BMJ Open · vaccine: study protocol of a randomized non-inferiority trial in China Jing Jing...

For peer review only

Safety and immunogenicity of a new 13-valent pneumococcal conjugate vaccine versus a licensed 7-valent

pneumococcal conjugate vaccine: study protocol of a randomized non-inferiority trial in China

Journal: BMJ Open

Manuscript ID bmjopen-2016-012488

Article Type: Protocol

Date Submitted by the Author: 01-May-2016

Complete List of Authors: Chen, Jing Jing; Fourth Military Medical University, Department of Health Statistics; Walvax Biotechnology Co., Ltd., Registration & Clinical Affairs Department Yuan, Lin; Walvax Biotechnology Co., Ltd., Registration & Clinical Affairs Department Huang, Zhen; Walvax Biotechnology Co., Ltd. Shi, Nian Min; Beijing Chaoyang District Centre for Disease Control and Prevention Zhao, Yu Liang; Heibei Province Centre for Disease Control and Prevention Xia, Sheng Li; Henan Province Centre for Disease Control and Prevention

Li, Guo Hua; Shanxi Province Centre for Disease Control and Prevention Li, Rong Cheng; Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention Li, Yan Ping; Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention Yang, Shu Yuan; Walvax Biotechnology Co., Ltd., Registration & Clinical Affairs Department Xia, Jie-Lai; Fourth Military Medical University, Department of Health Statistics

<b>Primary Subject Heading</b>:

Immunology (including allergy)

Secondary Subject Heading: Epidemiology

Keywords: Pneumococcal conjugate vaccine, Sequential test, Non-inferiority

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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Safety and immunogenicity of a new 13-valent pneumococcal

conjugate vaccine versus a licensed 7-valent pneumococcal conjugate

vaccine: study protocol of a randomized non-inferiority trial in China

Jing Jing Chen,1,2

Lin Yuan,2 Zhen Huang,

2 Nian Min Shi,

3 Yu Liang Zhao,

4 Sheng Li Xia,

5 Guo Hua

Li,6 Rong Cheng Li,

7 Yan Ping Li,

7 Shu Yuan Yang,

2 Jie Lai Xia

1*

Corresponding author: 1*Jie Lai Xia, Department of Health Statistics, Fourth Military Medical University, 169 Changle

Western Road, Xi’an, Shanxi Province, China, Tel: +86 029-84774861, Email: [email protected]

Co-authors:

1. Jing Jing Chen; Department of Health Statistics of Fourth Military Medical University, Xi’an,

Shanxi, China; Walvax Biotechnology Co., Ltd., Kunming, Yunnan, China

2. Lin Yuan; Walvax Biotechnology Co., Ltd., Kunming, Yunnan, China

3. Zhen Huang; Walvax Biotechnology Co., Ltd., Kunming, Yunnan, China

4. Nian Min Shi; Beijing Chaoyang District Centre for Disease Control and Prevention, Beijing,

China

5. Yu Liang Zhao; Heibei Province Centre for Disease Control and Prevention, Shijiazhuang,

Heibei, China

6. Sheng Li Xia; Henan Province Centre for Disease Control and Prevention, Zhengzhou, Henan,

China

7. Guo Hua Li; Shanxi Province Centre for Disease Control and Prevention, Taiyuan, Shanxi,

China

8. Rong Cheng Li; Guangxi Zhuang Autonomous Region Center for Disease Control and

Prevention, Nanning, Guangxi, China

9. Yan Ping Li; Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention,

Nanning, Guangxi, China

10. Shu Yuan Yang; Walvax Biotechnology Co., Ltd., Kunming, Yunnan, China


Word count: 4261

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ABSTRACT

Introduction: The invasive pneumococcal diseases (IPDs) caused by Streptococcus pneumoniae

pose an enormous threat to children under 5 years of age. However, routine use of

pneumococcal conjugate vaccines could aid in reducing the incidence of IPDs. The purpose of this

clinical trial is to assess the non-inferiority of the investigational 13-valent pneumococcal

conjugate vaccine (PCV13) to the currently licensed 7-valent pneumococcal conjugate vaccine

(PCV7).

Methods and analysis: 1,040 infants will receive a three-dose of either PCV13 or PCV7 at ages 3,

4 and 5 months respectively, and a booster dose at 12-15 months. Primary endpoints are the

percentage of subjects reaching a serotype-specific IgG concentration of ≥ 0.35µg/ml and the

IgG antibody geometric mean concentrations (GMCs) measured 30 days after the primary

immunization. Secondary endpoints include the percentage of vaccine recipients reaching

serotype-specific IgG concentration threshold of 1.0µg/ml, the percentage of subjects reaching

the pneumococcal opsonophagocytic assay (OPA) titer threshold of 1:8, and the geometric mean

titers (GMTs) of OPA measured 30 days after primary and booster doses. The number of standard

IgG responders and IgG GMCs measured 30 days after the booster immunization will also be

determined. To evaluate differences between two groups, the sequential testing of the

non-inferiority of PCV13 for the 7 common serotypes and its effectiveness in treating the 6

additional serotypes will be performed.

Ethics and dissemination: Ethics approvals have been granted by the Ethics Committees at the 3

provinces involved in this study: Shanxi, Henan and Hebei Provinces. The trial will be reported in

accordance with the CONSORT guidance.

Trial registration number: NCT02736240.

Strengths and limitations of this study

� This is the first study to investigate the immune responses induced by a locally developed

and manufactured 13-valent pneumococcal conjugate vaccine among Chinese infants.

� 1,040 infants will be recruited to support the randomized non-inferiority study design and a

sequential test method is adopted.

� Primary outcomes are proportions of vaccine recipients achieving a predefined

specific-serotype IgG concentration threshold and geometric mean IgG antibody

concentrations measured 30 days after primary immunization, both of which are

recommended by WHO.

� Besides the complete evaluation of immunogenicity and safety of the new PCV13, not

involving the assessment of concomitantly immunization with other vaccines specified in

pediatric vaccination might be seen as a potential limitation of this trial.

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INTRODUCTION

Background

Streptococcus pneumoniae (S. pneumoniae or pneumococcus) is a leading cause of bacterial

pneumonia, meningitis, and sepsis in children, and thus poses a major threat to public health

around the world. According to a World Health Organization (WHO) investigation in 2005, an

estimated 0.7 to 1 million children under the age of 5 die from pneumonia every year; most of

whom lived in developing countries.[1] The top ten countries with the highest number of

reported pneumococcal cases were all in Asia and Africa, with China accounting for 12% of the

total.[2] Immunization against Hib, pneumococcus, measles and pertussis is the most effective

way to prevent pneumonia.[3] Routine use of the 7-valent pneumococcal conjugate vaccine

(PCV7), has resulted in a dramatic reduction in the incidence of invasive pneumococcal disease

(IPD) attributable to pneumococcal serotypes contained in the vaccine.[4] However, there is still

an urgent need for a pneumococcal conjugate vaccine with expanded coverage for IPD resulting

from serotypes not included in the PCV7.[5]

On 24 February 2010, the US Food and Drug Administration licensed a 13-valent pneumococcal

conjugate vaccine (PCV13) for children from 2 months to 5 years old. Since then, several studies

have been conducted on PCV13 in many countries except China. The licensed PCV13 has been

shown to be as effective as PCV7 in the prevention of disease caused by the 7 common serotypes

and could provide expanded protection against the 6 additional serotypes with a comparable

safety profile.[6] When co-administered with diphtheria, tetanus and acellular pertussis vaccine

(DTaP), PCV13 is well tolerated and as immunogenic as PCV7.[7] The flexible primary

immunization schedules of PCV13 for infants found no significant differences in antibody levels

for almost all serotypes after the booster dose at 12 months of age,[8 9] and thus recommended

by WHO.[10] Furthermore, the clinical efficacy of PCV13 for multiple purposes in age groups

ranging from 6 to over 70 years old has been confirmed.[11-16] Nevertheless, it is still unknown

whether the licensed PCV13 or a new PCV13 will be effective for the Chinese population to date.

To address the issue, we plan to initiate this trial for a pre-licensing evaluation of a new PCV13.

The investigational PCV13 (batch number 201511003) is manufactured by Yuxi Walvax

Biotechnology Co. Ltd. (an affiliate of Walvax Biotechnology Co., Ltd.), and supplied in penicillin

bottles. Each 0.5ml dose contains 2.2µg pneumococcal polysaccharide serotypes 1, 3, 4, 5, 6A, 7F,

9V, 14, 18C, 19A, 19F, and 23F and 4.4µg pneumococcal polysaccharide serotype 6B; each

serotype is conjugated to a tetanus toxoid carrier protein and adsorbed on aluminum phosphate.

In accordance with the guidelines formulated by the WHO,[17] and the requirements established

by national regulatory authorities, licensing a new vaccine requires randomized clinical trials to

show the non-inferiority of the new vaccine to an existing pneumococcal conjugate vaccine. PCV7

will serve as the control vaccines, since it is the only pneumococcal conjugate vaccines that has

been licensed in mainland China. The control PCV7 (Prevnar, batch number H29315H13880) is

manufactured by Wyeth and supplied in pre-filled 0.5ml syringes. Each 0.5ml dose contains 2µg

pneumococcal polysaccharide serotypes 4, 9V, 14, 18C, 19F, and 23F and 4µg pneumococcal

polysaccharide serotype 6B; each serotype is conjugated to a CRM197 carrier protein and

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adsorbed on 0.5 mg aluminum phosphate.

Objectives

The purpose of this study is to i) determine if the 7 common serotype-specific pneumococcal IgG

responses elicited by PCV13 are all non-inferior to those elicited by PCV7 and ii) determine if the

6 additional serotype-specific pneumococcal IgG responses induced by PCV13 are all clinically

effective 30 days after the primary immunization.

We hypothesize that for each of the 7 common pneumococcal serotypes (4, 6B, 9V, 14, 18C,

19F, 23F) i) the lower bound of the 97.5% (98.25%, one-sided) Confidence Interval (CI) for the

difference (PCV13 – PCV7) in the proportion of vaccine recipients reaching the serotype-specific

IgG concentration threshold of 0.35μg/ml is no less than -10%; or ii)The lower bound of the 97.5%

(98.25%, one-sided) CI of the serotype-specific IgG geometric mean concentration (GMC) ratio

(PCV13/PCV7) is greater than 0.5 (-0.3, logarithmically transformed by base 10).

As a parallel hypothesis, we expect that for each of the 6 additional pneumococcal serotypes (1,

3, 5, 6A, 7F, 19A) i)The proportion of the serotype-specific IgG responders achieving an IgG

threshold of 0.35μg/ml in the PCV13 group is greater than that of the PCV7 group; and ii) the

lower limit of the 95% (2-sided) CI for the proportion of vaccine recipients reaching a

serotype-specific IgG concentration threshold of 0.35μg/ml is greater than or equal to 70%.

Trial design

This study is a multi-center phase III, randomized, parallel group, allocation concealed

non-inferiority trial with two groups to evaluate the immunogenicity and safety of PCV13

compared with PCV7 among healthy infants in China.

METHODS

Study setting

The study includes 6 sites scattered in 3 provinces in North China. Each site has been ratified by

the Center for Food and Drug Inspection (CFDI), a department of China Food and Drug

Administration (CFDA), to join the research team of this trial and recruit participants.

Eligibility criteria

Inclusion criteria

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Participants will only be recruited when he or she meets all of the following criteria at the time of

randomization:

• Healthy infants, as established by medical history and clinical examination before entering

into the study, that are 3 months old at the time of the first vaccination

• Obtained written informed consent from the legally responsible representative(s)

• Have the compliance of the subjects’ legally responsible representative(s) with the

requirements of the protocol

• No pneumococcal vaccine history or use of other preventive vaccine at least 7 days before

study entry

• Axillary temperature ≤ 37℃

In addition, participants must not encounter any of the following exclusion criteria:

• Vaccinated by on sale or other on trial pneumococcal vaccines

• Have had an invasive disease with streptococcus pneumonia as the verified cause

• Severely allergic to any vaccines or drugs, or sensitive to temperatures ≥ 39℃ associated

with biological products inoculation

• Birth weight < 2.5 kg

• History or family history of convulsion, seizure, encephalopathy or neurological disorder

• Born from abnormal labors (difficult labors, aided by instruments) or have a history of

asphyxia or nerve damage

• Confirmed thrombocytopenia or a history of blood coagulation disorder

• Confirmed pathological jaundice

• Any confirmed or suspected immunodeficiency involving immunosuppressive therapy

(radiotherapy, chemotherapy, corticosteroid hormone, antimetabolite, cytotoxic drugs),

human immunodeficiency virus (HIV) infection, etc.

• Any confirmed or suspected congenital defect or serious chronic illnesses (trisomy 21

syndrome, diabetes, sickle cell anemia, neurological disorder or Guillain-Barré syndrome)

• Any confirmed or suspected diseases including respiratory diseases, acute infection, active

period of chronic disease, cardiovascular disease, hepatic-nephrotic disease, cancer and

dermatosis

• Administration of immunoglobulin and/or any blood products, except Hepatitis B

hyper-immune globulin(HBlg)

• Concurrent participation in another clinical study

• Other exclusion criteria affirmed by investigators

Intervention

Eligible infants will be randomized to either the PCV13 or the PCV7 group to receive a three-dose

series of PCV13 or PCV7 at ages 3, 4 and 5 months respectively, and a booster dose between 12

and 15 months. For all subjects, blood samples will be obtained at four different time points:

immediately before the first dose, 30 days after the primary series, immediately before the

booster dose, and 30 days after the toddler dose.

Serum concentrations of anti-capsular polysaccharide IgG for each of the 13 pneumococcal

serotypes will be measured for all subjects at the previously mentioned time points, using the

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standardized enzyme-linked immunosorbent assay (ELISA) method.[18] Additionally, serum

functional opsonophagocytic activity (OPA) for each serotype will be assayed at the last 3 time

points for a randomly selected subset of approximately 100 subjects in each group (200 infants in

total), composed of infants assigned the first 20-36 subject numbers from each of the six sites.

Each participant will be observed for 30 min after each vaccination for any immediate reaction

by the research staff. Any noted adverse events (AEs) will be recorded at that time. After leaving

the site, local reactions (pain, redness, swelling, and pruritus), systemic events (somnolence,

vomiting, diarrhea, crying, and irritability), axially temperature, other AEs, and concomitant

medications to treat or prevent symptoms will be recorded in daily cards by the parents/legally

responsible representatives for 8 days. On the eighth day after vaccination, the documents will be

returned to the site. AEs occurring between the 8th and the 30th day after each dose together

with the usage of relevant concomitant medications will be recorded in connection cards and

handed in at the next visit. Serious adverse events (SAEs) will be collected throughout the study

until 6 months after the last dose. The intervention procedures are shown in Table 1.

Table 1 The intervention procedure

Interventions

Primary series Booster dose

3

months

4

months

5

months

30 days

postdose

12-15

months

30 days

postdose

6 months

postdose

Informed consent X

Eligibility screen X

Randomization X

Temperature X X X

X

Blood draw X

X X X

Vaccination X X X

X

Safety observations*

Immediate reaction ◎ ◎ ◎

◎

Local reactions and

systemic events ▲ ▲ ▲

▲

Adverse events ◆ ◆ ◆

◆

Serious adverse

events ★ ★ ★ ★ ★ ★ ★

*Safety observations occur after vaccination for a planned period.

◎Immediate reaction will be observed for 30 min after vaccination.

▲Local reactions and systemic events will be actively collected for 8 days after vaccination.

◆Other adverse events will be recorded by parents/ legally responsible representative(s) for 30 days

after vaccination.

★Serious adverse events will be self-reported by parents/ legally responsible representative(s) from

the first visit till the 6 months after the last dose.

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Outcome measures

Primary immunogenicity outcomes

For each of the 13 pneumococcal serotypes covered in PCV13:

• Proportion of vaccine recipients reaching the serotype-specific IgG concentration threshold

of 0.35μg/ml 30 days after the primary series.

• GMC of serotype-specific IgG antibodies 30 days after the primary series.

Secondary immunogenicity outcomes


• Proportion of vaccine recipients reaching the OPA threshold of 1:8 30 days after the primary

series.

• Geometric mean titer (GMT) of OPA 30 days after the primary series.




of 0.35μg/ml 30 days after the booster dose.

• GMC of serotype-specific IgG antibodies 30 days after the booster dose.

• Proportion of vaccine recipients reaching an OPA threshold of 1:8 30 days after the booster

dose.

• GMT of OPA 30 days after the booster dose.

• Proportion of vaccine recipients reaching a serotype-specific IgG concentration threshold of

1.0μg/ml 30 days after the booster dose.

Safety outcomes

Safety outcomes include all recorded local reactions and systemic AEs that occur within the 30

days following the primary series and booster doses and the percentage of vaccine recipients that

reported each AE.

Trial duration

The study will last for 26 months. If unsuspected acute abnormal reactions occur during the trial,

or the daily proportion of subjects who experienced AEs rated grade 3 or above reaches 15%

after any dose vaccination, the trial should be suspended. A panel will be involved in discussions

of the safety profile and decide whether the study should be continued.

Sample size

For each of the 7 common serotypes in both PCV13 and PCV7: Based on data from previous

studies, we assume the percentage of vaccine recipients reaching the serotype-specific IgG

concentration threshold of 0.35μg/ml will be 85%.[19] The non-inferior margin for the trial will

be set at 10%. If the non-inferiority does exist for a proportion of the test group, a sample size of

434 infants per group, 868 total, will provide 80% power to ensure that the lower limit of 97.5%

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two-sided CI for difference (test group – control group) will be no less than -10%. We also

postulate the common variance of serotype-specific IgG GMC, which has been logarithmically

transformed by base 10, will not be greater than 1.0. A sample size of 379 infants per group, 758

total, will have 80% power to detect whether the lower limit of 97.5% two-sided CI for

serotype-specific IgG GMC ratio (test group to control group) is above 0.5 or not. To take account

of α inflation and β consumption, Bonferroni correction will be employed to α, producing

corrected α= 0.025/2=0.0125 and corrected power = 1-0.2/7= 0.97.

For each of the 6 additional serotypes in PCV13 only: Based on the preclinical research, we

hypothesize that the proportion of vaccine recipients reaching the serotype-specific IgG

concentration threshold of 0.35μg/ml in the test group will be about 80% while that in the

control group will not be greater than 50%. We will still set the non-inferior difference for the

trial at 10%. If there is a notable difference between the two groups, a sample size of 274 infants

per group, 548 total, will provide 80% power to demonstrate that the lower limit of 95%

two-sided CI for a proportion of the test group will be no less than 70%. To control family-wise

type II error, power will be adjusted to 0.97 (equals to 1-0.2/6).

Final decision: Theoretically a total of 868 evaluable participants (434 per group) should enable

the trial to achieve the primary outcomes. To take blood draw failures and blood collection

refusals into consideration, we will allow for an anticipated 20% dropout rate.[20] Therefor, the

total sample size required is 1,040 infants (520 per group).

Randomization and allocation

The allocation sequence is generated by Department of Health Statistics of Fourth Military

Medical University using SAS (SAS Institute Inc., Cary, NC, USA) Plan procedure. In order to

guarantee the group balance in different sites, the block randomization kit will be used. Each site

will receive consecutively coded vaccines.

Because of the difference in appearance of PCV13 and PCV7, the administrators cannot be

blinded, but the group assigners, lab staff and investigators will be. Before recruitment, all

vaccines will be masked in identical white small boxes and labeled with vaccine numbers based

on the allocation schedule by those who are not involved in the clinical trial procedures. Each

vaccine number is composed of two parts: the subject identification number and the dose

specification number. Four vaccines with the same subject number prefix will belong to the same

participant. In case any unexpected situations arise, additional vaccines including PCV13 and

PCV7 in a ratio of 2:1 will be prepared and wrapped separately in individual white boxes labeled

with numbers from B0001 to B0540. The link between the additional vaccine number and subject

number will be established based on an allocation sequence list by Medidata Rave—the

electronic data capture (EDC) system for this study. Emergency letters will be sent to each of the

sites, and properly preserved until needed.

Each eligible participant will be sequentially allotted a unique subject number according to site

allocation list by authorized assigners, and thus will have an equal chance of being assigned to

either the test group or the control group. Blood samples will be labeled with subject numbers

and collected independently of the vaccination process. The inoculator is responsible for taking

out the vaccine related to a specific subject number and administering the injection. Inoculators

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must not share any allocation information to investigators or those involved in follow-up

procedures.

Withdrawal

The participations’ parents or legally responsible representatives will be aware that their decision

to take part in the study is voluntary and that they are free to withdraw consent at any time. All

withdrawals from the randomized intervention will be reported. The investigator may drop

participants during the study in the case of intercurrent illness, AEs, SAEs, protocol violations or

other reasons that meet the exclusion criteria.

Data management

The trial data will be managed using the Medidata Rave EDC system. The database software

provides several features to help maintain data quality. These features include, but are not

limited to keeping audit trails on all data fields, allowing custom functions in configurations and

opening both automatic and manual queries. At the same time, the original record cards will be

designed in accordance with the protocol to collect raw clinical data and to support the trial

procedures. The source data obtained from each participant will be examined and verified by

investigators and clinical research assistants (CRAs) at each study site. The entered data will be

systematically validated and audited not only by EDC system itself using edit checks but also by

CRAs and data managers (DMs). Data query forms generated by medically trained personnel will

be sent to the site investigators for identification. The electronic-Case Report Form (e-CRF) will be

inspected by DMs at regular intervals throughout the trial to verify the protocol compliance. The

entered data should be complete, consistent and accurate. The blinded immunology assay results

will be sent in an additional Excel spreadsheet via email to the data manager to be linked with

the central database.

Statistical methods

Data set: The full analysis set (FAS) will comply with the principles of intent-to-treat (ITT),[21] and

be comprised of all participants who receive at least one dose of vaccine and one follow-up visit.

The per-protocol analysis set (PPS) will be comprised of ITT participants who have received the

integrated vaccination schedule and participated in all follow-up visits. Whether a subject with

protocol deviations should be eliminated from the PPS set will be determined through blind data

review process before analyzing. The safety analysis set will be comprised of participants that

were randomized to a certain group and vaccinated including those with protocol deviations.

Analysis principle: Analysis will be conducted following the CONSORT[22] flow diagram (Figure 1)

of the phases of the study: enrollment, allocation, interventions, follow-up, and analysis. Baseline

characteristics analysis will be given for each group to depict the premises of this study using

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means, standard deviation (SD), minimum and maximum value as well as the 2-sided 95% CIs (if

any). Continuous data will be portrayed with means, SDs and CIs if a normal distribution

hypothesis of data is met. Binomial data will be summarized as frequencies and proportions. All

statistical tests will be demonstrated with a two-sided p-value, and all CIs will be calculated as 95%

at a two-sided level unless otherwise specified. A detailed statistical analysis plan will be finalized

before the first substantive statistical analysis.

Immunogenicity: The immunogenicity population consists of all subjects that belong to PPS and

have available serological data before and after immunization. The primary immunogenicity

endpoints for each of the pneumococcal serotypes are the proportion of subjects reaching the

serotype-specific IgG concentration threshold of 0.35µg/ml, and the geometric mean IgG

antibody concentration, in the PCV13 group measured 30 days after the primary series. Within

each group, for each pneumococcal serotype, the proportion of subjects with a specific-IgG

antibody concentration threshold of 0.35μg/ml and the two-sided 95% CI for the proportion will

be calculated; for each antibody concentration, the value will be logarithmically transformed to

the base 10, and the two-sided 95% Cl will be structured. To evaluate differences between two

groups, the sequential test (Figure 2) of hypotheses, including the non-inferiority for the 7

common serotypes and the efficacy for the 6 additional serotypes, will be performed. The

non-inferiority for each of the 7 common serotypes will be declared if the lower limit of the

two-sided 97.5% (one-sided 98.75%) CI, which is calculated using the exact binomial method,[23

24] for the difference in proportions (PCV13 - PCV7) is no less than -10%, or the lower bound of

the two-sided 97.5% (one-sided 98.75%) CI of the IgG GMC ratio (PCV13/ PCV7) is greater than

0.5. To control familywise Type I error, Bonferroni correction will be used to address multiple test,

and thus a two-sided significance level of 0.025 (0.0125, one-sided) will be adopted. Only after

each of the 7 common serotypes has been shown to be non-inferior, will the other 6 additional

serotypes be worth assessing. The efficacy criteria for each of the 6 additional serotypes will be

met if both the lower limit of the 2-sided 95% CI for the proportion of vaccine recipients reaching

the serotype-specific IgG concentration threshold of 0.35μg/ml conducted by normal

approximation method is no less than 70%, and the 2-sided 95% CI for the difference in

proportion (PCV13 - PCV7) compared by a Chi-squared test lies almost to the right of the zero

(zero or positive mean difference). A p-value of less than 0.05 is considered statistically

significant.

The secondary immunogenicity endpoints for each of the pneumococcal serotypes in the

PCV13 group are the percentage of vaccine recipients reaching a serotype-specific IgG

concentration threshold of 0.35µg/ml 30 days after the toddler dose and the percentages of

vaccine recipients reaching a serotype-specific IgG concentration threshold of 1.0µg/ml 30 days

after primary series and booster dose. The proportions of the subjects reaching the

pneumococcal opsonophagocytic assay (OPA) titer threshold of 1:8 after primary and booster

immunization in pre-defined subgroups also serve as the secondary immunogenicity endpoints.

Within each group and for each antibody concentration or OPA titer, geometric mean will be

calculated and each concentration or titer will be logarithmically transformed for analyzing. To

assess differences between the two groups and to test the non-inferiority of the PCV13 group,

the analysis method described in the primary endpoints section will be employed.

As reported in previous studies,[25 26] antibody responses to serotypes 19A, 6A, and 5 were

noted in the PCV7 group. Therefore, when evaluating the efficacy of 6A, 19A, and 5 in the PCV13

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group, the OPA results should be combined.[27]

Safety: The safety population includes all subjects in the safety analysis set that will receive at

least one dose of study vaccine. Safety analysis including comparisons of incidences of local

reactions, systemic events, use of concomitant medications, dropouts and AEs between PCV13

and PCV7 will be demonstrated with the corresponding 2-sided 95% CIs and p-values base on

Fisher’s exact test methodology for each dose respectively and for all in total as well. A p-value of

equal to or less than 0.05 indicates a statistically significant difference.

Harms

Any serious adverse events (SAEs) will be reported to regulatory authorities, sponsors and Ethics

Committees (ECs) within 24 hours by fax, email or in person. Any suspected or unexpected

serious events will be reported to regulatory authorities by sponsors within 7 calendar days and

its follow-up investigation report will be submitted within 8 calendar days of the first report

submission day.

Auditing

Monitoring of this trial will be conducted by a Contract Research Organization (CRO, Simoon

Record Pharma Information Consulting Co., Ltd). Guidelines of Good Clinical Practice (GCP) will

ensure compliance.

ETHICS AND DISSEMINATION

Research ethics approval

This study was approved by the ECs at 3 provinces (Shanxi, Henan and Hebei Province), and will

be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice.[28] The

registration number of this trial is NCT02736240.

Informed consent

All participants’ parents/ legally responsible representatives will receive adequate information

about the nature, purpose, and possible risks and benefits of the trial by an informed consent

form approved by the EC. The original version of signed consent forms will be retained by the

investigators as a trial record, and a copy will be kept by the participants’ parents/legally

responsible representatives.

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Confidentiality

To assure confidentiality, all participants will be allotted a unique subject number throughout the

trial. Personal information will be collected with standardized paper forms by face to face

interviews. Paper-based data will be stored in locked cabinets with limited access at each site,

and the electronic data will be saved on password protected computers.

Access to data

The final dataset will be under the custody of the sponsor together with the CRO selected

beforehand. The data managers will be permitted to access the full analyzed final dataset. Access

to the final or identifiable data by others is subject to the sponsor's approval.

Dissemination policy

The trial will be reported in accordance with the CONSORT guidance.

Discussion

To date, the efficacy and safety of PCV13 among the Chinese population is still largely unknown.

Hence, this study intends to characterize the PCV13 among Chinese infants and develop a safety

profile for the vaccine. To fulfill these objectives, we calculated sample sizes under different

hypothetical conditions and determined the optimal sample size to use to take all of all factors

into consideration. In study design, we adopted the sequential test method to inspect the

non-inferiority of each of the 7 common pneumococcal serotypes and the efficacy of each of the

6 additional pneumococcal serotypes step by step to avoid false positive error inflation. To be

more discreet and conservative, instead of setting pneumococcal serotype 6B in PCV7 as a

baseline when verifying the immunogenicity of each of the 6 additional serotypes in PCV13, as

many other researchers have done, we defined 70% as the lower limit of the 2-sided 95% CI for

the percentage of responders that reach the serotype-specific IgG concentration threshold of

0.35μg/ml and supposed that the corresponding percentages in PCV7 are less than 50%.[29]

Allowing for the cross-reactivation between 6A and 6B as well as 19A and 19B in PCV7, we will

select a subgroup of which to obtain the OPA results for each of the 13 serotypes to correct for

potential bias.

Given the main focus of the research, this study is not designed to involve the assessment of

concomitant immunization with other vaccines specified in pediatric vaccination schedules such

as diphtheria, tetanus and acellular pertussis vaccine (DTaP), which might be regarded as a

potential limitation. Because the feasibility of PCV7 administered concomitantly with DTaP in

mainland Chinese infants has been shown in the research reported by Li RC et al.,[30] and the

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immunogenicity of PCV13 co-administered with DTaP was demonstrated by Togashi T et al.,[7]

we will not prohibit the usage of vaccines listed in the expanded program on immunization (EPI),

but we will compulsively demand at least a fortnight interval between two kinds of vaccination.

Footnotes

Author affiliations:

1 DHSFMMU, Department of Health Statistics of Fourth Military Medical University, Xi’an, Shanxi, China

2 Walvax, Walvax Biotechnology Co., Ltd., Kunming, Yunnan, China

3 Beijing Chaoyang CDC, Beijing Chaoyang District Centre for Disease Control and Prevention, Beijing, China

4 Hebei CDC, Heibei Province Centre for Disease Control and Prevention, Shijiazhuang, Heibei, China

5 Henan CDC, Henan Province Centre for Disease Control and Prevention, Zhengzhou, Henan, China

6 Shanxi CDC, Shanxi Province Centre for Disease Control and Prevention, Taiyuan, Shanxi, China

7 Guangxi CDC, Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention, Nanning, Guangxi,

China

Contributors

JLX provided statistical expertise and created the study design together with JJC. ZH and LY conceived the study and

participated in study design. JJC drafted the manuscript and calculated the sample size. NMS, YLZ, SLX and GHL are

the primary investigators and helped with protocol revise. RCL and YPL are the senior consultants and contributed to

protocol development. SYY compiled the original protocol in Chinese and participated in study design discussion. All

authors read and proved the final manuscript.

Funding The study is supported by a grant from Bio-pharmaceutical Major Scientific & Technological Project

(biological product development section) of Yunnan Province (project number 2015ZJ005).

Disclaimer The views expressed are those of the author(s) and not necessarily those of the DHSFMMU, Walvax or

CDCs which involved.

Competing interests The authors declare that there is no interest conflict regarding the publication of this paper.

Ethics approval The trial is approved by: the Beijing Chaoyang District Centre for Disease Control and Prevention

Ethics Committee (the lead institution), the Heibei Province Centre for Disease Control and Prevention Ethics

Committee, the Henan Province Centre for Disease Control and Prevention Ethics Committee, and the Shanxi

Province Centre for Disease Control and Prevention Ethics Committee.

Provenance and peer review Not commissioned; internally peer reviewed.

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14. Durando P, Rosselli R, Cremonesi I, et al. Safety and tolerability of 13-valent pneumococcal

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10.1016/j.vaccine.2014.02.002[published Online First: 5 March 2014].

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17. WHO. Guidelines on clinical evaluation of vaccines: regulatory expectations. WHO Tech Rep Ser

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19. Siber GR, Chang I, Baker S, et al. Estimating the protective concentration of anti-pneumococcal

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20. Leach AJ, Mulholland EK, Santosham M, et al. Pneumococcal conjugate vaccines PREVenar13

and SynflorIX in sequence or alone in high-risk Indigenous infants (PREV-IX_COMBO): protocol

of a randomised controlled trial. BMJ Open 2015;5(1) doi:

10.1136/bmjopen-2014-007247[published Online First: 16 January 2015].

21. ICH Efficacy Guidelines topic E9 guideline for good clinical practice, step 4 version.

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Sep 2015).

22. Schulz KF, Altman DG, Moher D, et al. CONSORT 2010 statement: updated guidelines for

reporting parallel group randomised trials. Int J Surg 2011;9(8):672-7 doi:

10.1016/j.ijsu.2011.09.004[published Online First: 13 October 2011].

23. NEWCOMBE RG. Interval estimation for the difference between independent proportions

comparison of eleven methods. Stat Med 1998;17:873-90

24. NEWCOMBE RG. Two-sided confidence intervals for the single proportion comparison of seven

methods. Stat Med 1998;17:857-72

25. Esposito S, Tansey S, Thompson A, et al. Safety and immunogenicity of a 13-valent

pneumococcal conjugate vaccine compared to those of a 7-valent pneumococcal conjugate

vaccine given as a three-dose series with routine vaccines in healthy infants and toddlers. Clin

Vaccine Immunol 2010;17(6):1017-26 doi: 10.1128/CVI.00062-10[published Online First: 28

April 2010].

26. Olivier C, Belohradsky BH, Stojanov S, et al. Immunogenicity, reactogenicity, and safety of a

seven-valent pneumococcal conjugate vaccine (PCV7) concurrently administered with a fully

liquid DTPa-IPV-HBV-Hib combination vaccine in healthy infants. Vaccine 2008;26(25):3142-52

doi: 10.1016/j.vaccine.2007.11.096[published Online First: 6 May 2008].

27. Cooper D, Yu X, Sidhu M, et al. The 13-valent pneumococcal conjugate vaccine (PCV13) elicits

cross-functional opsonophagocytic killing responses in humans to Streptococcus pneumoniae

serotypes 6C and 7A. Vaccine 2011;29(41):7207-11 doi:



1996;http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html.

(Accessed 5 Aug 2015).

29. Elberse KE, de Greeff SC, Wattimena N, et al. Seroprevalence of IgG antibodies against 13

vaccine Streptococcus pneumoniae serotypes in the Netherlands. Vaccine 2011;29(5):1029-35

doi: 10.1016/j.vaccine.2010.11.054[published Online First: 1 December 2010].

30. Li RC, Li FX, Li YP, et al. Safety and immunogenicity of a 7-valent pneumococcal conjugate

vaccine (Prevenar): primary dosing series in healthy Chinese infants. Vaccine

2008;26(18):2260-9 doi: 10.1016/j.vaccine.2008.02.029[published Online First: 29 February

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2008].

Figure 1 The study flow diagram

Figure 2 The sequential test flow chart

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Figure 1 The study flow diagram CONSORT flow diagram

281x174mm (96 x 96 DPI)

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281x182mm (96 x 96 DPI)

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SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*

Section/item Item No

Description Addressed on page number

Administrative information

Title 1 Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym ______1 _____

Trial registration 2a Trial identifier and registry name. If not yet registered, name of intended registry ______2______

2b All items from the World Health Organization Trial Registration Data Set _____N/A_ ___

Protocol version 3 Date and version identifier _____N/A_____

Funding 4 Sources and types of financial, material, and other support ______13_____

Roles and

responsibilities

5a Names, affiliations, and roles of protocol contributors _____1,13 ____

5b Name and contact information for the trial sponsor _____N/A_ ___

5c Role of study sponsor and funders, if any, in study design; collection, management, analysis, and

interpretation of data; writing of the report; and the decision to submit the report for publication, including

whether they will have ultimate authority over any of these activities

_____N/A_ ___

5d Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint

adjudication committee, data management team, and other individuals or groups overseeing the trial, if

applicable (see Item 21a for data monitoring committee)

_____N/A_ ___

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2

Introduction

Background and

rationale

6a Description of research question and justification for undertaking the trial, including summary of relevant

studies (published and unpublished) examining benefits and harms for each intervention

______3______

6b Explanation for choice of comparators ______3______

Objectives 7 Specific objectives or hypotheses ______4______

Trial design 8 Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group),

allocation ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory)

______4______

Methods: Participants, interventions, and outcomes

Study setting 9 Description of study settings (eg, community clinic, academic hospital) and list of countries where data will

be collected. Reference to where list of study sites can be obtained

______4______

Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and

individuals who will perform the interventions (eg, surgeons, psychotherapists)

______4______

Interventions 11a Interventions for each group with sufficient detail to allow replication, including how and when they will be

administered

______5______

11b Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose

change in response to harms, participant request, or improving/worsening disease)

_____N/A_ ___

11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence

(eg, drug tablet return, laboratory tests)

______6______

11d Relevant concomitant care and interventions that are permitted or prohibited during the trial _____N/A_ ___

Outcomes 12 Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood

pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg,

median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen

efficacy and harm outcomes is strongly recommended

______7______

Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for

participants. A schematic diagram is highly recommended (see Figure)

______6______

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Sample size 14 Estimated number of participants needed to achieve study objectives and how it was determined, including

clinical and statistical assumptions supporting any sample size calculations

______6______

Recruitment 15 Strategies for achieving adequate participant enrolment to reach target sample size _____N/A_ ___

Methods: Assignment of interventions (for controlled trials)

Allocation:

Sequence

generation

16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any

factors for stratification. To reduce predictability of a random sequence, details of any planned restriction

(eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants

or assign interventions

______8______

Allocation

concealment

mechanism

16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered,

opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned

______8______

Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to

interventions

______8______

Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome

assessors, data analysts), and how

______8______

17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s

allocated intervention during the trial

______8______

Methods: Data collection, management, and analysis

Data collection

methods

18a Plans for assessment and collection of outcome, baseline, and other trial data, including any related

processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of

study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known.

Reference to where data collection forms can be found, if not in the protocol

______9______

18b Plans to promote participant retention and complete follow-up, including list of any outcome data to be

collected for participants who discontinue or deviate from intervention protocols

_____N/A_ ___

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Data management 19 Plans for data entry, coding, security, and storage, including any related processes to promote data quality

(eg, double data entry; range checks for data values). Reference to where details of data management

procedures can be found, if not in the protocol

______9______

Statistical methods 20a Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the

statistical analysis plan can be found, if not in the protocol

______9______

20b Methods for any additional analyses (eg, subgroup and adjusted analyses) _____ 10 _____

20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any

statistical methods to handle missing data (eg, multiple imputation)

______9______

Methods: Monitoring

Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of

whether it is independent from the sponsor and competing interests; and reference to where further details

about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not

needed

_____N/A_ ___

21b Description of any interim analyses and stopping guidelines, including who will have access to these interim

results and make the final decision to terminate the trial

_____N/A_ ___

Harms 22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse

events and other unintended effects of trial interventions or trial conduct

_____ 11 _____

Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent

from investigators and the sponsor

_____ 11 _____

Ethics and dissemination

Research ethics

approval

24 Plans for seeking research ethics committee/institutional review board (REC/IRB) approval _____ 11 _____

Protocol

amendments

25 Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes,

analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals,

regulators)

_____N/A_ ___

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Consent or assent 26a Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and

how (see Item 32)

_____ 11 _____

26b Additional consent provisions for collection and use of participant data and biological specimens in ancillary

studies, if applicable

_____N/A_ ___

Confidentiality 27 How personal information about potential and enrolled participants will be collected, shared, and maintained

in order to protect confidentiality before, during, and after the trial

_____ 12 _____

Declaration of

interests

28 Financial and other competing interests for principal investigators for the overall trial and each study site _____ 12 _____

Access to data 29 Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that

limit such access for investigators

_____ 12 _____

Ancillary and post-

trial care

30 Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial

participation

_____N/A_ ___

Dissemination policy 31a Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals,

the public, and other relevant groups (eg, via publication, reporting in results databases, or other data

sharing arrangements), including any publication restrictions

_____ 12 _____

31b Authorship eligibility guidelines and any intended use of professional writers _____ 13 _____

31c Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code _____N/A_ ___

Appendices

Informed consent

materials

32 Model consent form and other related documentation given to participants and authorised surrogates _____N/A_ ___

Biological

specimens

33 Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular

analysis in the current trial and for future use in ancillary studies, if applicable

_____N/A_ ___

*It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Explanation & Elaboration for important clarification on the items.

Amendments to the protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT Group under the Creative Commons

“Attribution-NonCommercial-NoDerivs 3.0 Unported” license.

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Journal: BMJ Open

Manuscript ID bmjopen-2016-012488.R1


Date Submitted by the Author: 20-Jun-2016








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Jing Jing Chen,1,2


2 Nian Min Shi,

3 Yu Liang Zhao,

4 Sheng Li Xia,

5 Guo Hua

Li,6 Rong Cheng Li,

7 Yan Ping Li,

7 Shu Yuan Yang,

2 Jie Lai Xia

1*



Co-authors:






China


Heibei, China


China


China







Word count: 4280

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ABSTRACT






(PCV7).

























recommended by WHO.


involving the assessment of concomitant immunization with other vaccines specified in


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INTRODUCTION

Background































In accordance with the guidelines formulated by WHO,[17] and the requirements established by

national regulatory authorities, licensing a new vaccine requires randomized clinical trials to







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Objectives
















Trial design




METHODS

Study setting





Inclusion criteria

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randomization:

1. Healthy infants, as established by medical history and clinical examination before entering


2. Obtained written informed consent from the legally responsible representative(s)

3. Have the compliance of the subjects’ legally responsible representative(s) with the


4. No pneumococcal vaccine history or use of other preventive vaccine at least 7 days before

study entry

5. Axillary temperature ≤ 37℃


1. Vaccinated by on sale or other on trial pneumococcal vaccines

2. Have had an invasive disease with streptococcus pneumonia as the verified cause

3. Severely allergic to any vaccines or drugs, or sensitive to temperatures ≥ 39℃ associated


4. Birth weight < 2.5 kg

5. History or family history of convulsion, seizure, encephalopathy or neurological disorder

6. Born from abnormal labors (difficult labors, aided by instruments) or have a history of


7. Confirmed thrombocytopenia or a history of blood coagulation disorder

8. Confirmed pathological jaundice

9. Any confirmed or suspected immunodeficiency involving immunosuppressive therapy



10. Any confirmed or suspected congenital defect or serious chronic illnesses (trisomy 21


11. Any confirmed or suspected diseases including respiratory diseases, acute infection, active


dermatosis

12. Administration of immunoglobulin and/or any blood products, except Hepatitis B


13. Concurrent participation in another clinical study

14. Other exclusion criteria affirmed by investigators

Intervention








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vomiting, diarrhea, crying, and irritability), axillary temperature, other AEs, and concomitant








Interventions


3

months

4

months

5

months

30 days

postdose

12-15

months

30 days

postdose

6 months

postdose

Informed consent X


Randomization X

Temperature X X X

X

Blood draw X

X X X

Vaccination X X X

X



◎

Local reactions and


▲


◆

Serious adverse

events ★ ★ ★ ★ ★ ★ ★





after vaccination.



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Outcome measures



1. Proportion of vaccine recipients reaching the serotype-specific IgG concentration threshold


2. GMC of serotype-specific IgG antibodies 30 days after the primary series.



1. Proportion of vaccine recipients reaching the OPA threshold of 1:8 30 days after the primary

series.

2. Geometric mean titer (GMT) of OPA 30 days after the primary series.





5. GMC of serotype-specific IgG antibodies 30 days after the booster dose.

6. Proportion of vaccine recipients reaching an OPA threshold of 1:8 30 days after the booster

dose.

7. GMT of OPA 30 days after the booster dose.

8. Proportion of vaccine recipients reaching a serotype-specific IgG concentration threshold of


Safety outcomes



reported each AE.

Trial duration





Sample size






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control group will not be greater than 50%. If there is a notable difference between the two

groups, a sample size of 274 infants per group, 548 total, will provide 80% power to demonstrate

that the lower limit of 95% two-sided CI for a proportion of the test group will be no less than 70%

(the target rate). To control family-wise type II error, power will be adjusted to 0.97 (equals to

1-0.2/6).



























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procedures.

Withdrawal






Data management















Statistical methods











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significant.














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Harms





submission day.

Auditing



ensure compliance.






Informed consent






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Confidentiality





Access to data






Discussion















potential bias.






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Footnotes









China

Contributors







(biological product development section) of Yunnan Province (project number 2015ZJ005).



Competing interests The authors declare that there is no interest conflict regarding the publication of this paper.






REFERENCES









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2010].



2009].






2015;34(10):1096-104 doi: 10.1097/INF.0000000000000819.







2:S119-29 doi: 10.1097/INF.0000000000000079.




10.1517/14712598.2013.824419.





















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15


2004; 924



2003;10(4):514-19 doi: 10.1128/cdli.10.4.514-519.2003.










Sep 2015).












April 2010].


















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16

2008].



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281x174mm (300 x 300 DPI)

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Roles and

responsibilities






_____N/A_ ___




_____N/A_ ___

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2

Introduction

Background and

rationale



______3______





______4______




______4______



______4______


administered

______5______



_____N/A_ ___



______6______






______7______



______6______

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3



______6______



Allocation:

Sequence

generation





______8______

Allocation

concealment

mechanism



______8______


interventions

______8______



______8______



______8______


Data collection

methods





______9______



_____N/A_ ___

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4




______9______



______9______




______9______

Methods: Monitoring




needed

_____N/A_ ___



_____N/A_ ___



_____ 11 _____



_____ 11 _____


Research ethics

approval


Protocol

amendments



regulators)

_____N/A_ ___

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5


how (see Item 32)

_____ 11 _____



_____N/A_ ___



_____ 12 _____

Declaration of

interests




_____ 12 _____

Ancillary and post-

trial care


participation

_____N/A_ ___




_____ 12 _____



Appendices

Informed consent

materials


Biological

specimens



_____N/A_ ___




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Journal: BMJ Open

Manuscript ID bmjopen-2016-012488.R2


Date Submitted by the Author: 03-Sep-2016








BMJ Open on F


http://bmjopen.bm

j.com/

BM



ownloaded from



1




Jing Jing Chen,1,2


2 Nian Min Shi,

3 Yu Liang Zhao,

4 Sheng Li Xia,

5 Guo Hua

Li,6 Rong Cheng Li,

7 Yan Ping Li,

7 Shu Yuan Yang,

2 Jie Lai Xia

1*



Co-authors:






China


Heibei, China


China


China







Word count: 4280

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ABSTRACT






(PCV7).

























recommended by WHO.


involving the assessment of concomitant immunization with other vaccines specified in


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3

INTRODUCTION

Background































In accordance with the guidelines formulated by WHO,[17] and the requirements established by

national regulatory authorities, licensing a new vaccine requires randomized clinical trials to







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Objectives
















Trial design




METHODS

Study setting





Inclusion criteria

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5


randomization:

1. Healthy infants, as established by medical history and clinical examination before entering


2. Obtained written informed consent from the legally responsible representative(s)

3. Have the compliance of the subjects’ legally responsible representative(s) with the


4. No pneumococcal vaccine history or use of other preventive vaccine at least 7 days before

study entry

5. Axillary temperature ≤ 37℃


1. Vaccinated by on sale or other on trial pneumococcal vaccines

2. Have had an invasive disease with streptococcus pneumonia as the verified cause

3. Severely allergic to any vaccines or drugs, or sensitive to temperatures ≥ 39℃ associated


4. Birth weight < 2.5 kg

5. History or family history of convulsion, seizure, encephalopathy or neurological disorder

6. Born from abnormal labors (difficult labors, aided by instruments) or have a history of


7. Confirmed thrombocytopenia or a history of blood coagulation disorder

8. Confirmed pathological jaundice

9. Any confirmed or suspected immunodeficiency involving immunosuppressive therapy



10. Any confirmed or suspected congenital defect or serious chronic illnesses (trisomy 21


11. Any confirmed or suspected diseases including respiratory diseases, acute infection, active


dermatosis

12. Administration of immunoglobulin and/or any blood products, except Hepatitis B


13. Concurrent participation in another clinical study

14. Other exclusion criteria affirmed by investigators

Intervention








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vomiting, diarrhea, crying, and irritability), axillary temperature, other AEs, and concomitant








Interventions


3

months

4

months

5

months

30 days

postdose

12-15

months

30 days

postdose

6 months

postdose

Informed consent X


Randomization X

Temperature X X X

X

Blood draw X

X X X

Vaccination X X X

X



◎

Local reactions and


▲


◆

Serious adverse

events ★ ★ ★ ★ ★ ★ ★





after vaccination.



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Outcome measures





2. GMC of serotype-specific IgG antibodies 30 days after the primary series.



1. Proportion of vaccine recipients reaching the OPA threshold of 1:8 30 days after the primary

series.

2. Geometric mean titer (GMT) of OPA 30 days after the primary series.





5. GMC of serotype-specific IgG antibodies 30 days after the booster dose.

6. Proportion of vaccine recipients reaching an OPA threshold of 1:8 30 days after the booster

dose.

7. GMT of OPA 30 days after the booster dose.

8. Proportion of vaccine recipients reaching a serotype-specific IgG concentration threshold of


Safety outcomes



reported each AE.

Trial duration





Sample size






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control group will not be greater than 50%. If there is a notable difference between the two

groups, a sample size of 274 infants per group, 548 total, will provide 80% power to demonstrate

that the lower limit of 95% two-sided CI for a proportion of the test group will be no less than 70%

(the target rate). To control family-wise type II error, power will be adjusted to 0.97 (equals to

1-0.2/6).



























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procedures.

Withdrawal






Data management















Statistical methods











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significant.














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Harms





submission day.

Auditing



ensure compliance.






Informed consent






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Confidentiality





Access to data






Discussion















potential bias.






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Footnotes









China

Contributors







(biological product development section) of Yunnan Province (project number 2015ZJ005). The funding source has no

role in the trial design and will have no role in the trial conduct, data analysis and interpretation, or writing or reporting.



Competing interests We have read and understood BMJ policy on declaration of interests and declare the following

interests: This trial is sponsored by Walvax Biotechnology Co., Ltd.. Walvax, as the sponsor, is responsible for

organizing and managing the study to support the pre-licensing evaluation of the investigational PCV13. The new

PCV13 was researched and developed by Walvax and manufactured by an affiliate of Walvax. JJC, LY, ZH and SYY

work at Walvax and belong to the clinical research team of PCV13.






REFERENCES




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2010].



2009].






2015;34(10):1096-104 doi: 10.1097/INF.0000000000000819.







2:S119-29 doi: 10.1097/INF.0000000000000079.




10.1517/14712598.2013.824419.
















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2004; 924



2003;10(4):514-19 doi: 10.1128/cdli.10.4.514-519.2003.










Sep 2015).












April 2010].













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2008].



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Roles and

responsibilities






_____N/A_ ___




_____N/A_ ___

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2

Introduction

Background and

rationale



______3______





______4______




______4______



______4______


administered

______5______



_____N/A_ ___



______6______






______7______



______6______

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3



______6______



Allocation:

Sequence

generation





______8______

Allocation

concealment

mechanism



______8______


interventions

______8______



______8______



______8______


Data collection

methods





______9______



_____N/A_ ___

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4




______9______



______9______




______9______

Methods: Monitoring




needed

_____N/A_ ___



_____N/A_ ___



_____ 11 _____



_____ 11 _____


Research ethics

approval


Protocol

amendments



regulators)

_____N/A_ ___

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5


how (see Item 32)

_____ 11 _____



_____N/A_ ___



_____ 12 _____

Declaration of

interests




_____ 12 _____

Ancillary and post-

trial care


participation

_____N/A_ ___




_____ 12 _____



Appendices

Informed consent

materials


Biological

specimens



_____N/A_ ___




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BMJ Open · vaccine: study protocol of a randomized non-inferiority trial in China Jing Jing...

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