The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12614001325695
Ethics application status
Approved
Date submitted
21/11/2014
Date registered
17/12/2014
Date last updated
9/11/2015
Type of registration
Retrospectively registered

Titles & IDs
Public title
Follow up of immunogenicity and safety of acellular pertussis vaccine given at birth to 4 years of age
Scientific title
In 4 year old children, does having received a birth dose of acellular pertussis vaccine compared to not having received a birth dose of acellular pertussis vaccine affect immunogenicity and safety before and after a booster dose of an acellular pertussis vaccine.
Secondary ID [1] 285719 0
Nil
Universal Trial Number (UTN)
U1111-1164-4349
Trial acronym
Nil
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pertussis immunogenicity 293601 0
Condition category
Condition code
Inflammatory and Immune System 293887 293887 0 0
Normal development and function of the immune system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All study participants in the intervention group will be vaccinated with acellular pertussis vaccine at 4 years of age. The intervention group refers to the study allocation from phase I of the study (already occurred), that is, those subjects who received a birth dose of monovalent acellular pertussis vaccine.

The intervention subgroup who received a booster dose of Infanrix-IPV (Registered trademark) (DTPa-IPV) at 18 months will receive the same Infanrix-IPV (Registered trademark) (DTPa-IPV) for the 4 year old booster dose.

The intervention subgroup who received Boostrix-IPV (Registered trademark) (dTpa-IPV) at 18 months will receive the same Boostrix-IPV (Registered trademark) (dTpa-IPV) for the 4 year old booster dose.

The intervention subgroup who did not receive any booster dose at 18 months old, will receive Infanrix-IPV (Registered trademark) (DTPa-IPV) for the 4 year old booster dose.

All participants in the intervention group will also be vaccinated at 4 years old with the measles-mumps-rubella vaccine (M-M-R-II), which is due according to the Australian Immunisation Schedule, but is not the study intervention.

Vaccine product information:
1. Infanrix-IPV (Registered trademark) (DTPa-IPV) will be administered, by intramuscular injection. Infanrix-IPV (diphtheria-tetanus-acellular pertussis-inactivated poliovirus).

Each 0.5 ml dose contains 30 IU diphtheria toxoid, 40 IU tetanus toxoid, 25 ug pertussis toxoid, 25 ug filamentous haemagglutinin, 8 ug pertactin, 40 D-antigen units inactivated poliovirus type 1 (Mahoney), 8 D-antigen units type 2 (MEF-1) and 32 D-antigen units type 3 (Saukett), adsorbed onto aluminium hydroxide; traces of formaldehyde, polysorbate 80, polymyxin and neomycin.

2. Boostrix-IPV (Registered trademark) (dTpa-IPV) will be administered, by intramuscular injection. Boostrix-IPV (diphtheria-tetanus-acellular pertussis-inactivated poliovirus).

Each 0.5 ml dose contains 2 IU diphtheria toxoid, 20 IU tetanus toxoid, 8 ug pertussis toxoid, 8 ug filamentous haemagglutinin, 2.5 ug pertactin, 40 D-antigen units inactivated poliovirus type 1 (Mahoney), 8 D-antigen units type 2 (MEF-1) and 32 D-antigen units type 3 (Saukett), adsorbed onto aluminium hydroxide and aluminium phosphate; traces of formaldehyde, polysorbate 80, polymyxin and neomycin.

3. M-M-R II (live attenuated measles virus [Schwarz strainEnders’ attenuated Edmonston strain], mumps virus [RIT 4385 strain, derived from the Jeryl Lynn B level strain] and rubella virus [Wistar RA 27/3 strain]) will be administered by intramuscular injection. Lyophilised pellet in a monodose vial with separate diluenta pre-filled diluent syringe. Each 0.5 ml reconstituted dose contains 10003.0 tissuecell culture infectious dose 50% (TCCID50) of the Schwarz Enders’ attenuated Edmonston measles virus, 12 50003.7 TCCID50 of the RIT 4385Jeryl Lynn B level mumps virus, and 10003.0 TCCID50 of the Wistar RA 27/3 rubella virus; lactose; neomycin; sorbitol; sucrose; hydrolysed gelatin; human albumin; fetal bovine serum; neomycinmannitol.
Intervention code [1] 290677 0
Prevention
Comparator / control treatment
All study participants in the control group will be vaccinated with an acellular pertussis vaccine at 4 years of age. The control group refers to study allocation from phase I of the study (already occurred), that is, those subjects who did not receive a birth dose of monovalent acellular pertussis vaccine.

The control subgroup who received a booster dose of Infanrix-IPV (Registered trademark) (DTPa-IPV) at 18 months will receive the same Infanrix-IPV (Registered trademark) (DTPa-IPV) for the 4 year old booster dose.

The control subgroup who received Boostrix-IPV (Registered trademark) (dTpa-IPV) at 18 months will receive the same Boostrix-IPV (Registered trademark) (dTpa-IPV) for the 4 year old booster dose.

The control subgroup who did not receive any booster dose at 18 months old, will receive Infanrix-IPV (Registered trademark) (DTPa-IPV) for the 4 year old booster dose.

All participants in the control group will also be vaccinated at 4 years old with the measles-mumps-rubella vaccine, M-M-R-II, which is due according to the Australian Immunisation Schedule, but is not the study intervention.

Vaccine product information:
1. Infanrix-IPV (Registered trademark) (DTPa-IPV) will be administered, by intramuscular injection. Infanrix-IPV (diphtheria-tetanus-acellular pertussis-inactivated poliovirus).

Each 0.5 ml dose contains 30 IU diphtheria toxoid, 40 IU tetanus toxoid, 25 ug pertussis toxoid, 25 ug filamentous haemagglutinin, 8 ug pertactin, 40 D-antigen units inactivated poliovirus type 1 (Mahoney), 8 D-antigen units type 2 (MEF-1) and 32 D-antigen units type 3 (Saukett), adsorbed onto aluminium hydroxide; traces of formaldehyde, polysorbate 80, polymyxin and neomycin.

2. Boostrix-IPV (Registered trademark) (dTpa-IPV) will be administered, by intramuscular injection. Boostrix-IPV (diphtheria-tetanus-acellular pertussis-inactivated poliovirus).

Each 0.5 ml dose contains 2 IU diphtheria toxoid, 20 IU tetanus toxoid, 8 ug pertussis toxoid, 8 ug filamentous haemagglutinin, 2.5 ug pertactin, 40 D-antigen units inactivated poliovirus type 1 (Mahoney), 8 D-antigen units type 2 (MEF-1) and 32 D-antigen units type 3 (Saukett), adsorbed onto aluminium hydroxide and aluminium phosphate; traces of formaldehyde, polysorbate 80, polymyxin and neomycin.

3. M-M-R II (live attenuated measles virus [Schwarz strainEnders’ attenuated Edmonston strain], mumps virus [RIT 4385 strain, derived from the Jeryl Lynn B level strain] and rubella virus [Wistar RA 27/3 strain]) will be administered by intramuscular injection. Lyophilised pellet in a monodose vial with separate diluenta pre-filled diluent syringe. Each 0.5 ml reconstituted dose contains 10003.0 tissuecell culture infectious dose 50% (TCCID50) of the Schwarz Enders’ attenuated Edmonston measles virus, 12 50003.7 TCCID50 of the RIT 4385Jeryl Lynn B level mumps virus, and 10003.0 TCCID50 of the Wistar RA 27/3 rubella virus; lactose; neomycin; sorbitol; sucrose; hydrolysed gelatin; human albumin; fetal bovine serum; neomycinmannitol.
Control group
Dose comparison

Outcomes
Primary outcome [1] 293668 0
To compare surrogate measures of protection (absolute serum IgG concentration of anti-Pertussis Toxin (PT), anti-pertactin and anti-filamentous hemagglutinin (FHA) will be measured by ELISA in serum samples at MIPR laboratory CDC using a well-standardised assay) against pertussis before and after a DTPa-IPV or dTpa-IPV booster vaccine at 4 years old in children previously recruited to a randomised trial of acellular pertussis (Pa) vaccine at birth.
Timepoint [1] 293668 0
At the time of 4 year old vaccination (baseline) and 1 month after (28-42 days post visit 1).
Secondary outcome [1] 311538 0
To compare adverse reactions and frequency between the study subgroups following the 4 year old pertussis boosting schedule.

Known and possible adverse reactions to the pertussis containing vaccines, DTap and dTap, include local site reactions such as redness, swelling, hardness and pain, and systemic reactions such as fever, headache, chills, vomiting, diarrhoea, loss of appetite, drowsiness, generalized muscle aches and joint aches. These possible side effects will be screened for by the use of a daily diary card to be completed by the parent for the first seven days after administration of vaccination with respect to specific symptoms and signs as well as a separate general 30 day (28-42 days post visit 1) diary card to record general symptoms and illnesses as well as medication use. In addition, limb swelling will be monitored by means of daily limb circumference measurements performed and recorded on the 7 day diary card by the parent again for the first seven days after vaccination. These diary cards will then be collected and reviewed at the followup visit at 1 month after vaccination. A followup phone call to the parents will also be completed in the 2-7 days post-immunization time frame to ensure that no serious adverse effects have occurred.
Timepoint [1] 311538 0
The secondary timepoint will consist of the 7 day period after vaccination with the use of a 7 day specific symptom diary card as well as the 1 month interval (28-42 days post visit 1) between visit one and visit two with the use of a general 30 day diary card to record general symptoms, illnesses and medication use during this period.
Secondary outcome [2] 311539 0
To evaluate antibodies to other concomitantly administered vaccine antigens before and after a 4 year old pertussis boosting schedule. Specifically, absolute serum IgG concentration of anti-tetanus, anti-diphtheria and anti-polio (serotypes 1, 2, 3) antibodies will be measured at MIPR laboratory CDC using well-standardised ELISA assays.
Timepoint [2] 311539 0
At the time of 4 year old vaccination (baseline) and 1 month after (28-42 days post visit 1).

Eligibility
Key inclusion criteria
Children who are between 4 years and 4 years 364 days old are eligible to participate in this study and who are subjects previously enrolled in the First Phase study.
(ACTRN12609000905268)
Minimum age
4 Years
Maximum age
5 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Contraindications to vaccination as listed in the current NHMRC Australian Immunisation Handbook 10th Edition or as listed in the Infanrix-IPV or Boostrix-IPV Product Information. DTPa-IPV or dTpa-IPV 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).
2. Evidence of a second booster diphtheria, tetanus, pertussis vaccination since completion of the first booster vaccine at 18- 24 months old.
3. Administration of immunoglobulins or any blood products within the 3 month period prior to the first visit; in which case, a delay in enrolment will be considered in the absence of other excluding criteria.
4. Any confirmed or suspected immunosuppressive or immunodeficient condition contraindicating MMR vaccination.
5. History of serious chronic illness or condition which in the judgement of the clinical investigator would preclude study participation.
6. History of neurologic disease or seizure (excluding simple febrile seizure).
7. Must not have had the vaccinations scheduled for age 4 years (ie Infanrix-IPV and measles mumps rubella vaccine).

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)
Potential subjects will be contacted from a database of original study subjects from the Immunogenicity and safety of acellular pertussis vaccine at birth trial.

Eligible participants must meet inclusion and exclusion criteria at the time of enrolment and informed consent must be obtained from the parent/carer.

Treatment allocation depends on whether they participated in the second phase study, Persistence of immunity and response to a booster dose of DTPa or dTpa vaccine at 18 months old following acellular pertussis vaccine given at birth in healthy infants. If they participated, then the diphtheria-tetanus-acellular pertussis-polio vaccine they will receive at 4 years of age will be the same as what they received at the 18 month old trial. If they did not participate in the 18 month trial, then the subjects will receive Infanrix-IPV.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Subjects will not be randomised.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
This study is open and not blinded. It will maintain group allocation determined in the second phase (Persistence of immunity and response to a booster dose of DTPa or dTpa vaccine at 18 months old following acellular pertussis vaccine given at birth in healthy infants) study.
Phase
Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Immunogenicity: Continuous (geometric mean antibody concentration) and categorical (presumptive threshold) measures of antibodies to pertussis and other contemporaneously administered antigens will be examined. All serum antibody concentrations will be log transformed for statistical analysis as geometric mean concentrations (GMC) with 95% confidence limits. Where protective thresholds are well-established, the proportions with 95% confidence limits at or above the assay cut off will be calculated – anti-diphtheria (0.1 IU/ml)*, anti-tetanus (0.1 IU/ml). Between-group comparisons will be performed using appropriate statistical methods e.g. t-tests for comparisons of continuous data; Chi square tests for comparisons of categorical data.
Note: * this threshold is significantly above the known protective level of 0.01 IU/ml but is the lower limit of assay detection.

Safety and reactogenicity: descriptive analyses will be performed on the number, type and severity of local and systemic reactions and severe adverse reactions that occur following vaccination and presented by treatment group. Comparisons between groups will be performed using Student’s T-Test for continuous variables and chi-square tests for proportions.

With respect to sample size calculations, in the first phase study, a total of 221 subjects received Pa vaccine at birth (Groups 1-3) and 219 no Pa vaccine at birth (Groups 4-6). Therefore, it is estimated that allowing for 25% drop out, approximately 300 children may be available for follow up at 4 years.

The sample sizes for the third phase subgroups are based on the goal of comparing pertussis immunogenicity endpoints pre and post-4 year booster vaccine between Pa at birth recipients and no Pa vaccine at birth.

Groups sizes of 95 subjects each were calculated to achieve 90% power to detect non-inferiority in GMCs for antibodies to all pertussis antigens, using a one-sided, two-sample t-test, with a significance level of 0.025.

Groups sizes of 80 subjects each were calculated to achieve 80% power to detect non-inferiority in GMCs for antibodies to all pertussis antigens, using a one-sided, two-sample t-test, with a significance level of 0.025.

Recruitment
Recruitment status
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,SA,WA,VIC
Recruitment hospital [1] 3196 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [2] 3197 0
Womens and Childrens Hospital - North Adelaide
Recruitment hospital [3] 3198 0
Princess Margaret Hospital - Subiaco
Recruitment hospital [4] 4598 0
The Royal Childrens Hospital - Parkville
Recruitment postcode(s) [1] 8977 0
2145 - Westmead
Recruitment postcode(s) [2] 8978 0
5006 - North Adelaide
Recruitment postcode(s) [3] 8979 0
6840 - Perth
Recruitment postcode(s) [4] 12202 0
3052 - Parkville

Funding & Sponsors
Funding source category [1] 290295 0
Commercial sector/Industry
Name [1] 290295 0
GlaxoSmithKline Biologicals
Address [1] 290295 0
GSK
Level 4, 436 Johnston Street, Abbotsford, Victoria, 3067.
PO Box 18095, Melbourne, Victoria, 8003.
Country [1] 290295 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] 289005 0
Individual
Name [1] 289005 0
A/Prof Helen Marshall
Address [1] 289005 0
Vaccinology and Immunology Research Trials Unit
Discipline of Paediatrics
Women's and Children's Hospital
72 King William Rd
North Adelaide SA 5006
Country [1] 289005 0
Australia
Secondary sponsor category [2] 289006 0
Individual
Name [2] 289006 0
A/Prof Peter Richmond
Address [2] 289006 0
Vaccine Trials Group, Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute
Co-Director, Wesfarmers Centre of Vaccines and Infectious Diseases
Consultant Paediatric Immunologist and Paediatrician,
Princess Margaret Hospital for Children
GPO Box D184
Perth WA 6840
Country [2] 289006 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292003 0
The Sydney Children's Hospitals Network Human Research and Ethics Committee
Ethics committee address [1] 292003 0
Locked bag 4001
Westmead
NSW 2145
Ethics committee country [1] 292003 0
Australia
Date submitted for ethics approval [1] 292003 0
12/05/2014
Approval date [1] 292003 0
26/08/2014
Ethics approval number [1] 292003 0
HREC/14/SCHN/198

Summary
Brief summary
This study is the third phase follow up at 4 years of age of subjects who received neonatal acellular pertussis vaccination. This study looks at safety and immunogenicity of pertussis vaccination, and extends knowledge from the first phase (birth to 13 months) and the second phase (18-24 months).
Trial website
There is no trial website.
Trial related presentations / publications
There have been no trial related presentations or publications as yet.
Public notes

Contacts
Principal investigator
Name 53002 0
Dr Nicholas Wood
Address 53002 0
National Centre for Immunisation Research and Surveillance of Vaccine Preventable Diseases
The Children's Hospital at Westmead
Locked bag 4001
Westmead
NSW 2145
Country 53002 0
Australia
Phone 53002 0
+61298451433
Fax 53002 0
+61298451418
Email 53002 0
nicholas.wood@health.nsw.gov.au
Contact person for public queries
Name 53003 0
Dr Nicholas Wood
Address 53003 0
National Centre for Immunisation Research and Surveillance of Vaccine Preventable Diseases
The Children's Hospital at Westmead
Locked bag 4001
Westmead
NSW 2145
Country 53003 0
Australia
Phone 53003 0
+61298451433
Fax 53003 0
+61298451418
Email 53003 0
nicholas.wood@health.nsw.gov.au
Contact person for scientific queries
Name 53004 0
Dr Nicholas Wood
Address 53004 0
National Centre for Immunisation Research and Surveillance of Vaccine Preventable Diseases
The Children's Hospital at Westmead
Locked bag 4001
Westmead
NSW 2145
Country 53004 0
Australia
Phone 53004 0
+61298451433
Fax 53004 0
+61298451418
Email 53004 0
nicholas.wood@health.nsw.gov.au

No information has been provided regarding IPD availability
Summary results
No Results