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Trial registered on ANZCTR


Registration number
ACTRN12615000898550
Ethics application status
Approved
Date submitted
7/08/2015
Date registered
27/08/2015
Date last updated
27/08/2015
Type of registration
Retrospectively registered

Titles & IDs
Public title
Optimising pertussis vaccination in infants: a new approach. Effects of delaying the third pertussis vaccine to 11 months old.
Scientific title
Comparing the immunogenicity and safety of healthy infants who receive a delayed third dose of pertussis vaccine to those vaccinated according to the standard Australian vaccination schedule.
Secondary ID [1] 285833 0
Nil
Universal Trial Number (UTN)
U1111-1165-1232
Trial acronym
Nil
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Immunogenicity and safety after pertussis vaccination 293752 0
Condition category
Condition code
Inflammatory and Immune System 294050 294050 0 0
Normal development and function of the immune system
Respiratory 296245 296245 0 0
Other respiratory disorders / diseases
Infection 296246 296246 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Changed timing for the administration of the pertussis-containing vaccine known as Infanrix hexa (contains diphtheria, tetanus, acellular pertussis, hepatitis B, polio and haemophilus influenza B antigens), which is given to all Australian children as part of the National Immunisation Program. That is, for the study participants, only the timing has been altered for Infanrix hexa vaccination and not the vaccine itself.
The study schedule is that Infanrix hexa is given at 6 weeks, 12 weeks, and 11 months old (compared to the standard schedule of 12 weeks, 4 months and 6 months old).
The vaccine will be administered by intramuscular injection by a registered nurse or doctor with specialisation in immunisation. The vaccination will be recorded in the subject's study documentation, the subject's personal immunisation record (known as the Blue Book in NSW), and on the Australian Childhood Immunisation Register.

Intervention code [1] 290812 0
Treatment: Drugs
Comparator / control treatment
The standard Australian vaccination schedule for administration of Infanrix hexa is at 6 weeks, 4 months and 6 months old.
In this study, there is no control group and all participants enrolled will receive the intervention of changed timing of Infanrix hexa vaccine administration.
Data collected from this study will be compared with control group data from another NHMRC-funded study, "Immunogenicity and safety of acellular pertussis vaccine given at birth in healthy infants" (ACTRN12609000905268), collected between June 2010 to Dec 2012.
Control group
Historical

Outcomes
Primary outcome [1] 293827 0
The proportion of infants achieving a four-fold rise in pertussis antibody level from baseline to post completion of a 3 dose alternate pertussis vaccine schedule.
Antibody levels are assessed by measuring immunoglobulin G to anti pertussis toxin, pertactin and filamentous haemagglutinin by a validated enzyme-linked immunosorbent assay.
Timepoint [1] 293827 0
Blood is collected from study participants at 6 weeks, 6 months and 12 months old.
Secondary outcome [1] 312237 0
Adverse reactions following the alternate schedule vaccinations. These are classified into solicited, unsolicited, onset of chronic illness and serious adverse event.
Carers of the study participant will be given a diary card to record in every day for the first 7 days after every vaccination. The diary card asks about temperature, vomiting, diarrhoea, irritability, restlessness, drowsiness and feeding. It also asks about injection site reactions and if present, requests the carer to record redness, pain and swelling size and severity. A thermometer and ruler are issued at study enrolment, and instructions given for recording adverse events.
Unsolicited adverse events are recorded in another diary card and to be written in for any other events from one study visit until the next study visit eg viral illness. It also asks the carer to record all medications given.
Specific instructions are given to the carer to notify study staff as soon as possible if the participant is hospitalised as this is a serious adverse event.
All adverse events are reviewed by the study investigator and severity and causality to vaccines determined.
Timepoint [1] 312237 0
Adverse events are recorded in detail for 7 days after each vaccination (at 6 weeks, 12 weeks, 4 months, 6 months and 11 months old) but there is also continuous monitoring by the carer from the time of the first vaccination to the study conclusion at 12-13 months old.
Secondary outcome [2] 312238 0
There will be a composite secondary outcome looking at the immune response to other concomitantly administered vaccine antigens, measured by antibody levels. The antibody levels will be log transformed into geometric mean concentration (GMC) and compared with control data as a continuous variable and by categorical analysis (above protective threshold level). A positive response is defined as a 4-fold increase from pre-vaccination level or percentage above protective threshold antibody levels.

Antibodies tested will be diphtheria, tetanus, hepatitis B, haemophilius influenza type B and polio serotypes 1, 2 and 3 from collected blood samples.
Method of testing will be by standard and validated enzyme-linked immunosorbent assays (ELISA) for diphtheria, tetanus, hepatitis B and haemophilus influenza type B. Antibody to polio serotypes 1, 2 and 3 will be measured by microneutralisation assay and the lowest dilution tested at 1:8.
Timepoint [2] 312238 0
12-13 months of age

Eligibility
Key inclusion criteria
Eligible infants of English-speaking parents must be healthy (by history and physical examination) at the time of the first vaccine, born at 36 completed weeks gestation or greater, between 6-7 weeks of age at the time of enrolment, and whose parents give written informed consent.
Minimum age
42 Days
Maximum age
7 Weeks
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Infant has received the 6 week old vaccines.

Contraindications to vaccination as listed in the current NHMRC Australian Immunisation Handbook (at time of study 10th edition, online access http://www.health.gov.au/internet/immunise/publishing.nsf/Content/Handbook10-home). The relevant vaccine will not be administered to individuals known to be hypersensitive to any component of the vaccine or residues carried over from manufacture (such as formaldehyde and glutaraldehyde).

Infant of a mother known to be a carrier of hepatitis B virus.

Administration of immunoglobulins and any blood products preceding the first dose of study vaccine or planned administration during the study period.

Any confirmed or suspected immunosuppressive or immunodeficient condition, in child.

Major congenital defects or serious chronic illness.

Neurologic disease or seizure.

Study design
Purpose of the study
Prevention
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Subjects will be enrolled if they fulfil all of the inclusion criteria and none of the exclusion criteria. Written informed consent will be obtained prior to any study procedures occurring. Infant demographics will be obtained including name, birth weight, height, head circumference, gestation and history of infant medical illness. A brief medical evaluation will occur if necessary, followed by ascertainment of axillary temperature.

All subjects enrolled will be allocated to the treatment group. That is, all subjects enrolled will receive the pertussis-containing vaccine, Infanrix hexa, at the intervention schedule (at 6 weeks, 12 weeks, and 11 months old).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
This study is not randomised.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Control group data will be sourced from another study (NHMRC-funded study: Immunogenicity and safety of acellular pertussis vaccine at birth ACTRN12609000905268) using the same outcomes and time endpoints.
Phase
Phase 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
All efficacy analyses will be undertaken using the Full Analysis Set comprising all participants. The safety analyses will be undertaken using the Safety Analysis Set comprising all participants that receive at least one vaccination.

All serum antibody concentrations will be log transformed for statistical analysis as geometric mean concentrations (GMC). Where protective thresholds are well established, the proportions at or above the assay cut off – anti-diphtheria (0.1 IU/ml), anti-tetanus (0.1 IU/ml) anti-Hib (PRP) (0.15 micrograms/ml) and hepatitis B surface antibody (10mIU/ml) – will be compared by vaccine group. Antibody to polio serotypes 1, 2 and 3 will be measured by microneutralisation assay and the lowest dilution tested at 1:8. Statistical analysis will include both comparisons of GMC (with 95% confidence intervals) as a continuous variable (t test) and categorical analysis of relevant Ab. Thresholds (chi square). The frequency of seroresponses defined as a 4-fold increase from pre-vaccination antibody level, will be compared between our study group and the NHMRC cohort by the Chi square test statistic.

Comparisons of the study results with immunogenicity data from our current NHMRC study (Immunogenicity and safety of acellular pertussis vaccine at birth) will be made as follows:
Prior to any Pa dose at 6 weeks old, after 2 Pa doses, and after 3 Pa doses

Sample size calculations:
Pertussis vaccine efficacy trials conclude that anti pertussis toxin (PT) and pertactin (PRN) IgG antibodies are the current best surrogate measures of protection. In US National Institutes of Health (NIH) sponsored comparative immunogenicity trials for acellular pertussis vaccines seroconversion to PT and PRN, as measured by enzyme-linked immunosorbent assay (ELISA) unit (EU) value, was defined as a fourfold rise above the minimum detectable level. Therefore, proportions of infants achieving a fourfold rise in PT antibody level after 2 and 3 doses compared to pre vaccine levels has been used to calculate the sample size required. Data from the NIH studies and our previous study indicate that 90% of infants achieve a fourfold rise in PT antibody from baseline after 2 and 3 doses when given as 2,4,6 months schedule. Our planned sample size of 80 infants will allow us to accurately detect a similar fourfold rise in antibody in 90% of participants with 95%CI of 81-95% following a 6 week, 12 week and 11-12 month old schedule.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 3310 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 9092 0
2145 - Westmead
Recruitment postcode(s) [2] 9093 0
2112 - Ryde

Funding & Sponsors
Funding source category [1] 290523 0
Charities/Societies/Foundations
Name [1] 290523 0
Financial Markets Foundation for Children
Address [1] 290523 0
Foundation for Children
PO Box 3655
Sydney NSW 2000
Country [1] 290523 0
Australia
Primary sponsor type
Hospital
Name
The Sydney Children's Hospitals Network
Address
The Children's Hospital at Westmead
Locked bag 4001
Westmead
NSW 2145
Country
Australia
Secondary sponsor category [1] 290561 0
Hospital
Name [1] 290561 0
The Sydney Children's Hospitals Network
Address [1] 290561 0
The Children's Hospital at Westmead
Locked bag 4001
Westmead NSW 2145
Country [1] 290561 0
Australia
Other collaborator category [1] 278588 0
Commercial sector/Industry
Name [1] 278588 0
GlaxoSmithKline Biologicals
Address [1] 278588 0
Level 4, 436 Johnston Street, Abbotsford, Victoria, 3067
Country [1] 278588 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292173 0
The Sydney Children's Hospitals Network Human Research Ethics Committee
Ethics committee address [1] 292173 0
The Children's Hospital at Westmead
Locked bag 4001
Westmead
NSW 2145
Ethics committee country [1] 292173 0
Australia
Date submitted for ethics approval [1] 292173 0
Approval date [1] 292173 0
19/04/2013
Ethics approval number [1] 292173 0
12SCHN223

Summary
Brief summary
This study aims to protect infants and young children from whooping cough, also known as pertussis, by finding a more effective timing for immunisations. Possibly the best way to prevent whooping cough in early infancy and also in 3-5 year olds may be by a vaccine schedule consisting of two early doses in infancy (6 and 12 weeks old) and a third dose at 11-12 months old.

This study aims to look at whether an alternate pertussis vaccination schedule (given at 6 weeks, 12 weeks and 11-12 months old), gives the same immune protection as the current pertussis vaccination schedule (at 6 weeks, 4 months and 6 months old).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 52606 0
Dr Nicholas Wood
Address 52606 0
National Centre for Immunisation Research
The Children's Hospital at Westmead
Locked bag 4001
Westmead
NSW 2145
Country 52606 0
Australia
Phone 52606 0
+61298450000
Fax 52606 0
+61298451418
Email 52606 0
nicholas.wood@health.nsw.gov.au
Contact person for public queries
Name 52607 0
Dr Nicholas Wood
Address 52607 0
National Centre for Immunisation Research
The Children's Hospital at Westmead
Locked bag 4001
Westmead
NSW 2145
Country 52607 0
Australia
Phone 52607 0
+61298450000
Fax 52607 0
+61298451418
Email 52607 0
nicholas.wood@health.nsw.gov.au
Contact person for scientific queries
Name 52608 0
Dr Nicholas Wood
Address 52608 0
National Centre for Immunisation Research
The Children's Hospital at Westmead
Locked bag 4001
Westmead
NSW 2145
Country 52608 0
Australia
Phone 52608 0
+61298450000
Fax 52608 0
+61298451418
Email 52608 0
nicholas.wood@health.nsw.gov.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary