaluate the persistence of antibody elicited by H. pylori vaccine in children (aged 6 to 15 years old) within two years after the third dose vaccination.

To evaluate the persistence of antibody elicited by H. pylori vaccine in children (aged 6 to 15 years old) within three years after the third dose vaccination.

Primary Efficacy Endpoints:

H. pylori infection happened during the one-year surveillance period (Month 1, Month 4, Month 8 and Month 12). H. pylori infection should be confirmed with the evidence of positive in a 13C-urea breath test and successive positive of H. pylori-specific serum by ELISA.

 

Secondary Endpoints for Safety:

1. Frequency of adverse reactions after each vaccination.

2. Occurrence of serious adverse events during the vaccination period.

 

Secondary Endpoints for Immunogenicity:

1. GMTs, GMFIs and conversion rates in serum and saliva after three-dose vaccination of subjects in immunogenicity subgroup at Month 1.

2. GMTs, GMFIs and conversion rates in serum and saliva after three-dose vaccination of subjects in immunogenicity subgroup at Month 6.

3. GMTs, GMFIs and conversion rates in serum and saliva after three-dose vaccination of subjects in immunogenicity subgroup at Month 12.

 

Methodology

This clinical trial is a randomized, double-blind (subjects, caregivers, investigators), placebo-controlled superiority trial to assess the efficacy, safety, immunogenicity and immunogenic persistency.

Screening will be conducted before taking the oral recombinant H. pylori vaccine. Subject who is both negative in the serology ELISA and 13C-urea breath test can be recruited in phase 3 clinical trial.

The planned sample size is 4000. Subjects are randomly assigned to receive H. pylori vaccine or placebo in a ratio of 1:1, i.e. about 2000 subjects in each treatment group. The vaccine is given orally in subjects (aged 6-15 years old) at day 0, day14 and day 28.

Subjects should attend 9 site visits within first-year study (10 site visits for the immunogenicity subgroup):

Visit 1 (Screening 1), informed consent, screening, blood and saliva sample taking for serology ELISA;

Visit 2 (Screening 2), screening, 13C-urea breath test;

Visit 3 (Day 0), randomizing, first dose vaccination, and 30 mins safety observation after vaccination;

Visit 4 (Day 14), second dose vaccination, and 30 mins safety observation after vaccination;

Visit 5 (Day 28), third dose vaccination, and 30 mins safety observation after vaccination;

Visit 6 (1 month after the third dose vaccination), blood and saliva sample taking; SAEs ;

Visit 7 (4 months after the third dose vaccination), 13C-urea breath test / serology ELISA test, SAEs;

Visit 8 (6 months after the third dose vaccination), blood and saliva sample taking in the immunogenicity subgroup of subjects

Visit 9 (8 month after the third dose vaccination), 13C-urea breath test / serology ELISA test, SAEs;

Visit 10 (12 months after the third dose vaccination), 13C-urea breath test / serology ELISA test, SAEs; blood and saliva sample taking in the immunogenicity subgroup of subjects.

Extended visits

Visit 11 (24 months after the third dose vaccination), 13C-urea breath test / serology ELISA test, SAEs; blood and saliva sample taking in the immunogenicity subgroup of subjects.

Visit 12 (36 months after the third dose vaccination), 13C-urea breath test / serology ELISA test, SAEs; blood and saliva sample taking in the immunogenicity subgroup of subjects.

Time Points for Biological Specimen Collection:

1. For the subjects in the immunogenicity subgroup, blood and saliva samples will be collected from them before first dose (visit 1), at Month 1 (visit 6), Month 6 (visit 8) and Month 12 (visit 10) after the third dose. In extended follow up, blood and saliva samples will be collected from them at Month 24 (visit 11) and Month 36 (visit 12) after the third dose.

2. For all subjects, blood and saliva sample will be collected before the first dose (visit 1) and one month after the third dose vaccination (visit 6).

3. For the screening subjects for the H. pylori infection cases in the surveillance period, 13C-urea breath test will be conducted at Month 4 (visit 7), Month 8 (visit 9) and Month 12 (visit 10), Month 24 (visit 11), Month 36 (visit 12). Blood samples will be collected when the results of the 13C-urea breath test are positive.

Time Points for Safety Assessment:

1. Temperature and solicited adverse reactions will be recorded by subjects’ guardians on the diary cards within 3 days after each vaccination.

3. Any serious adverse events (SAEs) happened during the first-year study will be reported.

Number of Subjects (Planned):

The planned total number of subjects will be 4000 with 2000 per treatment group. The subjects will receive Oral Recombinant Helicobacter Pylori Vaccine or placebo randomly.

Inclusion Criteria

1)      Healthy children aged from 6-15 years old as established by medical history and clinical examination;

2)      The subjects’ guardians are able to understand and sign the informed consent;

3)      Subjects who can and will comply with the requirements of the protocol;

4)      Subjects with temperature <=37.0°C on axillary setting.

Exclusion Criteria for the First Dose

1)        Subject who has a medical history of stomach illness;

2)        Positive in either serology ELISA test for Helicobacter pylori diagnose kit or 13C-urea breath test;

3)        Subject who has suffered from heart, liver, and kidney disease;

4)        Subject who has a medical history of any of the following: allergic history, or allergic to any ingredient of vaccine (for example: mannitol);

5)        Subject who is suffering from thrombocytopenia or other coagulation disorder;

6)   Subject who has a diminished function of the immune system or autoimmune disease;

7)        Subject who is suffering from congenital deformities, developmental disorders or serious chronic diseases;

8)        Family history of seizures or progressive neurological disease

9)        Severe malnutrition or dysgenopathy, major congenital defects or serious chronic illness, including perinatal brain damage

10)      Any acute infections in last 7 days

11)      Any prior administration of immunodepressant or corticosteroids in last 6month

12)      Any prior administration of other research medicines in last 1 month

13)      Any condition that in the opinion of the investigator, may interfere with the evaluation of study objectives

 

Exclusion Criteria for the Second and the Third Dose

Subjects will not be eligible for the second dose if any of following happened after first dose.

1)   Subject who has allergic reaction after last dose;

2)   Any situation meets the exclusion criteria occurred after the last dose;

3)   Subject who has any serious adverse events (SAE) related to the vaccination.

4)   Any condition that in the opinion of the investigator, may interfere with the evaluation of study objectives;

Duration of Study:

Primary study duration: 16 months

Whole study duration (including extended follow-up): 40 months

Statement for Further Following Studies:

Subjects may be asked to participate in further follow-up after complete the planned surveillance period. However, before any further following studies initiated permission must be obtained from Chongqing Kangwei biological technology Co., Ltd (renamed as Wuhu Kangwei biological technology Co., Ltd. in 2011) and institutional review board.

       

 


 

TABLE OF CONTENTS

 

ABBREVIATIONS- 15

1.       INTRODUCTION-- 17

1.1         Indication- 17

1.2         Background and rationale- 17

1.2.1     Preclinical investigation with the H. pylori vaccine- 18

1.2.2     Phase 1 clinical trial with the H. pylori vaccine- 18

1.2.3     Phase 2 clinical trial with the H. pylori vaccine- 19

1.2.4     Determination of dosage and regimen for phase 3 clinical trial 19

1.2.5     Consideration of placebo for phase 3 clinical trial 20

1.2.6     Risk-benefit assessment 20

2.       STUDY OBJECTIVES AND ENDPOINTS- 20

2.1         Primary objectives 20

2.2         Endpoint for the primary objectives 20

2.3         Secondary objectives 21

2.4         Endpoints for secondary objectives 21

2.4.1     Safety- 21

2.4.2     Immunogenicity- 21

2.5         Exploratory objectives 21

3.       STUDY DESIGN-- 22

3.1         Description- 22

3.2         Approximate duration of subject participation- 22

3.3         Approximate duration of study- 22

3.4         Sample size- 22

3.5         Study center 23

3.6         Setting of immunogenicity and immunogenic persistency subgroup- 24

4.       SUBJECT SELECTION-- 25

4.1         Inclusion and exclusion criteria- 25

4.2         Criteria for withdraw-- 26

5.       INVESTIGATIONAL PRODUCTS AND ADMINISTRATION-- 26

5.1         Investigational product supplies 26

5.1.1     Study vaccine and placebo- 26

5.1.2     Packaging and labeling- 27

5.1.3     Dosage and administration- 27

5.1.4     Storage and dispensing of study medication- 27

5.2         Treatment allocation and randomization- 28

5.2.1     Randomization and blinding- 28

5.2.2     Treatment allocation- 28

5.3         Method of blinding, unblinding and breaking the study blind- 28

5.3.1     Method of blinding- 28

5.3.2     Method of unblinding- 29

5.3.3     Method of emergency unblinding- 29

5.4         Back-up vaccine doses 30

5.5         Investigational product accountability- 30

5.6         Compliance monitoring- 30

6.       CONDUCT OF THE STUDY-- 31

6.1         Study procedures description- 31

6.2         Informed consent 33

6.3         Screening- 34

6.4         Subject identification- 35

6.5         Safety follow-up- 35

6.6         Detailed description of study stages/visits 35

Visit 1: Screening 1- 35

Visit 2: Screening 2- 36

Visit 3: Day 0- 36

Visit 4: Day 14- 36

Visit 5: Day 28- 37

Visit 6: Month 1- 37

Visit 7: Month 4- 38

Visit 8: Month 6- 38

Visit 9: Month 8- 38

Visit 10: Month 12- 38

Visit 11: Month 24- 39

Visit 12: Month 36- 39

7.       SURVEILLANCE- 39

7.1         Surveillance target population- 39

7.2         Duration of surveillance period- 39

7.3         Set up of the active surveillance system-- 39

7.3.1  Diagnostic criteria for Helicobacter pylori infection: 39

7.3.2  Treatment of subjects infected by Helicobacter pylori 41

8.       ASSESSMENTS- 41

8.1         Safety assessments 41

8.1.1     Grading for adverse events 42

8.1.2     Adverse event and adverse reaction definition- 44

8.1.3     Serious adverse event/reaction (SAE) definition- 45

8.1.4     Reporting SAEs 45

8.1.5     Treatment of adverse reaction- 46

8.1.6     Causality assessment 46

8.1.7     Withdrawal due to serious adverse events (see also section on Subject Withdrawal) 46

8.2         Estimation of immunogenicity- 46

8.2.1     Handling of Blood Samples Collected by the Investigator 47

8.2.2     Handling of saliva samples collected by the investigator 49

8.2.3     Shipment of serum and saliva samples to NIFDC- 50

8.2.4     Determination of specific IgG antibody from serum-- 50

8.2.5     Determination of specific sIgA antibody from saliva- 51

8.3         Protective efficacy against H. pylori assessment 51

9.       DATA COLLECTION AND MANAGEMENT- 52

9.1         Source documents and source data- 52

9.2         Data management 52

9.2.1     Clinical data management 53

9.2.2     Surveillance data management 53

10.         CLINICAL INVESTIGATOR’S BROCHURE- 53

11.         ARCHIVING-- 54

12.         QUARLITY CONTROL AND QUARLITY ASSURANCE- 54

12.1       Monitoring- 54

12.2       Audits 56

13.         STATISTICAL CONSIDERATIONS- 56

13.1       Study cohorts to be evaluated- 57

13.1.1        Safety analysis cohort 57

13.1.2        Per-protocol cohort for analysis of efficacy- 57

13.1.3        Per-protocol cohort for analysis of immunogenicity- 57

13.1.4        Cohort for analysis of the surrogate of protection- 57

13.2       Derived and transformed data- 58

13.3       Description of analyses 58

14.         ETHICAL AND LEGAL ISSUES- 59

14.1       Guideline- 59

14.2       Institutional review board- 59

14.3       Responsibilities of the investigator 60

14.4       Ethical conduct of the study- 61

14.5       Protocol amendments and administrative changes 61

14.6       Confidentiality of data and access to subject records 62

15.         FINANCIAL CONTRACT AND INSURANCE COVERAGE- 62

16.         SPONSOR’S TERMINATION OF STUDY-- 62

17.         OWNERSHIP AND PUBLICATION-- 63

17.1       Ownership- 63

17.2       Publication- 64

18.         SIGNATURES- 64

19.         REFERENCES- 65

20.         APPENDIX-- 67

The screening form for the volunteers 67

Monitor table of the vaccine precaution- 68

Informed Consent Form (ICF) 69

Informed Consent Form (ICF) For Subjects in Immunogenicity Subgroup Only- 76

Informed Consent Form (ICF) for Extended Follow-up at Month 24- 83

Informed Consent Form (ICF) for Extended Follow-up at Month 36- 86

 


ABBREVIATIONS

AE

Adverse Event

AR

Adverse Reaction

ATP

According to Protocol

CagA

Cytotoxin Associated Antigen

CDC

Center for Disease Control and Prevention

CI

CISDCP

Confidence Interval

China Information System for Diseases Control and Prevention

CRF

Case Report Form

°C

Degrees Celsius

ELISA

Enzyme Linked Immunosorbent Assay

FAS

Full Analysis Set

GCP

Good Clinical Practice

GLP

Good Laboratory Practice

GMT

Geometric Mean Titer

GMFI

Geometric Mean Fold Increase

HP

Helicobacter Pylori

HSP58

Heat Shock Protein 58

ICF

Informed Consent Form

ICH

International Conference on Harmonization (Technical

Requirements for Registration of Pharmaceuticals for Human Use)

IRB

Institutional Review Board

ITT

Intent-to-treat

NIFDC

National Institutes for Food and Drug Control, People’s Republic of China

QA

Quality Assurance

P.R. China

People’s Republic of China

ROC

Receiver Operating Characteristic Curve

SFDA

State Food and Drug Administration, China

SAE

Serious Adverse Event

SOP

Standard Operation Procedure

sIgA

Secreting IgA

UreB

Urease Subunit B

WHO

World Health Organization


1.        INTRODUCTION

1.1    Indication

Helicobacter pylori (H. pylori) is a Gram-negative, microaerophilic bacterium that persistently colonizes the human stomach; more than half of the human population is infected worldwide. It has been established that H. pylori is associated with chronic gastritis, peptic ulcer disease, gastric cancer, gastric mucosa associated lymphoid tissue lymphoma1-3.

At present, the main clinical treatment for H. pylori infection is the application of antibiotics and bismuth agent or H+ antagonists. Due to the widespread drug resistance, toxic side effects, high medical costs as well as poor patient compliance, it is unworkable to practice antibiotics therapy for H. pylori eradication on every patient. Vaccination is the most effective way for prevention H. pylori infection.

The phase 1 and 2 clinical trial has completed in Jiangsu Provence in China. The data from phase 1 and 2 clinical trial suggested that the oral recombinant Helicobacter pylori vaccine had a clinically acceptable safety and good immunogenicity for health adults and children on a 0, 14, 28 day vaccination schedule. In order to provide critical evidence for the efficacy of the oral recombinant Helicobacter pylori vaccine, a phase 3 clinical trial will be conducted.

1.2    Background and rationale

The development of the vaccine against H. pylori is active and ongoing in several countries. Several studies have examined the effectiveness of inactivated viral vaccines against H. pylori in animal model. A wide range of experimental vaccine against H. pylori approaches have been studied, including oral H. pylori whole-cell vaccine 4-5, genetic engineering subunit-based vaccine 6-8 , Live vector-based vaccines 9-10. Urease is considered to be an excellent candidate antigen for vaccine against H. pylori. However, no vaccine against H. pylori has been tested in phase 3 efficacy trial.

1.2.1            Preclinical investigation with the H. pylori vaccine

Third Military Medical University (Chongqing, China) developed the oral recombinant Helicobacter pylori vaccine, using purified genetically engineered expressed H. pylori urease B subunit and immune adjuvant Escherichia coli LT toxin B subunit fusion protein. The recombinant fusion protein was produced in Escherichia coli BL21 (DE3). Protein analysis was performed with SDS-PAGE on purified material from the E.coli expression system and concentrations were determined using the Bio-Rad DC protein assay. The concentrated suspension was purified by gel filtration chromatography followed by ion exchange chromatography, and then inactivation by formaldehyde and adsorption on aluminum hydroxide. The antigen content was measured by double-antibody sandwich ELISA.

The immunogenicity experiment in mice was a 0, 14, 28 day vaccination schedule. The safe evaluation in mice showed that the vaccine was safe with a dose of 40 times of clinical dosage.

1.2.1.1 Antigenicity and immunogenicity

The antigenicity and immunogenicity results showed that rLTB-UreB antigen of oral recombinant H. pylori vaccine had a good antigenic reactivity, and the activity of rLTB-UreB antigen to bind GM1 ganglioside, suggesting that LTB remained a fine mucosal adjuvant property.

Comparative study between injection and oral administration of immunizing BALB/c mice suggested that oral immunization induced more effective antibody-secreting cells responses and produced a high level of specific gastrointestinal mucosal sIgA and IgA, which indicated that oral immunization was the optimal approach.

1.2.2            Phase 1 clinical trial with the H. pylori vaccine

The phase 1 study of the oral recombinant H. pylori Vaccine (H. pylori Vaccine) had been performed in Jiangsu Province in China, in 2003.

Phase 1 was an open label, non-randomized safety study in healthy young adults (aged from 26 to 45 years old) and older children (aged from 6 to 15 years old). The total number of subjects in phase 1 study was 40 (10 adults and 30 children). Before using this product, subjects first took 80ml of oral acid neutralization liquid, and then immediately took 30ml of the oral vaccine. 10 adults aged 26 to 45 years old were firstly recruited, and sequentially received vaccine with the dose of 45mg. Then, 30 older children aged from 6 to 15 years old were recruited, and sequentially received vaccine with the dose of 45mg in the same manner.

Results of the phase 1 study suggested that the oral recombinant H. pylori vaccine had a clinically acceptable safety for healthy adults (aged from 26-45 years old) and children (aged from 6-15 years old). However, the immunogenicity and protection efficiency of vaccine had not been evaluated.

1.2.3            Phase 2 clinical trial with the H. pylori vaccine

The phase 2 clinical trial was completed in 2004. The total number of subjects was 623 divided into 4 arms (Placebo: 151; 15mg/dose: 148; 30mg/dose: 171; 45mg/dose: 153). Data from phase 2 trial showed that the H. pylori vaccine was well tolerated with no treatment-related serious adverse events. Adverse events were mainly mild and transient. The results showed that the oral recombinant H. pylori vaccine had a clinically acceptable safety for healthy children, and effectively stimulated human body to produce serum-specific IgG antibodies, serum-specific total Ig antibodies, saliva-specific sIgA antibodies and gastrointestinal tract-specific sIgA antibodies. But no statistical difference of the immune response was found between different dosage groups of the H. pylori vaccine. Taking immunogenicity, safety, and production capacity into account, 15mg/dose with a total of 3 times vaccination of the oral recombinant H. pylori vaccine was probably the best possible formulation for phase 3 trials.

1.2.4            Determination of dosage and regimen for phase 3 clinical trial

Based on the above results from Phase 1 and 2 studies, taking safety, immunogenicity and product capacity into account, the 15mg/dose with three-dose regimen is more suitable for being used in the Phase 3 study to evaluate the prophylactic efficacy of the H. pylori vaccine in a larger children (aged from 6 to 15 years old) population.

 

1.2.5            Consideration of placebo for phase 3 clinical trial

In order to ensure the randomization and blindness, a placebo contains no fusion protein of UreB antigen and LTB is chosen as control vaccine.

1.2.6            Risk-benefit assessment

Benefits:

Subjects may be benefit from following three aspects:

Immunization against H. pylori infection;

Pathogenic assay for free during the surveillance period;

Free vaccination of the H. pylori vaccine for the subjects who will receive placebo by randomization in this study after the approval for marketing of the H. pylori vaccine.

 

Risks:

The H. pylori vaccine is supposed to have an excellent safety profile, according to the safety data from phase 1 and phase 2 clinical trials. However, subjects may suffer from adverse reactions after vaccination including fever, diarrhea, nausea and vomiting.

2.        STUDY OBJECTIVES AND ENDPOINTS

2.1    Primary objectives

To investigate vaccine efficacy in participants (aged from 6 to 15 years old) within one year after three-dose vaccinations.

2.2    Endpoint for the primary objectives

H. pylori infection should be confirmed with the evidence of positive in a 13C-urea breath test and positive of H. pylori-specific serum by ELISA.

2.3    Secondary objectives

To evaluate the safety of H. pylori vaccine in children (aged from 6 to 15 years old).

To evaluate the immunogenicity of H. pylori vaccine in children (aged from 6 to15 years old).

To evaluate the persistence of antibody elicited by H. pylori vaccine in children within one year(aged from 6 to 15 years old).

2.4    Endpoints for secondary objectives

2.4.1            Safety

1. Frequency of adverse reactions within 3 days after each vaccination.

2. Occurrence of serious adverse events during the first-study year.

2.4.2            Immunogenicity

1. Geometric mean titers (GMTs), seroconversion, Geometric mean fold increase (GMFIs) of UreB-specific antibody of subjects measured 1 month after the third dose vaccination.

2. GMTs, seroconversion, GMFIs of UreB-specific antibody of subjects measured 6 months after the third dose vaccination.

3. GMTs, seroconversion, GMFIs of UreB-specific antibody of UreB-specific antibody of subjects measured 12 months after the third dose vaccination.

2.5    Exploratory objectives

To explore the relationship between antigen-specific antibody levels one month after third-dose vaccination and protection efficiency.

The efficacy of H. pylori vaccine against H. pylori infection in subjects within two years after the three-dose vaccination.

The efficacy of H. pylori vaccine against H. pylori infection in subjects within three years after the three-dose vaccination.

GMTs, seroconversion, GMFIs of UreB-specific antibody of UreB-specific antibody of subjects measured 24 months after the third dose vaccination.

GMTs, seroconversion, GMFIs of UreB-specific antibody of UreB-specific antibody of subjects measured 36 months after the third dose vaccination.

3.        STUDY DESIGN

3.1    Description

Before enrollment, all the volunteers will be tested This clinical trial is a Phase 3, randomized, double-blind (subjects, caregivers, investigators), placebo-controlled study to assess the efficacy of 15mg/dose oral recombinant H. pylori vaccine in about 4000 healthy children (aged from 6 to 15 years old). Subjects are randomized to receive the H. pylori vaccine (2000) or the placebo (2000) on day 0, day 14 and day 28.

3.2    Approximate duration of subject participation

In initial study, subjects will be followed for 12 months after the third-dose vaccination.

In extended follow-up study, subjects will be followed up to three years.

3.3    Approximate duration of study

The study will be completed in approximately 40 months after the start of the study. The end of the clinical phase of the study is the complement of surveillance at month 36. At that time, sites are closed out, the institutional review board/independent ethics committee (IRB/IEC) are informed.

3.4    Sample size

Estimation of sample size

The sample size is estimated as follows:

N1: the number of vaccine group;

N0: the number of placebo group;

P0: the rate of infection (placebo group);

P1= (1-expected protection rate) P0

Q0: Q0=1- P0

Q1: Q1=1- P1

α=0.05, β=0.1, so Zα=1.96, Zβ=1.282.

The estimation of sample size is based on the different protection rate under the average rate of natural infection of different year.

 

Infection rate in placebo group P0 (%)

sample size N0= N1

80% protection rate

70% protection rate

60% protection rate

1

1957

2768

4057

2

971

1374

2013

3

643

909

1332

4

479

677

991

5

380

537

787

6

315

445

651

7

268

378

553

8

232

328

480

9

205

290

423

10

183

259

183

According to the results of epidemiological investigation, the average rate of infection of children of 6-15 years old is 2%. Considering the average rate of infection of the year, expected protection rate, failure of follow-up and so on, the number of people in vaccine group and placebo group in the clinical trial is about 2000 respectively.

3.5    Study center

The study site is Ganyu County, which is located in the northeast of Jiangsu Province. The total area of Ganyu County is 1402.5 square kilometers. The total population of Ganyu County is 1078928, in which there are about 196675 children aged between 6 and 15 years.

We will recruit subjects of this study from Shiqiao Town, Chengtou Town and Shahe Town in Ganyu County. Shiqiao Town is located in the northeast of Ganyu County with a total population of 42340 (6-15 years old children: 8284); Chengtou Town is located in the west part of Ganyu County with a total population of 46838 (6-15 years old children: 8417); Shahe Town is located in the south part of Ganyu County with a total population of 115957 (6-15 years old children: 19360). The prospective volunteers will be recruited from 12 local schools in the three Towns for eligibility assessment.

 

Town

School

Number of children between 6 and 15 years

Shiqiao Town

Shiqiao Central School

674

 

Shiqiao Dazhuang School

438

 

Shiqiao Guanzhuang School

424

Chengtou Town

Chengtou Central School

813

 

Chengtou Zhucundian School

504

 

Chengtou Botuogou School

304

 

Chengtou Haizi School

321

 

Chengtou Dagoutou School

328

 

Chengtou Dahuangdun School

466

Shahe Town

Shahe Central School

1491

 

Shahe Huibu School

547

 

Shahe Tangzhuang School

693

 

3.6    Setting of immunogenicity and immunogenic persistency subgroup

Approximate 800 subjects will be recruited from 2 local schools in Chengtou Town by a cluster sampling, Jiangsu Province, to form the immunogenicity and immunogenic persistency subgroup. Blood and saliva samples will be collected from these subjects at day 0 and one month after the third dose vaccination to evaluate the immunogenicity of H. pylori vaccine, and on Month 6 and Month 12 after the third dose vaccination to evaluate the immunogenic persistency of H. pylori vaccine. Blood and saliva sample of the subjects in this subgroup will also be collected during the extended surveillance period (at Month 24 and Month 36) for evaluating the immunogenic persistency.

4.        SUBJECT SELECTION

4.1    Inclusion and exclusion criteria

The following inclusion and exclusion criteria are used to select the subjects for this study.

Inclusion criteria

1)      Healthy children aged from 6 to 15 years old as established by medical history and clinical examination;

2)      The subjects’ guardians are able to understand and sign the informed consent;

3)      Subjects who can and will comply with the requirements of the protocol;

4)      Subjects with temperature <=37.0°C on axillary setting.

Exclusion criteria for the first dose

1)  Subject who has a medical history of stomach illness;

3)        Positive in either serology ELISA test for Helicobacter pylori diagnose kit or 13C-urea breath test;

3)  Subject who has suffered from heart, liver, and kidney disease;

4)  Subject who has a medical history of any of the following: allergic history, or allergic to any ingredient of vaccine (for example: mannitol);

5)  Subject who is suffering from thrombocytopenia or other coagulation disorder;

6)  Subject who has a diminished function of the immune system or autoimmune disease;

7)  Subject who is suffering from congenital deformities, developmental disorders or serious chronic diseases;

8)  Family history of seizures or progressive neurological disease

9)  Severe malnutrition or dysgenopathy, major congenital defects or serious chronic illness, including perinatal brain damage

10)  Any acute infections in last 7 days

11)  Any prior administration of immunodepressant or corticosteroids in last 6month

12)  Any prior administration of other research medicines in last 1 month

13)  Any condition that in the opinion of the investigator, may interfere with the evaluation of study objectives

Exclusion criteria for the second and third dose

Subjects will not be eligible for the second or third dose if any of following happen after first dose.

1)    Subject who has allergic reaction to the last dose;

2)    Any situation meets the exclusion criteria occurred after the last dose;

3)    Subject who has any serious adverse events related to the vaccination.

4)    Any condition that in the opinion of the investigator, may interfere with the evaluation of study objectives

4.2    Criteria for withdraw

1)      Severe violation of the protocol.

2)      Some food and/or medicine can interfere with the immune response during the vaccination period (day 0 to one month after the third dose vaccination).

3)      Unwilling to continue the study and request to withdraw.

4)      Any intolerable adverse events (related to vaccination or not).

5)      New diagnosed disorder which makes the subjects not suitable to continue the study.

6)      The presence of any condition needs to be withdrawn determined by investigators.

5.        INVESTIGATIONAL PRODUCTS AND ADMINISTRATION

5.1    Investigational product supplies

5.1.1            Study vaccine and placebo

The vaccine is the fusion protein of mucosal immune adjuvant (Escherichia coli heat-labile toxin B subunit, LTB) and the Helicobacter pylori antigens UreB (Urease B subunit) utilizing DNA recombinant technology. The molecular weight is about 75 kD. The vaccine (batch number 200403-1) and placebo (batch number 200403-1A) of Phase 3 clinical study are sent to test in NIFDC. The results are in line with its production and quality control procedures.

5.1.2            Packaging and labeling

All the investigational vaccines and placebo are identical in appearance and single dose per vial. Both investigational vaccines and placebos are manufactured by Chongqing Kangwei biological technology Co., Ltd. Any flaws in the investigational products are reported to Chongqing Kangwei biological technology Co., Ltd.

The vaccines are packed in labeled boxes. Each label contains the following information: name of vaccine, manufacturing enterprises, vaccine code, expiry date, storage conditions and “only used for investigation”.

5.1.3            Dosage and administration

The specification of the H. pylori vaccines is 15mg /vial.

The vaccine will be given orally in children subjects (aged from 6 to 15 years old) at day 0, day 14 and day 28.

 

5.1.4            Storage and dispensing of study medication

All vaccines will be shipped at +2°C to +8°C to the study site upon request. Upon receipt at the study site, the vaccines should be immediately transferred to a +2°C to +8°C temperature-monitored refrigerator for storage. Vaccines must not be frozen. Storage conditions stated in the investigator brochure may be superseded by the label storage.

The refrigerator in which vaccines are stored must be secure and have limited access. The storage temperature of study vaccines/controls will be monitored daily while using validated temperature monitoring devices and the temperature measurements will be recorded during working days, preferably at the same time of the day (e.g. at the beginning of the day). Freezing indication will be continuously controlled by an appropriate device placed close to the study vaccines.

Any temperature deviation, meaning temperature outside the defined range (i.e. +2 to +8°C), must be reported within 2 working days to the sponsor and investigator Unit. Following exposure to a temperature deviation, the study vaccines/controls should be placed separately to avoid the confused with normal vaccines, and will not be used until written approval is given by the sponsor.

5.2    Treatment allocation and randomization

5.2.1            Randomization and blinding

Vaccine and placebo are randomized in a 1:1 ratio according to a randomization list prepared by a statistician from the third party, using SAS 8.2 software. The vaccine and placebo will be relabeled with randomization code as the only identifier. To allow 15% deviation in the actual number of the enrollment, the assigned numbers consist of 4 digits, ranging from 0001 to 4600, containing 367 blocks. Investigators who involve in the randomization will not participate in any other process of the trial. All the subjects and investigators will be masked to the allocation of treatment.

An emergency code-break list will also be prepared with the form of scratch cards by the third party. The completed code-break scratch cards, together with the labeled investigation vaccines, will be shipped to the study centers.

5.2.2            Treatment allocation

A sequential number will be assigned to each subject based on the sequence of enrollment to identify them. The sequential number (as ID number for each subject) must be recorded by the investigator in the CRF (Randomization/Treatment Allocation Section). The subjects will receive doses labeled with the same sequential numbers. Therefore, the subjects will be randomly assigned to receive either vaccine or placebo in a 1:1 ratio.

5.3    Method of blinding, unblinding and breaking the study blind

5.3.1            Method of blinding

This study will be performed in a double-blinded manner. Blinding will be maintained for all subjects and investigators and their study staff participating in this study with regard to the individual subject treatment (vaccine or control) assignments allocated in this study. Chongqing Kangwei biological technology Co. Ltd personnel directly involved in the conduct of this study (e.g. site monitors, medical monitors, laboratory personnel, etc.) will also be blinded to the subject’s treatment assignments.

In order to maintain the blinding, any interim analyses will be carried out by an external statistician. All Chongqing Kangwei biological technology Co. Ltd personnel, investigators and their study staff will remain blinded to individual subject assignments. No stopping rule will be applied.

5.3.2            Method of unblinding

The treatment allocation corresponding to each sequential number is provided to the investigator in separate sealed envelopes labeled with the sequential numbers. Additionally, each envelope is labeled “To Be Opened Only in Case of Emergency”.

The breaking of the treatment code is forbidden, except in the event of a medical emergency where the investigator believes it is necessary to determine the treatment code in order to initiate appropriate treatment. If knowledge of the treatment code is required, the investigator will open only the specific subject’s code envelope. A signature, date, time and reason will be written on the opened code envelope and the participant with this code has to be withdrawn from this study.

The investigator will assess the relationship of the adverse event to the study vaccine before the treatment code is unblinded. The investigator will immediately notify Chongqing Kangwei biological technology Co. Ltd at the 24 hours emergency call number (see contact list) when the treatment code is broken on any subject for any reason during the study. The reason for the treatment code being broken must be documented in the subject’s medical records and in the CRF. If a code envelope is opened for any reason other than a medical emergency, the subject must be withdrawn.

At the end of the study, all code envelopes (intact and opened) must be accounted for and are to be collected by the Monitor to be destroyed.

5.3.3            Method of emergency unblinding

The code will be broken only in the case of medical events, in the opinion of the investigator/physician in charge of the subject, whom cannot be treated without knowing the identity of the study vaccine(s).

The investigator, or person designated by the investigator, should contact Chongqing Kangwei biological technology Co. Ltd to discuss the need for emergency unblinding. Authorized by Chongqing Kangwei biological technology Co. Ltd, the principle investigator is allowed to access the individual randomization code.

5.4    Back-up vaccine doses

In cases of the breakage of the investigational vaccine/placebo, 200 additional vaccines and placebos will be supplied as back-up in a 1:1 ratio.

5.5    Investigational product accountability

The investigator will maintain accurate records of the disposition of all study vaccine supplies received during the study. These records will include the amounts and dates that clinical supplies are received from Chongqing Kangwei biological technology Co. Ltd, dispensed to the subject and returned by the subject. If errors or damages in the investigational vaccine supply shipments occur, the investigator will contact Chongqing Kangwei biological technology Co. Ltd.

Unused investigational product must be destroyed according to procedures and local environment regulations after all investigational product accountability documentation has been completed and authorizing of Chongqing Kangwei biological technology Co. Ltd. Empty investigational product containers may be destroyed after the sponsor has performed accountability.

All investigational vaccines will be accounted at the termination of the study and written explanation provided for discrepancies. All unused investigational vaccines and packaging materials will be inventoried and returned to Chongqing Kangwei biological technology Co. Ltd.

 

5.6    Compliance monitoring

The following measures will ensure that the treatment administered complies with the treatments planned, or that any non-compliance is documented so that it can be accounted for in the data analyses. All vaccines and placebo will be administered at trial site and monitored by investigators. The investigator or the person in charge of product management will maintain records of product delivery to the trial site, product inventory at the site, number assigned to each subject, and the return of unused doses to the sponsor. Labels with bar code will be affixed in the source document, in the CRF and on the product dispensing list if needed after administration of each dose of vaccine.

6.        CONDUCT OF THE STUDY

6.1    Study procedures description

 

 

 

Table 1 Scheduled visits.

Visit timing

Sampling time point

Visit

1

Visit

2

Visit

3

Visit

4

Visit

5

Visit

6

Visit

7

Visit

8

Visit

9

Visit

10

Visit

11

Visit

12

-

-

Day

0

Day

14

Day

28

Month

1*

Month

4*

Month

6*

Month

8*

Month

12*

Month

24^

Month

 36^

Informed consent

 

 

 

 

 

 

 

 

 

 

 

Demographic information

 

 

 

 

 

 

 

 

 

 

 

Blood sampling for screening

 

 

 

 

 

 

 

 

 

 

 

Breath sampling for screening

 

 

 

 

 

 

 

 

 

 

 

Physical examination

 

 

 

 

 

 

 

 

 

 

 

Check inclusion criteria

 

 

 

 

 

 

 

 

 

 

 

Check exclusion criteria

 

 

 

 

 

 

 

 

Check elimination criteria

 

 

 

 

 

 

 

 

 

 

 

Randomization

 

 

 

 

 

 

 

 

 

 

 

Blood and saliva sampling (total cohort)a

 

 

 

 

 

 

 

 

 

 

Blood and saliva sampling (immunogenicity subset)a

 

 

 

 

 

 

Pre-vaccination temperature

 

 

 

 

 

 

 

 

 

Vaccination

 

 

 

 

 

 

 

 

 

Observation for 30 minutes post-vaccination

 

 

 

 

 

 

 

 

 

Solicited symptoms (Days 0-3) post-vaccination

 

 

 

 

 

 

 

 

 

Breath sampling for H. pylori infection surveillance

 

 

 

 

 

 

 

Blood sampling for H. pylori infection surveillance

 

 

 

 

 

 

 

Final analysis

 

 

 

 

 

 

 

 

 

 

 

Site closure

 

 

 

 

 

 

 

 

 

 

 

a We will collect the blood and saliva from all volunteers at the screening stage, and store them. After confirming by the serology ELISA and breath test that a volunteer without H. pylori-infection, then his or her blood and saliva samples will be detected for baseline antibody titers.

* The time is calculated right after the third dose (Visit 4);

^ an extended visit.

6.2    Informed consent

In obtaining and documenting informed consent, the investigator should comply with the applicable regulatory requirement(s), and should adhere to GCP and to the ethical principles that have their origin in the Declaration of Helsinki. Prior to the beginning of the trial, the investigator should have the IRB/IEC’s written approval/favorable opinion of the written informed consent form and any other written information to be provided to the volunteers and their guardians.

Freely given informed consent should be obtained from every guardian of subject prior to clinical trial participation.

Information should be given in both oral and written form whenever possible and as deemed appropriate by the IRB/IEC. An investigator will describe the protocol to potential subjects face to face.

The Informed Consent Form may be read to the subjects, but, in any event, the investigator shall give the subjects ample opportunity to inquire about details of the study and ask any questions before dating and signing the Informed Consent Form.

Informed Consent Form must be in a language fully comprehensible to the prospective subjects. Informed consent shall be documented by the use of a written consent form approved by the IRB/IEC and signed and dated by the subjects and by the person who conducted the informed consent discussion. The signature confirms the consent is based on information that has been understood.

Each signed Informed Consent Form must be kept on file by the investigators for possible inspection by regulatory authorities and/or Chongqing Kangwei biological technology Co., Ltd’ professional and regulatory compliance persons. The subjects should receive a copy of the signed and dated written Informed Consent Form and any other written information provided to the subjects, and should receive copies of any signed and dated consent form updates. Any amendments to the written information will be provided to subjects.

Chongqing Kangwei biological technology Co., Ltd will prepare a model Informed Consent Form which will embody all the elements described above. While it is strongly recommended that this model document should be followed as closely as possible, the informed consent requirements given in this document are not intended to pre-empt any local regulations which require additional information to be disclosed for informed consent to be legally effective. Clinical judgment, local regulations and requirements should guide the final structure and content of the document.

The investigator has the final responsibility for the final presentation of Informed Consent Form, respecting the mandatory requirements of local regulations. The consent form generated by the investigator with the assistance of the sponsor’s representative, must be approved (along with the protocol, and any other necessary documentation) by the IRB/IEC and be acceptable to Chongqing Kangwei biological technology Co., Ltd.

6.3    Screening

Screening will take place before the randomization at Day 0. Prior to inclusion into the study, all subjects will be screened to investigate their suitability for participation in the study, after the Informed Consents have been signed.

The following procedures/assessments are performed:

-    Compliance with inclusion/exclusion criteria.

-    Assessment of medical history.

-    Recording of demographic data.

-    Assessment of H. pylori infection

Only volunteers without an H. pylori-infection are eligible for this clinical study. Children with either a positive of the serum Helicobacter pylori antibody of the ELISA or 13C-urea breath test are excluded.

Serum antibody against Helicobacter pylori of the ELISA: serum antibodies against H. pylori are measured by using a commercial indirect enzyme-linked immunosorbent assay (ELISA) diagnostic kit manufactured by Beijing Bell Biological Engineering Co. Ltd. (Number S20010005).

13C-urea breath test: duplicate breath samples are collected at baseline and 30 minutes after administration of 13C-urea from volunteers who have a negative ELISA result. The 13C-urea breath test is performed using a commercial 13C-urea breath test kit manufactured by Beijing Boran Pharmaceutical Co. Ltd., in a mass spectrometer produced by PDZ Europa Ltd.

6.4    Subject identification

Identification numbers will be assigned sequentially to subjects consenting to participate in the study after medical examination. After assignment of the identification, this identification code will be used to identify and track subjects throughout following procedures.

6.5    Safety follow-up

After an on-site safety observation of 30 minutes’ duration following vaccination, subjects or their guardians will be asked to record axillary temperature and data on solicited and unsolicited adverse events (AEs) for 3 consecutive days, in a diary card provided by the investigators. Subjects will return on Day 14 (Visit 4) or Day 28 (Visit 5) or Month 1 (Visit 6) for review of the diary card, concomitant medications and medical history. During 1-14 days after each vaccination, subjects or their guardians will continue to record any unsolicited AEs and concomitant medications into the diary card.

In the following disease surveillance period, subjects or their guardians will report any serious adverse events (SAEs) occurred during the first-year follow-up.

6.6    Detailed description of study stages/visits

Visit 1: Screening 1

l    Obtain written informed consent. (All subjects’ guardians who agree to participate in the trial must sign an original written informed consent prior to enrolment/study procedures.)

l    Collect demographic data (birth date, sex, height and weight).

l    Collect medical history data.

l    Check inclusion and exclusion criteria.

l    Take 3 ml whole blood sample.

l    Take saliva sample.

Visit 2: Screening 2

l    Check inclusion and exclusion criteria.

l    Take breath samples from the subjects with negative serology ELISA.

l    Subjects with positive serology ELISA will be excluded.

Visit 3: Day 0

l    Allocate vaccine code to each subject.

l    Administration of the first dose of H. pylori vaccine.

l    The vaccinee is observed closely for any AE for at least 30 minutes, with appropriate medical treatment readily available in case of a rare anaphylactic reaction following the administration of vaccine.

l    Distribute diary cards for daily post-vaccination recording of safety observation (day 0-3 after vaccination) and instruct subjects’ guardians to bring the completed diary card to investigators at next visit (i.e. Visit 4).

Visit 4: Day 14

l    Check elimination criteria and contraindications for the 2nd dose.

l    Check the safety observation data in the diary card and record.

l    Collection of diary cards for safety observation post-vaccination.

l    Report all SAEs.

l    Record pre-vaccination body temperature.

l    Administration of the second dose of H. pylori vaccine or control vaccine, according to the vaccine code.

l    The vaccinee is observed closely for any AE for at least 30 minutes, with appropriate medical treatment readily available in case of a rare anaphylactic reaction following the administration of vaccine.

l    Distribute diary cards for daily post-vaccination recording of safety observation (Day 0-3 after the 2nd vaccination) and instruct subjects’ guardians to bring the completed diary card to the next visit (i.e. Visit 5).

Visit 5: Day 28

l    Check elimination criteria and contraindications for the 3nd vaccination.

l    Check the safety observation data in the diary card and record.

l    Collection of diary cards for safety observation post-vaccination.

l    Report all SAEs.

l    Record pre-vaccination body temperature.

l    Administration of the three dose of H. pylori vaccine or control vaccine, according to the vaccine code.

l    The vaccinee is observed closely for any AE for at least 30 minutes, with appropriate medical treatment readily available in case of a rare anaphylactic reaction following the administration of vaccine.

l    Distribute diary cards for daily post-vaccination recording of safety observation (Day 0-3 after the 3nd vaccination) and instruct subjects’ guardians to bring the completed diary card to the next visit (i.e. Visit 6).

Visit 6: Month 1

l    Check the safety observation data in the diary card and record.

l    Check concomitant medication/vaccination and record.

l    13C-urea breath test

l    Take 3 ml whole blood sample.  

l    Take saliva sample.

l    Report all SAEs.

l    Distribute emergency contact card and instruct guardians to immediately report to investigator once SAEs occur.

Visit 7: Month 4

l    13C-urea breath test

l    Taking blood samples for serology ELISA if subjects have a positive in the 13C-urea breath test

l    Report all SAEs.

l    Distribute emergency contact card and instruct guardians to immediately report to investigator once SAEs occur.

Visit 8: Month 6

l    Take 3 ml whole blood sample from subjects in immunogenicity subset.

l    Take saliva sample from subjects in immunogenicity subset.

l    Report all SAEs.

l    Distribute emergency contact card and instruct guardians to immediately report to investigator once SAEs occur.

Visit 9: Month 8

l    13C-urea breath test.

l    Taking blood samples for serology ELISA if subjects have a positive in the 13C-urea breath test

l    Report all SAEs.

l    Distribute emergency contact card and instruct guardians to immediately report to investigator once SAEs occur.

Visit 10: Month 12

l    13C-urea breath test

l    Take blood samples for serology ELISA if subjects have a positive in the 13C-urea breath test.

l    Take 3 ml whole blood sample from subjects in immunogenicity subset.

l    Take saliva sample from subjects in immunogenicity subset.

l    Report all SAEs.

 

Visit 11: Month 24

l    13C-urea breath test

l    Take blood samples for serology ELISA if subjects have a positive in the 13C-urea breath test.

l    Take 3 ml whole blood sample from subjects in immunogenicity subset.

l    Take saliva sample from subjects in immunogenicity subset.

Visit 12: Month 36

l    13C-urea breath test

l    Take blood samples for serology ELISA if subjects have a positive in the 13C-urea breath test.

l    Take 3 ml whole blood sample from subjects in immunogenicity subset.

l    Take saliva sample from subjects in immunogenicity subset.

7.        SURVEILLANCE

7.1    Surveillance target population

The target population is the H. pylori-naïve children. All the subjects who complete three-dose vaccination of the H. pylori vaccine or placebo are followed for H. pylori infection occurrence during surveillance.

7.2    Duration of surveillance period

The initial surveillance period will last 12 months (from month 1 after the third dose to month 12 after the third dose vaccination). The extended surveillance period will up to three years (visits at Month 24 and Month 36 after the third dose vaccination).

7.3    Set up of the active surveillance system

7.3.1  Diagnostic criteria for Helicobacter pylori infection:

According to the clinical diagnostic criteria of China Medical Association Digestive Diseases branch “Helicobacter pylori Consensus” (2003 Anhui Tongcheng)

Methods for diagnosis: see Table 1

Table 1 Comparison of sensitivity and specificity of regular examination methods of Helicobacter pylori

 

Test items

Sensitivity (%)*

Specificity (%)*

Diagnostic methods of the present infection

 

 

Bacteria culture

70-92

100

Histological examination (Warthin-Starry silver staining or Giemsa staining)

93-99

9599

Urea breath test#

90-98.9

89-99

Fast urea test#

75-98

70-98

Faeces antigen examination

89-96

87-94

Diagnostic methods of the once infected

 

 

Serum Helicobacter pylori antibody

88-99

86-99

* It’s the results reported in some articles, and there are big differences in the application for the differences of skills and reagents.

# Both are urea dependent test

Clinical diagnosis: diagnosed as positive by any diagnostic methods of the present infection as Helicobacter pylori infection.

Research diagnosisdiagnosed as positive by bacteria culture or any other two methods. Serum Helicobacter pylori antibody examination can be used for large sample epidemiological investigation.

For this clinical study, positive of the 13C-urea breath test and serum antibody against Helicobacter pylori are defined as Helicobacter pylori infection.

Serum antibody against Helicobacter pylori by the ELISA: serum antibodies against H. pylori are measured by using a commercial indirect enzyme-linked immunosorbent assay (ELISA) diagnostic kit manufactured by Beijing bell biological engineering Ltd (Number S20010005).

13C-urea breath test: duplicate breath samples are collected at baseline and 30 minutes after administration of 13C-urea from volunteers who have a negative ELISA result. The 13C-urea breath test is performed using a commercial 13C-urea breath test kit manufactured by Beijing Boran Pharmaceutical Ltd, in a mass spectrometer produced by PDZ Europa Ltd.

7.3.2  Treatment of subjects infected by Helicobacter pylori

The test results will be noticed to subjects. The subjects and their guardians can know whether the subject has been infected by H. pylori, and they can get professional medical consulting about the H. pylori treatment.

8.        ASSESSMENTS

Every effort should be made to ensure that the protocol required tests and procedures are completed as described. However it is anticipated that from time to time there may be circumstances, outside of the control of the investigator, which may make it unfeasible to perform the test. In these cases the investigator will take all steps necessary to ensure the safety and wellbeing of the subject. When a protocol required test cannot be performed, the investigator should document the reason for this and any corrective and preventive actions which he/she has taken to ensure that normal processes are adhered to as soon as possible. The study team will be informed of these incidents in a timely fashion.

8.1    Safety assessments

For safety assessments, the primary outcome measure is to evaluate the adverse reactions of H. pylori vaccine, and the secondary outcome measure is to evaluate the serious adverse events during the whole study period. Subjects are remained in the clinic to observe for the occurrence of any adverse events for 30 minutes after receipt of each dose. For the next 3 days following each vaccination, any solicited adverse events are recorded by subjects or their guardians on the diary cards. The daily axillary temperature will be measured by their guardians. And the adverse events recorded by their guardians are reviewed by study staffs.

The incidence of adverse events are recorded based on the most severe response, and expressed in terms of the number and proportion of individuals who have adverse events in each group.

Gastrointestinal response: including diarrhea, vomit, stomach-ache, nausea, bloating, and so on;

Self-conscious symptom: temperature, allergic reactions, headache, dizzy, fatigue, cough;

None: no need to treat, without gastrointestinal response or the slight response without treatment

Mild: gastrointestinal response disappeared with regular treatment

Moderate or severe: need several treatments or being in hospital

8.1.1            Grading for adverse events

-    Fever (axillary)

-         none                           =  37.0°C

-         Grade 1(mild)                = ≥ 37.1°C - ≤ 37.5°C

-         Grade 2(moderate)               = 37.6°C - ≤ 39.0°C

-         Grade 3(severe)             =39.0°C

-    Allergic reactions

-         none                             = lack of symptoms

-         Grade 1(mild)                = pruritus without rashes

-         Grade 2(moderate)               = localized urticaria

-         Grade 3(severe)             = generalized urticaria, angioedema

-          Grade 4(potentially life threatening)  = severe allergic reactions

-    Fatigue

-         none                                 = lack of symptoms

-          Grade 1(mild)                        = presence of mild symptoms that do not interfere with normal daily activities, last <=48 hours

-          Grade 2(moderate)                 = symptoms that have an impact on normal daily activities, last >48 hours

-          Grade 3 (severe)         = symptoms that have an impact on normal daily activities, last >72 hours

-          Grade 4 (potentially life threatening) =emergency or hospitalization

-    Vomiting:

-         none                                 = lack of symptoms

-          Grade 1(mild)                        = once per 24 hours, normal food intake and no impairment of activities

-          Grade 2(moderate)                 = twice to three times per 24 hours, food intake significantly reduced or limitations of activities

-          Grade 3(severe)                      = > four to six times per 24 hours, little food intake, necessity of intravenous infusion

-          Grade 4(potentially life threatening)  = > not eating or liquid food for more than 24hs

-    Diarrhea:

-         none                                          = lack of symptoms

-         Grade 1(mild)                          = slightly or transient, twice to three times of watery stools per day, or continuously slight diarrhea within one week

-         Grade 2(moderate)                  = moderate or continuously, four to five times per day or diarrhea > one week

-         Grade 3(severe)                       = > six times of watery stool per day, or bloody stool, postural hypotension, electrolyte imbalance and necessity of intravenous infusion > 2 liter

-         Grade 4(potentially life threatening)  = hospitalization due to hypotensive shock

-    Nausea:

-         none                                 = lack of symptoms

-          Grade 1(mild)                        = mild

-          Grade 2(moderate)                 = moderate, food intake reduced severe

-          Grade 3(serve)            = food intake significantly reduced

-          Grade 4(potentially life threatening)  = > six times per 24 hours

-    Stomach-ache

-         None                =lack of symptoms

-         Grade 1(mild)         =mild and resolved in 24 hours

-          Grade 2(moderate)                 = symptoms that have an impact on normal daily activities, last >48 hours

-          Grade 3(serve)            = symptoms that have an impact on normal daily activities, last >72 hours

-          Grade 4(potentially life threatening)  = > emergency or hospitalization

-    Bloating

-         None                =lack of symptoms

-         Grade 1(mild)         =mild and resolved in 24 hours

-          Grade 2(moderate)                 = symptoms that have an impact on normal daily activities, last >48 hours

-          Grade 3(serve)            = symptoms that have an impact on normal daily activities, last >72 hours

-          Grade 4(potentially life threatening)  = > emergency or hospitalization

-    Cough

-          none                                        = lack of symptoms

-          Grade 1(mild)                        = transient, treatment unnecessary

-          Grade 2(moderate)                 = continuous coughs, response to treatment

-          Grade 3(severe)                      = paroxysmal coughs, treatment uncontrolled

-          Grade 4(potentially life threatening)  = emergency of hospitalization

 

8.1.2            Adverse event and adverse reaction definition

An adverse event (AE) is any untoward medical occurrence in a subject administered an investigational product and which does not necessarily have a causal relationship with this treatment.

An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of the investigational products, whether or not considered related to it.

An adverse reaction (AR) is all untoward and unintended responses to a medical product related to any dose administered.

An unexpected adverse reaction is an adverse reaction, the nature or severity of which is not consistent with the applicable product information:

-   Investigator's brochure for an unauthorized experimental product.

-   Summary of product characteristics for an authorized product.

 

8.1.3             Serious adverse event/reaction (SAE) definition

A serious adverse event/reaction is occurrence of any untoward medical during the whole study period that:

-   Results in death.

-   Life-threatening (an event in which the subject is at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it is more severe).

-   Results in persistent or significant disability/incapacity.

-   Requires hospitalization or prolongation of an existing hospitalization.

-   A congenital anomaly/birth defect.

In addition, medical and scientific judgment exercised in deciding whether other conditions will also be considered serious, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject’s safety or may require intervention to prevent one of the other outcomes listed in the definition above. These will also be considered serious. Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm.

8.1.4             Reporting SAEs

Any serious adverse event, including death due to any cause, which occurs during this study, whether or not related to the investigational products, must be reported immediately (within 24 hours of the study site’s knowledge of the event) by telephone or fax to the China SFDA and the Jiangsu provincial SFDA, Chongqing Kangwei biological technology Co., Ltd., Jiangsu Center for Diseases Control and Prevention:

Co-principal Investigator: Feng-Cai Zhu, Tel +86-25-83759418, Fax: +86-25-83759409

Representative of sponsor: Wen-De Tong, Tel: 86-23-68771017, Fax: 86-23-68752377

All SAEs will be recorded on the case report form and source documents.

8.1.5            Treatment of adverse reaction

Guide the guardians and subjects to see a doctor and report to the researchers in time if there is a severe adverse reaction. Researchers must follow up the subjects who have adverse reactions such as medical history, medical examination and necessary laboratory examination, and deal with and follow until solving the problem. Researchers must fill in the investigation form of adverse reactions in detail.

8.1.6            Causality assessment

The assessment of causality must be provided for all SAEs: All the information related to SAEs will be reported to principle investigator, and the principle investigator is responsible to give a final decision of causality for SAEs. The investigator must record the causal relationship in the CRF. A causality assessment is the determination of whether there exists a reasonable possibility that the investigational product caused or contributed to an SAE.

8.1.7            Withdrawal due to serious adverse events (see also section on Subject Withdrawal)

Withdrawal due to SAE should be distinguished from withdrawal due to insufficient response, according to the definition of SAE noted earlier and recorded on the appropriate SAE CRF page.

8.2    Estimation of immunogenicity

The serum and saliva samples of all the subjects will be collected before the vaccination and one month after the third dose vaccination. But only samples collected from subjects in the immunogenicity subset will be tested for immunogenicity assessment. And subjects in the immunogenicity subset will also donate blood and saliva sample at month 6, 12, 24, and 36 after the third dose vaccination for immunogenicity assessment.

Specific IgG antibody titers and IgA antibody titers from serum and saliva samples will be determined by ELISA respectively. To quantify the immunogenicity of the vaccines, 4-fold increase is considered as seroconversion at month 1 after the third dose vaccination.

After blood collection and coagulation (at least 30 minutes at room temperature), sera will be separated, aliquoted in two tubes and kept frozen (-20°C) until titration. All samples are blindly assayed in duplicate and double-checked.

8.2.1        Handling of Blood Samples Collected by the Investigator

1. Collection

Study center should employ the professional qualified pediatric nurses to collect samples. The whole blood (by venous route) should be collected in appropriate aseptic conditions with blood taking needle and 3 ml vacuum tube provided by the sponsor. Serum separator integrated with serum separation glue and coagulant should be used to minimize the risk of hemolysis and to avoid blood cell contamination of the serum when transferring to standard serum tubes.

The plain tube should be labeled by unique mark printed by study center, with information vaccine code, and bar code of vaccine.

2. Serum separation

For separation of serum by using vacuum tubes, the instructions provided by the manufacturer should be followed. Often the manufacturer’s instruction states that the relative centrifugal acceleration known also as “G” must be “between 1000 G and 1300 G” with tubes spinning for ten minutes. Error in calculation of centrifuge speed can occur when laboratory personnel confuse “G” acceleration with “RPM” (revolutions per minute). The speed of centrifugation must be calculated using the “G” rate provided in the manufacturer’s instructions and the radius of the centrifuge head. After measuring the radius of the centrifuge machine, a speed/acceleration nomograph must be employed to determine the centrifuge speed in “RPM”.

Following separation, the serum should be aseptically transferred to the 1.5ml EP tubes using a sterile disposable pipette. The serum should be transferred as gently as possible to avoid blood cell contamination.

The tube should not be overfilled (max. 3/4 of the total volume) to allow room for expansion upon freezing.

The tube should be identified by the appropriate label provided by study center. (see point 3).

3. Labeling

The standard labels (water and freezing proof) provided by study center should be used to label each serum sample.

The label contains the only information of vaccine code.

If necessary, any hand-written additions to the labels should be made using indelible ink.

4. Sorting, checking and storage

Tubes should be placed in the Chongqing Kangwei biological technology Co., Ltd’ cardboard boxes in numerical order from left to right, starting from the lower left hand corner, beginning with the pre-vaccination samples series, then with the post-vaccination sample series.

Before storage of the serum, study staffs have to check the consistence of the label codes on the EP tubes and the vacuum tubes.

The tubes of serum should be stored in a vertical position at approximately -20°C (alternatively at approximately -70°/80°C is also acceptable) until ship to NIFDC. The storage temperature should be checked regularly and documented. Wherever possible, a backup facility for storage of serum samples should be available.

A standard Biological Specimen Listing Form, specifying the samples being shipped for individual subjects at each time point, should be prepared for each shipment. A copy of this list should be retained at the study site, while the original should be sealed in a plastic envelope and shipped with the serum samples.

Once shipment details are known, a standard Specimen Transfer Form must be completed and faxed to Chongqing Kangwei biological technology Co., Ltd. A copy of the Specimen Transfer Form must be put in the parcel.

 

8.2.2         Handling of saliva samples collected by the investigator

1. Collection

A total of 1.5-2 ml of saliva sample should be added into 20 ul frozen preservation solution (2590 mg/L bestatin, 250 mg/L approtinin, 500 mg/L leupeptin, 2.5 g/L AEBSF, 70 mg/L pepstain, and 20 mg/L EDTA.Na2) immediately provided by the sponsor. Saliva separator integrated with glue should be used to minimize the risk contamination.

The plain tube should be labeled by unique mark printed by study center, with information of vaccine code, and bar code of vaccine.

2. Saliva separation

For saliva separation, the instructions provided by the manufacturer should be followed. Often the manufacturer’s instruction states that the relative centrifugal acceleration must be 9000G with tubes spinning for 15 minutes at 4. Error in calculation of centrifuge speed can occur when laboratory personnel confuse “G” acceleration with “RPM” (revolutions per minute). The speed of centrifugation must be calculated using the “G” rate provided in the manufacturer’s instructions and the radius of the centrifuge head. After measuring the radius of the centrifuge machine, a speed/acceleration nomograph must be employed to determine the centrifuge speed in “RPM”.

Following separation, the supernatant of the saliva should be transferred to the 1.5ml EP tubes using a disposable pipette. The tube should not be overfilled (max. 3/4 of the total volume) to allow room for expansion upon freezing.

The tube should be identified by the appropriate label provided by study center. (see point 3).

3. Labeling

The standard labels (water and freezing proof) provided by study center should be used to label each saliva sample.

The label contains the only information of vaccine code.

If necessary, any hand-written additions to the labels should be made using indelible ink.

4. Sorting, checking and storage

Tubes should be placed in the Chongqing Kangwei biological technology Co., Ltd’ cardboard boxes in numerical order from left to right, starting from the lower left hand corner, beginning with the pre-vaccination samples series, then with the post-vaccination sample series.

Before storage of the saliva, study staffs have to check the consistence of the label codes on the EP tubes.

The tubes of saliva should be stored in a vertical position at approximately -20°C (alternatively at approximately -70°/80°C is also acceptable) until ship to NIFDC. The storage temperature should be checked regularly and documented. Wherever possible, a backup facility for storage of saliva samples should be available.

A standard Biological Specimen Listing Form, specifying the samples being shipped for individual subjects at each time point, should be prepared for each shipment. A copy of this list should be retained at the study site, while the original should be sealed in a plastic envelope and shipped with the saliva samples.

Once shipment details are known, a standard Specimen Transfer Form must be completed and faxed to Chongqing Kangwei biological technology Co., Ltd to the number provided below. A copy of the Specimen Transfer Form must be in the parcel.

The Biological Specimen Listing Form and the Specimen Transfer Form are standard documents used in Chongqing Kangwei biological technology Co., Ltd’ clinical trials. These documents are provided by Chongqing Kangwei biological technology Co., Ltd’ monitors at study initiation.

8.2.3        Shipment of serum and saliva samples to NIFDC

Serum and saliva samples should be sent to NIFDC after all subjects finish each required visit for each blood and saliva collection.

Serum and saliva samples must be placed with cold chain during shipment. Biological Specimen Listing Form should always accompany the shipment.

8.2.4        Determination of specific IgG antibody from serum

Serum is diluted by double dilution methods from 1:100 and performed by modified antigen-capture ELISA (100 ul per well). The positive control, negative control and blank control are also performed. Then the plates are kept for 45 minutes at 37. The HRP-labelled goat anti-human IgG antibody (1:20000) is added (100 ul per well) into the plates and then washed 4 times. Then the plates are kept for 30 minutes at 37. The OPD substrate chromogen is added into the plates. Then the plates are kept in dark for 10-15 minutes at 37. The stop solution is added (50 ul per well) into the plates and the OD value is determined by measuring the optical density at 492 nm of microplate-reader.

8.2.5        Determination of specific sIgA antibody from saliva

Saliva is diluted by double dilution methods from 1:4 and performed by modified antigen-capture ELISA (100 ul per well). The positive control, negative control and blank control are also performed. Then the plates are kept for 45 minutes at 37. The Biotin-labelled goat anti-human IgA antibody (1:80000) is added (100 ul per well) into the plates and then washed 4 times. Then the plates are kept for 30 minutes at 37. The HRP-labelled Avidin (1:10000) is added (100 ul per well) into the plates. Then the plates are kept for 30 minutes at 37. The OPD substrate chromogen is added into the plates. Then the plates are kept in dark for 10-15 minutes at 37. The stop solution is added (50 ul per well) into the plates and the OD value is determined by measuring the optical density at 492 nm of microplate-reader.

8.3    Protective efficacy against H. pylori assessment

Take the 13C-urea breath test at month 4, month 8 and month 12 in the initial one-year study, and month 24, 36 in the extended follow-up. Then, collect the blood sample when the 13C-urea breath test result is positive. If two positive results are confirmed, this subject will be considered as an H. pylori infection event.

Calculate the event rate:

Event rate (%) = (the number of infection event in the treatment group /the total person-years followed in the treatment group)× 100

Calculate the protection rate:

Protection rate = (the infection rate of placebo group-the infection rate of vaccine)/the infection rate of placebo group) × 100

9.        DATA COLLECTION AND MANAGEMENT

9.1 Source documents and source data

The purpose of source documents is to document the existence of the subject and substantiate the integrity of the trial data collected. The investigator must maintain the trial source documents accurate, complete, legible and up to date.

Examples of source documents are: subject screening, and enrolment log, subject’s diary cards, subject’s surveillance investigation forms, informed consent, investigational dispensing and reconciliation forms, subject’s file and records kept at the pharmacy or at the laboratories, mail, and certified letters.

Source data are the data contained in source documents (originals or certified copies).

Source documentation include two major parts, Case Report Forms (CRFs) which will be used to record data on the planned visit foreseen in the protocol, and Surveillance Forms which are used to record the H. pylori infection events. In addition, supplementary documents (lab test results, supplementary hospital or medical records, etc.) may form part of the source documentation for a study subject. The investigator is responsible for the accuracy and completeness of the data reported in CRFs and other source documents. Data reported in the CRFs are derived from source documents should be consistent with source documents and any discrepancies should be explained.

All CRFs must be signed by the investigator. Incorrect data must be crossed-out with a single line, then initialed and dated. Correction fluid or similar corrective methods that mask the original data will not to be used. These rules also apply to the completion of SAE Reporting Forms, Data Correction Forms, and ICFs.

9.2 Data management

Data generated during the trial are managed following three different processes, one related to visit data, defined as all data reported in the CRFs, one related to the surveillance data from H. pylori infected events, defined as all data reported in the surveillance forms, and the third one related to data pertaining to SAEs (i.e. data reported by the Investigator on the SAE Reporting Forms).

9.2.1         Clinical data management

During the trial, through regular data collection and monitoring, clinical data reported in the CRFs will be integrated into the clinical database under the responsibility of Chongqing Kangwei biological technology Co., Ltd Clinical Data Management team. For each batch of data, double entry, quality control and triggers to computerized logic and/or consistency checks will be systematically applied in order to detect errors or omissions. Queries are generated and submitted through Data Clarification Forms to the Investigator for resolution.

9.2.2        Surveillance data management

During the surveillance period, through active data collection and monitoring, surveillance data will be integrated into the surveillance database. For each batch of data, double entry, quality control and triggers to computerized logic and/or consistency checks will be systematically applied in order to detect errors or omissions. Queries will be generated and submitted through Data Clarification Forms to the investigator for resolution.

The validation of the central lab data will be performed at the laboratory level following the laboratory’s procedures. Information from the laboratories such as subject identifiers and dates or sample numbers will be checked for consistency before the integration into the surveillance database.

After integration of all corrections in the complete set of data, the whole database will be locked and saved before being released for statistical analysis.

10.    CLINICAL INVESTIGATOR’S BROCHURE

Investigators will receive the current version of the Clinical Investigator’s Brochure, which comprehensively describes all the available preclinical and human experience with the experimental vaccine. If relevant new information becomes available during the course of the trial, the investigators will receive a revised Investigator’s Brochure or an amendment to the current version.

11.    ARCHIVING

Following closure of the study, the investigator must maintain all site study records in a safe and secure location. The records must be maintained to allow easy and timely retrieval, when needed (e.g., audit or inspection), and, whenever feasible, to allow any subsequent review of data in conjunction with assessment of the facility, supporting systems, and staff. Where permitted by applicable laws/regulations or institutional policy, some or all of these records can be maintained in a validated format other than hard copy; however, caution needs to be exercised before such action is taken. The investigator must assure that all reproductions are legible and are a true and accurate copy of the original ones, and meet accessibility and retrieval standards, including re-generating a hard copy, if required. Furthermore, the investigator must ensure there is an acceptable back-up of these reproductions and that an acceptable quality control process exists for making these reproductions.

Trial-related documents will be maintained for a period of 10 years after final marketing approval of the vaccine, or 10 years after the formal discontinuation of clinical development of the product per the requirements by SFDA and IRB/IEC. The site investigators must be aware of all requirements and retain protocol records in accordance with the longest requirement that pertains to the study. No study document should be destroyed without prior written agreement between the Chongqing Kangwei biological technology Co., Ltd, the Principal Investigator and the site investigators. Storage of all trial-related documents will be such that confidentiality will be strictly maintained. Should the site investigators wish to assign the study records to another party or move them to another location, Chongqing Kangwei biological technology Co., Ltd must be notified in writing of the new responsible person and/or the new location.

12.    QUARLITY CONTROL AND QUARLITY ASSURANCE

12.1Monitoring

Before the start of the trial (i.e. before the inclusion of the first subject by the first center), the investigators and the sponsor’s monitoring staff will meet at the "Site-initiation visit" to discuss the trial protocol and the detailed trial procedures, with emphasis on inclusion and exclusion criteria, visit timing, safety procedures, informed consent procedures, SAE reporting procedures, CRF completion, and sample and product handling.

The sponsor’s monitoring staff ensured and document that all material to be used during the trial have been received and that the investigational team and local monitoring staff have been properly informed about the trial, GCP and regulatory requirements, and the sponsor’s procedures. Specific training sessions for the investigational team and CRAs on these topics may be performed, as necessary.

Specific instruction manuals are provided for the completion of the CRF and for the detailed trial procedures such as the laboratory and sample handling procedures (Operating Guidelines).

After the start of the trial, the sponsors monitoring staff will in regular contact with the investigational team through telephone calls and regular follow-up visits to the trial centers. The investigator must be available for these visits and would allow the monitoring staff direct access to subject medical files and CRFs. During monitoring visits, the monitoring staff would:

• Control the quality of the trial progress (e.g., with respect to the protocol and operating guidelines, quality of data collection and document completion, signature of consent forms, appearance of SAEs, sample and product management, cold chain monitoring, and archiving).

• Collect completed CRFs and any corresponding queries (Data Correction Forms).

• Evaluate the number of complete or ongoing observations.

Any identified problems discuss with the investigator and corrective or preventive actions will be determined, as appropriate.

Once the CRF pages corresponding to the last visit have been returned duly completed and signed, the investigator must be available to complete any queries (Data Correction Forms) forwarded by the Sponsor until database lock.

At the end of the trial, a close-out visit will be performed to ensure that:

• The center has all the documents necessary for archiving.

• All samples have been shipped to the appropriate laboratories.

• All unused material and products have been returned to the Sponsor.

12.2Audits

For the purpose of compliance with Good Clinical Practice (GCP) and Regulatory Agency Guidelines it may be necessary for Chongqing Kangwei biological technology Co., Ltd or a Drug Regulatory Agency to conduct a site audit. This may occur at any time from start to after completion of the study.

When an investigator signs the protocol, he agrees to permit drug regulatory agencies and Chongqing Kangwei biological technology Co., Ltd audits, providing direct access to source data/ documents. Furthermore, if an investigator refuses an inspection, his data is accepted in support of a New Drug Registration and/or Application, Biologics Licensing Application.

A quality assurance (QA) audit may be performed by the Sponsor’s QA Department or by independent auditors to verify that the trial have been conducted according to the protocol, GCP, ICH requirements and the applicable regulations. These audits usually take 1 to 2 days. Chongqing Kangwei biological technology Co., Ltd’s audits entail review of source documents supporting the adequacy and accuracy of CRFs, review documentation required to be maintained, and checked on vaccine accountability. Chongqing Kangwei biological technology Co., Ltd’s audit therefore help prepare an investigator for a possible regulatory agency inspection as well as assuring Chongqing Kangwei biological technology Co., Ltd of the validity of the database across investigational sites.

13.    STATISTICAL CONSIDERATIONS

Detailed methodology for summary and statistical analyses of the data collected in this study will be documented in a Statistical Analysis Plan (SAP), which will maintain by the sponsor.

Data in the CRFs and SAE Database will be analyzed by College of Public Health, Third Military Medical University, with SAS 9.1 software.

Statistical analysis will be performed when all the data are obtained.

 

13.1Study cohorts to be evaluated

13.1.1    Safety analysis cohort

The safety cohort will include all vaccinated subjects (i.e. those meeting all eligibility criteria, complying with the procedure of randomization, receive vaccination) for whom data are available. Thus, the cohort for analysis of safety included all subjects with at least one vaccine administration documented.

The safety analysis will be performed per treatment actually administered.

13.1.2    Per-protocol cohort for analysis of efficacy

The per-protocol cohort for analysis of efficacy will include all evaluable subjects (i.e. those meeting all eligibility criteria, complying with the procedures defined in the protocol, receive all three doses, with no elimination violations) for whom data concerning efficacy endpoint measures are available. The cohort is described in detail in the Statistical Analysis Plan (SAP).

For this cohort, the follow-up time for a subject will be started at Month 1 (one month after the third dose vaccination).

13.1.3    Per-protocol cohort for analysis of immunogenicity

The per-protocol cohort for analysis of immunogenicity and immunogenic persistency will includ all evaluable subjects in the immunogenicity subset (i.e. those meeting all eligibility criteria, complying with the procedures defined in the protocol, with no elimination criteria during the study) for whom data serum and saliva sample taken at Day 0 and one month after the third dose vaccination are available. Subjects who acquire H. pylori infection during the trial will be excluded from the per-protocol cohort for immunogenicity and immunogenic persistency. The cohort will be described in detail in the SAP.

13.1.4    Cohort for analysis of the surrogate of protection

The cohort for analysis of the surrogate of protection is consisted of subjects with H. pylori infected events and matched subjects free of H. pylori infection at a ratio of approximate 1:2.

13.2Derived and transformed data

• A seroconversion/conversion is defined as the post-vaccination titre increase equal to or more than 4 folds.

• The Geometric Mean Titers (GMTs) calculations will be performed by taking the antilog of the mean of the log titer transformations.

• The Geometric Mean Fold Increase (GMFIs) calculations will be performed by taking the antilog of the mean of the log titer increase folds transformations.

• In immunogenicity analysis, missing or non-evaluable measurements will not be replaced. Therefore, an analysis will exclude subjects with missing or non-evaluable measurements.

• In safety analysis, missing or non-evaluable measurements will not be replaced. Therefore the analysis of the solicited symptoms based on the total vaccinated cohort included only subjects/doses with documented safety data.

13.3Description of analyses

Vaccine efficacy is estimated according to Cox regression. If the estimated risk in the vaccine group is zero, the vaccine efficacy is evaluated using an exact conditional procedure depended on Poisson distribution.

Analyses for safety and immunogenicity endpoints are descriptive, using 95%CI, Student t test for log-transformed antibody titers, and Fisher’ exact or Chi-square for categorical data.

To assess the correlation between antibody titer and protective efficacy, the sensitivity (defined as the proportion of H. pylori event having a titer < the cutoff value at month 1 in total H. pylori events), specificity (defined as the proportion of H. pylori-free participants having a titer ≥ the cutoff values at month 1 in total H. pylori-free participants) and corresponding sum of sensitivity and specificity are computed to access the best cutoff value for a correlate of protection. A logistic regression model excluding the H. pylori vaccine group, are used in assess the possible effects of demographic factors and logarithm of neutralizing antibody titer one month after the third dose vaccination on the occurrence of H. pylori infection in natural population.

The analyses will be described in detail in the Statistical Analysis Plan (SAP).

14.    ETHICAL AND LEGAL ISSUES

14.1Guideline

The study will be conducted according to Good Clinical Practice (GCP), the Declaration of Helsinki, and local rules and regulations of China.

Submission of the protocol and any protocol amendments to regulatory agencies will occur in accordance with local regulatory requirements. When submission to the local regulatory authority is required, the timing of the submission relative to IEC/IRB submission or approval and whether or not the authority will provide their approval of or favorable opinion on the protocol or amendment before it can be implemented will depend on local regulatory requirements.

14.2Institutional review board

The investigator is responsible for obtaining written approval for the clinical study protocol (including all substantial protocol amendments), the written subject informed consent form, informed consent updates, subject recruitment procedures (e.g. advertisements) and any other written information to be provided to subjectsguardians from an Institutional Review Board which complies with local regulatory requirements. Any amendments will require approval by the Institutional Review Board.

Written approval of the study will be obtained from the Jiangsu CDC Institutional Review Board prior to the study implement. The investigator is responsible for maintaining a copy of the approval document in the study documentation files.

The only circumstance in which an amendment may be initiated prior to Jiangsu CDC Institutional Review Board approval is where the change is necessary to eliminate apparent immediate hazards to the subjects. In that event, the investigator must notify the Institutional Review Board and Chongqing Kangwei biological technology Co., Ltd in writing immediately after the implementation.

A final study notification will be forwarded by the investigator to the Jiangsu CDC Institutional Review Board within 90 days after the study has been completed or in the event of premature termination of the study within 15 days.

14.3Responsibilities of the investigator

- To ensure that he/she has sufficient time to conduct and complete the study and has adequate staff and appropriate facilities and equipments which are available for the duration of the study and to ensure that other studies do not divert essential subjects or facilities away from the study at hand.

- To submit an up-to-date curriculum vitae or Investigator Biography and other credentials to Chongqing Kangwei biological technology Co., Ltd and relevant authorities. It is recommended that this documentation indicates any previous clinical research experience and history of training in GCP.

- To acquire the reference ranges for laboratory tests performed locally and, if required by local regulations, obtain the laboratory’s current certification or Quality Assurance procedure manual.

- To ensure that all back-up clinical samples (including serum samples) are retained onsite according to the approval of Chongqing Kangwei biological technology Co., Ltd.

- To perform no other biological assays on the clinical samples except those described in the protocol or its amendment(s).

- To prepare and maintain adequate subject source data or raw data designed to record observations, and other data pertinent to the study.

- To conduct the study in compliance with the protocol any amendment and “Good Clinical Practice” (GCP) and all applicable regulatory requirements.

- To co-operate with a representative of Chongqing Kangwei biological technology Co., Ltd in the monitoring process of the study and in resolution of queries about the data.

- To permit drug regulatory agencies and Chongqing Kangwei biological technology Co., Ltd audits.

14.4Ethical conduct of the study

The study will be conducted in accordance with the principles of the Declaration of Helsinki1, the standards of Good Clinical Practice (as defined by the International Conference on Harmonization), and Chinese regulatory requirements, as stipulated by the Chinese Food and Drug Administration. These policies and procedures ensure that personnel are adequately trained to perform the study complying with these guidelines mentioned above. Written informed consent is obtained from each subject’s guardians.

14.5Protocol amendments and administrative changes

- No changes to the study protocol will be allowed unless discussed in detail with the Chongqing Kangwei biological technology Co., Ltd' Clinical Research Manager/Medical Monitor and filed as an amendment/administrative change to this protocol. This does not apply to changes made to reduce discomfort or avert risk to study volunteers. Furthermore, in the event of a medical emergency, the investigators shall perform any medical procedures that are deemed medically appropriate. The PI must notify the sponsor of all such occurrences.

- Any amendment/administrative change to the protocol will be adhered to by the participating center(s) and will be applied to all subjects. Written IRB/IEC approval of protocol amendments is required prior to implementation, except where permitted by all applicable regulatory requirements; administrative changes and amendments not submitted for approval are submitted to IRBs/IECs for information only. Submission of protocol amendments to regulatory agencies will occur in accordance with local regulatory requirements. When submission to the local regulatory authority is required, the timing of the submission relative to IEC/IRB submission or approval and whether or not the authority will provide their approval of or favorable opinion on the amendment before it can be implemented will depend on local regulatory requirements.

14.6Confidentiality of data and access to subject records

Prior to initiation of the trial, the investigator will sign a fully executed confidentiality agreement with the sponsor. All study-related information will be stored securely at the study sites. All Subject information will be stored in locked file cabinets in areas with access limited to study staff. All laboratory specimens, reports, study data collection, process, and administrative forms will be identified by coded number only to maintain subject confidentiality. All computer entries will be done by coded numbers only, and all local databases will be secured with password-protected access systems. Forms, lists, logbooks, appointment books, and any other listings that link subject ID numbers to other identifying information will be stored in a separate, locked file in an area with limited access.

Sponsor personnel, the IRB/IEC and the regulatory authorities will have direct access to source data/documents.

15.    FINANCIAL CONTRACT AND INSURANCE COVERAGE

An agreement will be signed by all the parties involved in the trial’s performance, if relevant. Adequate insurance coverage for all subjects to be included in the trial will supply by the sponsor.

16.    SPONSOR’S TERMINATION OF STUDY

Chongqing Kangwei biological technology Co., Ltd reserves the right to temporarily suspend or prematurely discontinue this study either at a single site or at all sites at any time for reasons including, but not limited to, safety or ethical issues or severe non-compliance. Reasons for suspension or early termination will be documented in the study file at Chongqing Kangwei biological technology Co., Ltd.

If Chongqing Kangwei biological technology Co., Ltd determines that suspension or early termination is needed, Chongqing Kangwei biological technology Co., Ltd will discuss this with the investigator (including the reasons for taking such action). When feasible, Chongqing Kangwei biological technology Co., Ltd will provide advance notification to the investigator of the impending action priorly. If the study is suspended or terminated for safety reasons, Chongqing Kangwei biological technology will also inform the regulatory authorities of the suspension or termination of the study and the reason(s) for the action. If required by applicable regulations, the investigator must inform the IEC/IRB promptly and provide the reason for the suspension or termination.

If the study is prematurely discontinued, all study data must be returned to Chongqing Kangwei biological technology Co., Ltd. In addition, arrangements will be made for all unused investigational product(s) in accordance with the applicable Chongqing Kangwei biological technology Co., Ltd procedures for the study. Financial compensation to investigators and/or institutions will be in accordance with the agreement established between the investigator and/or institutions and Chongqing Kangwei biological technology Co., Ltd.

17.    OWNERSHIP AND PUBLICATION

17.1Ownership

All information provided by Chongqing Kangwei biological technology Co., Ltd and all data and information generated by the sites as parts of the study (other than a subject’s medical records) are the sole property of Chongqing Kangwei biological technology Co., Ltd (renamed as Wuhu Kangwei biological technology Co., Ltd. in 2011). All rights, title, and interests in any inventions, know-how or other intellectual or industrial property rights which are conceived or reduced to practice by site staff during the course of or as a result of the study are the sole property of Chongqing Kangwei biological technology Co., Ltd, and are hereby assigned to Chongqing Kangwei biological technology Co., Ltd.

If a written contract for the conduct of the study which includes ownership provisions inconsistent with this statement is executed between Chongqing Kangwei biological technology Co., Ltd and the study site, that contract’s ownership provisions shall be applied rather than this statement.

17.2Publication

The first publication or disclosure of study results shall be a complete report and approved by Chongqing Kangwei biological technology Co., Ltd. Thereafter, any secondary publications will reference the original publication(s).

Prior to submitting for publication, presentation, use for instructional purposes, or otherwise disclosing the study results generated by the site (collectively, a “Publication”), the investigator shall provide Chongqing Kangwei biological technology Co., Ltd with a copy of the proposed publication and allow Chongqing Kangwei biological technology Co., Ltd a period to review the proposed publication (at least 21 (twenty-one) days [or at least 15 (fifteen) working days for abstracts/posters/presentations]. Proposed publications shall not include either Chongqing Kangwei biological technology Co., Ltd confidential information other than the study results or personal data on any subject, such as name or initials.

At Chongqing Kangwei biological technology Co., Ltd’s request, the submission or other disclosure of a proposed Publication will be delayed a sufficient time to allow Chongqing Kangwei biological technology Co., Ltd to seek patent or similar protection of any inventions, know-how or other intellectual or industrial property rights disclosed in the proposed Publication.

If a written contract for the conduct of the study, which includes publication provisions inconsistent with this statement is executed, that contract’s publication provisions shall be applied rather than this statement.

18.    SIGNATURES

SPONSOR: Chongqing Kangwei biological technology Co., Ltd

This Study Protocol has been subjected to critical review and has been approved.

Clinical Development Manager:  [Signature]      

Chongqing Kangwei biological technology Co., Ltd.

Date:

 

INVESTIGATOR:

I have reviewed this Study Protocol, including Appendices. I will conduct the clinical study as

described and will adhere to GCP and all the ethical and regulatory requirements stated.

I have read and understood the contents of the Investigator's Brochure.

 

Principal Investigator:    [Signature]                 

Professor Ming Zeng

National Institutes for Food and Drug Control, China

Date:

 

19.    REFERENCES

1.               Eidt S, Stolte M. The significance of Helicobacter pylori in relation to gastric cancer and lymphoma. Eur J Gastroenterol Hepatol. 1995 Apr;7(4):318-21.

2.               Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001 Sep 13;345(11):784-9.

3.               Wotherspoon AC, Doglioni C, Diss TC, Pan L, Moschini A, de Boni M, et al. Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet. 1993 Sep 4;342(8871):575-7.

4.               Kotloff KL, Sztein MB, Wasserman SS, Losonsky GA, DiLorenzo SC, Walker RI. Safety and immunogenicity of oral inactivated whole-cell Helicobacter pylori vaccine with adjuvant among volunteers with or without subclinical infection. Infect Immun. 2001 Jun;69(6):3581-90.

5.               Giudice GD. Helivax Antex Biologics. Curr Opin Investig Drugs. 2001 Jul;2(7):896-9.

6.               Banerjee S, Medina-Fatimi A, Nichols R, Tendler D, Michetti M, Simon J, et al. Safety and efficacy of low dose Escherichia coli enterotoxin adjuvant for urease based oral immunisation against Helicobacter pylori in healthy volunteers. Gut. 2002 Nov;51(5):634-40.

7.               Sougioultzis S, Lee CK, Alsahli M, Banerjee S, Cadoz M, Schrader R, et al. Safety and efficacy of E coli enterotoxin adjuvant for urease-based rectal immunization against Helicobacter pylori. Vaccine. 2002 Dec 13;21(3-4):194-201.

8.               Michetti P, Kreiss C, Kotloff KL, Porta N, Blanco JL, Bachmann D, et al. Oral immunization with urease and Escherichia coli heat-labile enterotoxin is safe and immunogenic in Helicobacter pylori-infected adults. Gastroenterology. 1999 Apr;116(4):804-12.

9.               DiPetrillo MD, Tibbetts T, Kleanthous H, Killeen KP, Hohmann EL. Safety and immunogenicity of phoP/phoQ-deleted Salmonella typhi expressing Helicobacter pylori urease in adult volunteers. Vaccine. 1999 Oct 14;18(5-6):449-59.

10.             Bumann D, Metzger WG, Mansouri E, Palme O, Wendland M, Hurwitz R, et al. Safety and immunogenicity of live recombinant Salmonella enterica serovar Typhi Ty21a expressing urease A and B from Helicobacter pylori in human volunteers. Vaccine. 2001 Dec 12;20(5-6):845-52.


20.    APPENDIX

The screening form for the volunteers

The subjects Basic Information

Parents names

Children names

Sex

Birthday

Tel

Screen number

Note

 

 

 

199_year_month

 

 

 

Address

______group _____village (number)_____ town(street), Ganyu county, Jiangsu province

The Selected criteria                                         results assessment

1.  Healthy children aged from 6-15 years old as established by medical history and clinical examination.        Yes□  No□

2.  The subjects’ guardians are able to understand and sign the informed consent.   Yes□  No□

3.  In the past, no vaccine is taken or other drugs in a month.              Yes□  No□

4.  Subjects can and will comply with the requirements of the protocol           Yes□  No□

5.  Subjects with temperature <=37.0°C on axillary setting                    Yes□  No□

The Exclusive criteria                                          results assessment

1.  Subject who has a medical history of stomach illness                  Yes□  No□

2.  Positive in either serology ELISA test for Helicobacter pylori diagnose kit or 13C urea breath test .            Yes□  No□

3.  Subject who has suffered from fever and heart, liver, kidney disease.           Yes□  No□

4.  Subject who has a medical history of any of the following: allergic history, or allergic to any ingredient of vaccine (for example: mannitol)                                     Yes□  No□

5.  Subject who is suffering from thrombocytopenia or other coagulation disorder                                                 

Yes□  No□

6.  Subject who has a diminished function of the immune system or autoimmune disease                                      

Yes□  No□

7.  Subject who is suffering from congenital deformities, developmental disorders or serious chronic diseases                                                               Yes□  No□

8.  Family history of seizures or progressive neurological disease                Yes□  No□

9.  Severe malnutrition or dysgenopathy, major congenital defects or serious chronic illness, including perinatal brain damage                                                   Yes□  No□

10.  Any acute infections in last 7 days                                     Yes□  No□

11.  Any prior administration of immunodepressant or corticosteroids in last 6month Yes□  No□

12 Any prior administration of other research medicines in last 1 month          Yes□  No□

13 Any condition that in the opinion of the investigator, may interfere with the evaluation of study objectives                                                              Yes□  No□

Doctor’s signature:____________                      date: ____/December/2004


Monitor table of the vaccine precaution

Vaccine ID:______    age:________    phone number:_________   No. :_________

Sex: female □ male□ 

Address: ______group______ village(number)______town(street), Ganyu county, Jiangsu province

Vaccine taken date

Observation time

General reaction

Gastrointestinal reaction

Observe subjects

note

Temperature

Headache

Dizzy

Fatigue

Cough

Allergy

Diarrhea frequency

Stomach ache

Bloating

Nausea

Vomiting

Others

 

 

1st  dose

30min

 

 

 

 

 

 

 

 

 

 

 

 

 

 

6h

 

 

 

 

 

 

 

 

 

 

 

 

 

 

24h

 

 

 

 

 

 

 

 

 

 

 

 

 

 

48h

 

 

 

 

 

 

 

 

 

 

 

 

 

 

72h

 

 

 

 

 

 

 

 

 

 

 

 

 

 

2nd

30min

 

 

 

 

 

 

 

 

 

 

 

 

 

 

dose

6h

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

24h

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

48h

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

72h

 

 

 

 

 

 

 

 

 

 

 

 

 

 

3rd

30min

 

 

 

 

 

 

 

 

 

 

 

 

 

 

dose

6h

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

24h

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

48h

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

72h

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Abnormal reaction or Disposition:

________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

 

Products name: Oral Recombinant H. pylori Vaccine

Products Lot:   

Unit of the filling blank      People fill in a form       Date of filing     /    /    

Informed Consent Form (ICF)

 

A Randomized, Double-blind, Placebo-Controlled, Phase 3 Clinical Trial with Oral Recombinant Helicobacter Pylori Vaccine in Chinese Healthy Children Aged from 6 to 15 Years Old

The clinical trial has been approved by the State Food and Drug Administration (SFDA) (Approval Document No.: 2004L04702).

Principal Investigator: Ming Zeng

Tel: +86-10-67058402

Organization: National Institute for Food and Drug Control, China

Sponsor: Chongqing Kangwei biological technology Co., Ltd.

Protocol Number & Version: TMMUHP03 (Version 1.0)

 

This Informed Consent Form has two parts:

· Information Sheet (to share information about the study with you)

· Certificate of Consent (for signatures if you agree that your child may participate)

You will be given a copy of the full Informed Consent Form

 

1. Brief introduction

I am going to give you information and invite your child to participate in this research.

This informed consent form intends to invite your child to take part in a clinical study. Before you make a decision for your child as to whether or not to take part in this study, this Informed Consent Form will help you understand the details of the entire study, the risks and benefits of participants as well as what needs to be done. There may be some words that you do not understand. Please ask me to stop as we go through the information and I will take time to explain. Please carefully read the following information. If you have any question later, you can consult me or the study doctor or the staff.

 

2. Objectives

Helicobacter pylori (H. pylori) is a Gram-negative, microaerophilic bacterium that persistently colonizes the human stomach; more than half of the human population is infected worldwide. It has been established that H. pylori is associated with chronic gastritis, peptic ulcer disease, gastric cancer, gastric mucosa associated lymphoid tissue lymphoma.

At present, the main clinical treatment for H. pylori infection is the application of antibiotics and bismuth agent or H+ antagonists. Due to the widespread drug resistance, toxic side effects, high medical costs as well as risk of reinfection following antibiotic-induced eradication, it is unworkable to practice antibiotics therapy for H. pylori eradication on every patient. Vaccination is the most effective way for prevention H. pylori infection.

This primary objective of this study is to evaluate the protective efficacy of the oral recombinant Helicobacter Pylori vaccine in Chinese healthy children aged from 6 to 15 years old.

.

3. Intervention

The oral recombinant Helicobacter Pylori vaccine was manufactured by Chongqing Kangwei biological technology Co., Ltd. Your child will be randomized allocated to receive vaccine or placebo.

 

4. Participants

A total of 4000 children will be enrolled in this study.

 

5. Information on the Investigational Products

Phase 1 studies had investigated the safety, tolerability of the oral recombinant Helicobacter Pylori vaccine in adults and children, and recommended a three-dose immunization schedule. In phase 2 trial, immunogenicity of four different formulations of Helicobacter Pylori vaccine had been compared, and 15mg of the vaccine had been chosen as the candidate for the phase 3 trials. According to data from previous studies, this vaccine has good safety profile and excellent immunogenicity in children.

 

6. Content and procedures of the trial

The trial included three phases: Screening, vaccination, and follow-up. If you agree to allow your child to participate in this trial, the doctor will give a medical examination to your child to determine whether he/she is suitable to enter this study. And your child need to donate 3ml blood for serology test and breath samples to confirm that he/she has not been infected by H. pylori. If your child has been infected, he/she can’t be eligible for this study and will be withdrawn.

If your child is eligible, he/she will be allocated randomly to receive the oral H. pylori vaccine or placebo. Your child will have 50% chance of receiving H. pylori vaccine. The immunization schedule consisted of three doses, 14 days apart. Safety follow-up will be conducted for 3 days after each dose. You and your child will need to stay in the clinic for about 30 minutes for safety observation. While you are in the clinic the study staff will show you how to record data on diary. The staff will also show you how to measure your child’s temperature at home.

You will get a diary card, a thermometer, and a measuring device to take home. You will be asked to record any local adverse events and systematic adverse events on the diary cards for at least 3 days following each vaccination. You will be asked to measure your child’s temperature for 3 days after each vaccination.

After the three-dose vaccination, 3 ml blood and 1.5ml saliva samples will be drawn from your child at month 1 for the assessment of UreB-specific antibody. We will visit your child for 13C-urea breath tests and/or serology ELISA at month 4, 8, and 12, to determine whether your child has an H. pylori infection. You will be notified test results by telephone.

If your child needs emergency vaccination of other vaccines (such as rabies or tetanus, etc.) out of medical needs, please must inform your child's doctor.

 

7. Duration

Your child will be in this study for approximately 14 months. You may need to visit the research site at least 9 times during the study. Additional visits may be required if you have any worries or concerns about your child’s health.

 

8. Discomfort, adverse reaction and possible risk

By participating in this study it is possible that your child may experience some discomfort. The vaccination may cause mild/moderate fever, or gastrointestinal discomfort. The fever usually goes away within 24 hours. The gastrointestinal reactions include diarrhea, vomit, stomachache, bloating, nausea, and so on, and allergic reactions may be observed occasionally. Generally, these reactions can disappear within 24 hours without treatment.

In addition to the potential adverse reactions caused by the investigated vaccine, blood drawing may also accompanied by some adverse impacts. Petechia and mild pain may occurred in a small number of people when do blood drawing. Rarely, syncope, infection at the blood drawing site may also occur.

While the possibility of serious adverse reaction happening is very low, you should still be aware of the possibility. If something unexpected happens and harm does occur, we will provide your child with the reasonable treatment and corresponding economic compensation.

 

9. Possible benefits for taking part in this trial

All the laboratory examination and vaccinations in study are free. By taking part in this trial, your child may develop resistance to H. pylori due to the vaccinations. But the vaccination cannot provide 100% guarantee for resistance against H. pylori. You can know whether your child has been infected by H. pylori, and you can get professional medical consulting about the H. pylori treatment. You can ask for vaccination of H. pylori vaccine for free if you received placebo in this study, after the H. pylori vaccine has been approval for market. The future generations are likely to benefit from this study.

 

10. Reimbursements

You will not be provided any incentive to take part in this research. Relevant medical expenses for your child to participate in this study are free, such as expense of vaccine, laboratory examination, and so on. Your child will not get other payments unrelated to the trial.

 

11. Confidentiality of the study data

The results of this study will be given to the sponsor. Your personal information will be kept confidentially. The name of your child will not appear in any published information on the study or report. In addition, the representative of the China State Food and Drug Administration (SFDA) may examine the medical history record of your child as related to this study, so as to verify the accuracy of the data collected in this study, but it will not involve the detailed personal information of your child. You and your child’s doctor will be informed of the treatment allocation of your child only after the study comes to an end.

 

12. Sharing of the results

Confidential information will not be shared. The knowledge that we get from this study will be shared with you before it is made widely available to the public. There will be small meetings in the community and these will be announced. Afterwards, we will publish the results in order that other interested people may learn from our research.

 

13. Right to Refuse or Withdraw

You may choose for your child not to participate in this study. You can change your mind and withdraw (drop out) later. There will be no penalty, and your child will not lose any benefits they receive now or have a right to receive proper treatment.

We will tell you if we learn new information that could change your mind about your child taking part or continuing in this research study. If you want your child to drop out, you should tell us. We will make sure he/she can end the study in the safest way. We will also talk to you about follow-up care, if needed.

The study doctor or the study sponsor may decide to take your child out of the study without your agreement if, for example:

· You do not follow the directions of the study team, or;

· The study doctor decides that the study is not in your child’s best interest, or;

· The study is stopped by the study sponsor, the institutional review board (IRB), or by a regulatory agency.

The decision of the participation of your child in the study is entirely voluntary. Your child may withdraw from the study without giving any reason at any time before the study or after it starts. If your child leaves the study for any reason, biological samples (for example, blood samples) that have been collected from your child (but not yet fully analyzed) can be destroyed by making a request to the study doctor. However, any data already generated from your child’s samples will be kept to preserve the value of the study. If your child leaves the study for any reason, your child will not receive any further investigational vaccines or tests.

 

14. Alternatives to participating

Because there is no H. pylori vaccines available in the market at present. If you do not wish your child to take part in this study, no other intervention can provide to your child.

 

15. Contact

If you have any questions you may ask the investigator or the study staff now or later, even after the study has started. If you wish to ask questions later, you may contact any of the following:

Ming Zeng  Tel: +86-10-67058402

Feng-Cai Zhu  Tel: +86-25-83759418

 

This proposal has been reviewed and approved by the IRB of Jiangsu Provincial Center for Disease Prevention and Control, which is a committee whose task is to make sure that research participants are protected from harm. If you wish to find more about the IRB, contact:

  Hua Wang  Tel: +86-25-83759304 

 

16. Certificate of Consent

By signing this Informed Consent Form, you confirm that you have read this information and have sufficiently considered it, that the doctor has explained this study to you, that your questions have been answered, that you have had enough time to make the decision on the participation of your child, and that you agree your child to take part in this study. You have learned that you may withdraw your child from this study at any time without any reason, and the withdrawal from the study will not affect the present or future treatment of your child.

 

Name of subject: ____( completed by doctor)

Name of guardian of subject:______   Relation with subject:____( completed by doctor)

Signature of guardian of subject:___   Date:_____ _____ _____( completed by guardian)

                                       year/month/day

 

17. Statement of investigator

I confirm that I have explained the content, procedures, possible risks and benefits of this study to the subject’s guardians, and have given his/her guardian the adequate answers about any question, and the family members of the subject have got satisfactory answers.

 

Signature of doctor:_____                                 Date:____ ____ ____

                                                            year/month/day

 

 

 

 

 

 

 

 

 

 

Informed Consent Form (ICF) For Subjects in Immunogenicity Subgroup Only

A Randomized, Double-blind, Placebo-Controlled, Phase 3 Clinical Trial with Oral Recombinant Helicobacter Pylori Vaccine in Chinese Healthy Children Aged from 6 to 15 Years Old

The clinical trial has been approved by the State Food and Drug Administration (SFDA) (Approval Document No.: 2004L04702).

Principal Investigator: Ming Zeng

Tel: +86-10-67058402

Organization: National Institute for Food and Drug Control, China

Sponsor: Chongqing Kangwei biological technology Co., Ltd.

Protocol Number & Version: TMMUHP03 (Version 1.0)

 

This Informed Consent Form has two parts:

· Information Sheet (to share information about the study with you)

· Certificate of Consent (for signatures if you agree that your child may participate)

You will be given a copy of the full Informed Consent Form

 

1. Brief introduction

I am going to give you information and invite your child to participate in this research.

This informed consent form intends to invite your child to take part in a clinical study. Before you make a decision for your child as to whether or not to take part in this study, this Informed Consent Form will help you understand the details of the entire study, the risks and benefits of participants as well as what needs to be done. There may be some words that you do not understand. Please ask me to stop as we go through the information and I will take time to explain. Please carefully read the following information. If you have any question later, you can consult me or the study doctor or the staff.

 

2. Objectives

Helicobacter pylori (H. pylori) is a Gram-negative, microaerophilic bacterium that persistently colonizes the human stomach; more than half the human population is infected worldwide. It has been established that H. pylori is associated with chronic gastritis, peptic ulcer disease, gastric cancer, gastric mucosa associated lymphoid tissue lymphoma.

At present, the main clinical treatment for H. pylori infection is the application of antibiotics and bismuth agent or H+ antagonists. Due to the widespread drug resistance, toxic side effects, high medical costs as well as risk of reinfection following antibiotic-induced eradication, it is unworkable to practice antibiotics therapy for H. pylori eradication on every patient. Vaccination is the most effective way for prevention H. pylori infection.

This primary objective of this study is to evaluate the protective efficacy of the oral recombinant Helicobacter Pylori vaccine in Chinese healthy children aged from 6 to 15 years old.

.

3. Intervention

The oral recombinant Helicobacter Pylori vaccine was manufactured by Chongqing Kangwei biological technology Co., Ltd. Your child will be randomized allocated to receive vaccine, or placebo.

 

4. Participants

A total of 4000 children will be enrolled in this study.

 

5. Information on the Investigational Products

Phase 1 studies had investigated the safety, tolerability of the oral recombinant Helicobacter Pylori vaccine in adults and children, and recommended a three-dose immunization schedule. In phase 2 trial, immunogenicity of four different formulations of Helicobacter Pylori vaccine had been compared, and 15mg of the vaccine had been chosen as the candidate for the phase 3 trials. According to data from previous studies, this vaccine has good safety profile and excellent immunogenicity in children.

 

6. Content and procedures of the trial

The trial included three phases: Screening, vaccination, and follow-up. If you agree to allow your child to participate in this trial, the doctor will give a medical examination to your child to determine whether he/she is suitable to enter this study. And your child needs to donate 3ml blood for serology test and breath samples to confirm that he/she has not been infected by H. pylori. If your child has been infected, he/she can’t be eligible for this study and will be withdrawn.

If your child is eligible, he/she will be allocated randomly to receive the oral H. pylori vaccine or placebo. Your children will have 50% chance of receiving H. pylori vaccine. The immunization schedule consisted of three doses, 14 days apart. Safety follow-up will be conducted for 3 days after each dose. You and your child will need to stay in the clinic for about 30 minutes for safety observation. While you are in the clinic the study staff will show you how to record data on diary. The staff will also show you how to measure your child’s temperature at home.

You will get a diary card, a thermometer, and a measuring device to take home. You will be asked to record any local adverse events and systematic adverse events on the diary cards for at least 3 days following each vaccination. You will be asked to measure your child’s temperature for 3 days after each vaccination.

After the three-dose vaccinations, 3 ml blood and 1.5ml saliva samples will be drawn from your child at month 1, 6, and 12 for the assessment of UreB-specific antibody, respectively. We will visit your child for 13C-urea breath tests and/or serology ELISA at month 4, 8, and 12, to determine whether your child has an H. pylori infection. You will be notified test results by telephone.

If your child needs emergency vaccination of other vaccines (such as rabies or tetanus, etc.) out of medical needs, please must inform your child's doctor.

 

7. Duration

Your child will be in this study for approximately 14 months. You may need to visit the research site at least 10 times during the study. Additional visits maybe required if you have any worries or concerns about your child’s health.

 

8. Discomfort, adverse reaction and possible risk

By participating in this study it is possible that your child may experience some discomfort. The vaccination may cause mild/moderate fever, or gastrointestinal discomfort. The fever usually goes away within 24 hours. The gastrointestinal reactions include diarrhea, vomit, stomachache, bloating, nausea, and so on, and allergic reactions may be observed occasionally. Generally, these reactions can disappear within 24 hours without treatment.

In addition to the potential adverse reactions caused by the investigated vaccine, blood drawing may also accompanied by some adverse impacts. Petechia and mild pain may occurre in a small number of people when do blood drawing. Rarely, syncope, infection at the blood drawing site may also occur.

While the possibility of serious adverse reaction happening is very low, you should still be aware of the possibility. If something unexpected happens and harm does occur, we will provide your child with the reasonable treatment and corresponding economic compensation.

 

9. Possible benefits for taking part in this trial

All the laboratory examination and vaccinations in study are free. By taking part in this trial, your child may develop resistance to H. pylori due to the vaccinations. But the vaccination cannot provide 100% guarantee for resistance against H. pylori. You can know whether your child has been infected by H. pylori, and you can get professional medical consulting about the H. pylori treatment. You can ask for H. pylori vaccine for free if you received placebo in this study, after the H. pylori vaccine has been approval for market. The future generations are likely to benefit from this study.

 

10. Reimbursements

You will not be provided any incentive to take part in this research. Relevant medical expenses for your child to participante in this study are free, such as expense of vaccine, laboratory examination, and so on. Your child will not get other payments unrelated to the trial.

 

11. Confidentiality of the study data

The results of this study will be given to the sponsor. Your personal information will be kept confidentially. The name of your child will not appear in any published information on the study or report. In addition, the representative of the China State Food and Drug Administration (SFDA) may examine the medical history record of your child as related to this study, so as to verify the accuracy of the data collected in this study, but it will not involve the detailed personal information of your child. You and your child’s doctor will be informed of the treatment allocation of your child only after the study comes to an end.

 

12. Sharing of the results

Confidential information will not be shared. The knowledge that we get from this study will be shared with you before it is made widely available to the public. There will be small meetings in the community and these will be announced. Afterwards, we will publish the results in order that other interested people may learn from our research.

 

13. Right to Refuse or Withdraw

You may choose for your child not to participate in this study. You can change your mind and withdraw (drop out) later. There will be no penalty, and your child will not lose any benefits they receive now or have a right to receive proper treatment.

We will tell you if we learn new information that could change your mind about your child taking part or continuing in this research study. If you want your child to drop out, you should tell us. We will make sure he/she can end the study in the safest way. We will also talk to you about follow-up care, if needed.

The study doctor or the study sponsor may decide to take your child out of the study without your agreement if, for example:

· You do not follow the directions of the study team, or;

· The study doctor decides that the study is not in your child’s best interest, or;

· The study is stopped by the study sponsor, the institutional review board (IRB), or by a regulatory agency.

The decision of the participation of your child in the study is entirely voluntary. Your child may withdraw from the study without giving any reason at any time before the study or after it starts. If your child leaves the study for any reason, biological samples (for example, blood samples) that have been collected from your child (but not yet fully analyzed) can be destroyed by making a request to the study doctor. However, any data already generated from your child’s samples will be kept to preserve the value of the study. If your child leaves the study for any reason, your child will not receive any further investigational vaccines or tests.

 

14. Alternatives to participating

Because there is no H. pylori vaccines available in the market at present. If you do not wish your child to take part in this study, no other intervention can provide to your child.

 

15. Contact

If you have any questions you may ask the investigator or the study staff now or later, even after the study has started. If you wish to ask questions later, you may contact any of the following:

Ming Zeng  Tel: +86-10-67058402

Feng-Cai Zhu  Tel: +86-25-83759418

 

This proposal has been reviewed and approved by the IRB of Jiangsu Provincial Center for Disease Prevention and Control, which is a committee whose task is to make sure that research participants are protected from harm. If you wish to find about more about the IRB, contact:

  Hua Wang  Tel: +86-25-83759304 

 

16. Certificate of Consent

By signing this Informed Consent Form, you confirm that you have read this information and have sufficiently considered it, that the doctor has explained this study to you, that your questions have been answered, that you have had enough time to make the decision on the participation of your child, and that you agree your child to take part in this study. You have learned that you may withdraw your child from this study at any time without any reason, and the withdrawal from the study will not affect the present or future treatment of your child.

 

Name of subject: ____( completed by doctor)

Name of guardian of subject:______   Relation with subject:____( completed by doctor)

Signature of guardian of subject:___   Date:_____ _____ _____( completed by guardian)

                                       year/month/day

 

17. Statement of investigator

I confirm that I have explained the content, procedures, possible risks and benefits of this study to the subject’s guardians, and have given his/her guardian the adequate answers about any question, and the family members of the subject have got satisfactory answers.

 

Signature of doctor:_____                                 Date:____ ____ ____

                                                            year/month/day

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Informed Consent Form (ICF) for Extended Follow-up at Month 24

 

A Randomized, Double-blind, Placebo-Controlled, Phase 3 Clinical Trial with Oral Recombinant Helicobacter Pylori Vaccine in Chinese Healthy Children Aged from 6 to 15 Years Old

The clinical trial has been approved by the State Food and Drug Administration (SFDA) (Approval Document No.: 2004L04702).

Principal Investigator: Ming Zeng

Tel: +86-10-67058402

Organization: National Institute for Food and Drug Control, China

Sponsor: Chongqing Kangwei biological technology Co., Ltd.

Protocol Number & Version: TMMUHP03 (Version 1.1)

 

This is an additional Informed Consent Form for the extended follow-up.

This Informed Consent Form has two parts:

· Information Sheet (to share information about the study with you)

· Certificate of Consent (for signatures if you agree that your child may participate)

You will be given a copy of the Informed Consent Form

 

Thank you for letting your child participated in our first year study of the Oral Recombinant Helicobacter Pylori Vaccine. Your child has completed the three-dose vaccination, and provided eligible data for vaccine efficacy assessment. We deeply appreciated your child’s contribution.

In order to get more information on the persistence of vaccine elicited antibody and the efficacy of H. pylori vaccine. We are gonging to extend the follow-up for the second year, so we invite your child to participate the extended visit at Month 24 after the third dose vaccination. We will perform 13C- urea breath tests and/or serology ELISA for your child to determine whether your child has an H. pylori infection. You will be notified test results by telephone. If your child is in the immunogenicity subgroup, we will ask your child for donating 3ml blood and 1.5ml saliva sample for antibody measurement.

All the tests for your child are free. But you will not get financial compensation for participating in the extended follow-up. The tests are safe and will not do harm to your child. But petechia and mild pain may occurred in a small number of people when do blood drawing. Rarely, syncope, infection at the blood drawing site may also occur.

This extended study has been reviewed and approved by the IRB of Jiangsu Provincial Center for Disease Prevention and Control, which is a committee whose task is to make sure that research participants are protected from harm.

The decision of the participation of your child in the extended visit is entirely voluntary. Your child could refuse to participate in without giving any reason. Your personal information will be kept confidentially. The name of your child will not appear in any published information on the study or report.

 

Contact

If you have any questions you may ask the investigator or the study staff now or later, even after the study has started. If you wish to ask questions later, you may contact any of the following:

Ming Zeng  Tel: +86-10-67058402

Feng-Cai Zhu  Tel: +86-25-83759418

 

This proposal has been reviewed and approved by the IRB of Jiangsu Provincial Center for Disease Prevention and Control, which is a committee whose task is to make sure that research participants are protected from harm. If you wish to find about more about the IRB, contact:

  Hua Wang  Tel: +86-25-83759304 

 

Certificate of Consent

By signing this Informed Consent Form, you confirm that you have read this information and have sufficiently considered it, that the doctor has explained this study to you, that your questions have been answered, that you have had enough time to make the decision on the participation of your child, and that you agree your child to take part in this study. You have learned that you may withdraw your child from this study at any time without any reason, and the withdrawal from the study will not affect the present or future treatment of your child.

 

Name of subject: ____( completed by doctor)

Name of guardian of subject:______   Relation with subject:____( completed by doctor)

Signature of guardian of subject:___   Date:_____ _____ _____( completed by guardian)

                                       year/month/day

 

Statement of investigator

I confirm that I have explained the content, procedures, possible risks and benefits of this study to the subject’s guardians, and have given his/her guardian the adequate answers about any question, and the family members of the subject have got satisfactory answers.

 

Signature of doctor:_____                                 Date:____ ____ ____

                                                            year/month/day

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Informed Consent Form (ICF) for Extended Follow-up at Month 36

 

A Randomized, Double-blind, Placebo-Controlled, Phase 3 Clinical Trial with Oral Recombinant Helicobacter Pylori Vaccine in Chinese Healthy Children Aged from 6 to 15 Years Old

The clinical trial has been approved by the State Food and Drug Administration (SFDA) (Approval Document No.: 2004L04702).

Principal Investigator: Ming Zeng

Tel: +86-10-67058402

Organization: National Institute for Food and Drug Control, China

Sponsor: Chongqing Kangwei biological technology Co., Ltd.

Protocol Number & Version: TMMUHP03 (Version 1.2)

 

This is an additional Informed Consent Form for the extended follow-up.

This Informed Consent Form has two parts: