Immunogenicity and Safety of Kinrix + (Measles Mumps Rubella) MMR Vaccine With and Without Varicella Vaccine in Healthy Children 4-6 Years

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00871117
• Collaborator: (none)
• Enrollment: 478
• Locations: 11
• Arms: 2
• Duration (Months): 14.5
• Patients Per Site: 43.5
• Patients Per Site Per Month: 3

Study Details

Study Description

Brief Summary

The purpose of the study is to evaluate the immunogenicity and safety of Kinrix when co-administered with varicella (Varivax® [varicella virus vaccine live], Merck and Company) and (measles mumps rubella) MMR vaccines, compared to Kinrix co-administered with MMR vaccine alone. Both Kinrix and the second dose of Varivax are indicated in children 4-6 years of age, and there is great potential for the vaccines to be given concurrently. The aim of this trial is to demonstrate that co-administered Varivax does not negatively affect the immunogenicity or reactogenicity of Kinrix.

Condition or Disease	Intervention/Treatment	Phase
Tetanus; Acellular Pertussis; Diphtheria	Biological: GSK Biologicals'Kinrix®; Biological: Merck and Company's MMRII; Biological: Merck and Company's Varivax	Phase 3

Detailed Description

Subjects 4-6 years of age will be randomized into two groups to receive either Kinrix, Varivax and M-M-RII on day 0 (Group 1) or Kinrix and M-M-RII on day 0 and Varivax at month 1(Group 2).

All subjects in both groups to provide blood samples prior to vaccination on day 0 and at month 1 (for Group 2, blood sampling is prior to vaccination with Varivax).

Duration of the study will be approximately 6 months for each subject with a safety telephone contact 6 months after vaccinations.

Study Design

• Study Type: Interventional
• Actual Enrollment: 478 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Immunogenicity and Safety Study of Kinrix® Co-administered With Varivax®
• Study Start Date: Mar 31, 2009
• Actual Primary Completion Date: Jan 15, 2010
• Actual Study Completion Date: Jun 15, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Kinrix + M-M-R II + Varivax Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II and Varivax each, subcutaneously in the deltoid of the right upper and lower arm, respectively.	Biological: GSK Biologicals'Kinrix®; One dose as intramuscular injection at visit 1; Biological: Merck and Company's MMRII; One dose as subcutaneous injection at visit 1; Biological: Merck and Company's Varivax; One dose as subcutaneous injection at visit 1 or at visit 2
Active Comparator: Kinrix + M-M-R II -> Varivax Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II, subcutaneously in the deltoid of the right upper arm. At Day 30 they received one dose of Varivax subcutaneously in the deltoid region of the right upper arm.	Biological: GSK Biologicals'Kinrix®; One dose as intramuscular injection at visit 1; Biological: Merck and Company's MMRII; One dose as subcutaneous injection at visit 1; Biological: Merck and Company's Varivax; One dose as subcutaneous injection at visit 1 or at visit 2

Outcome Measures

Primary Outcome Measures

1. Number of Subjects With Booster Responses to Diphteria and Tetanus [One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.]

   Anti-diphteria (anti-D) and anti-tetanus (anti-T) booster response was defined as: initially seronegative subjects (sero-) (pre-booster antibody concentration below cut-off of < 0.1 international units per milliliter (IU/mL)) with an increase of at least four times the cut-off one month after vaccination (post-booster antibody concentration ≥0.4 IU/mL) initially seropositive subjects (sero+) (pre-booster antibody concentration ≥0.1 IU/mL) with an increase of at least four times the pre-booster antibody concentration one month after vaccination

2. Number of Subjects With Anti-pertussis Toxoid (Anti-PT), Anti-filamentous Hemagglutinin (FHA) and Anti-pertactin (Anti-PRN) Booster Responses, Measured in Enzyme-Linked Immunosorbent Assay Units Per Milliliter (EL.U/mL) [One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.]

   anti-PT, anti-FHA and anti-PRN booster response : initially sero- (pre-booster antibody concentration below cut-off < 5.0 EL.U/mL) with increase of at least four times cut-off one month after vaccination (concentration post-booster ≥20.0 EL.U/mL) initially sero+ with pre-booster antibody concentration ≥5.0 EL.U/mL and < 20.0 EL.U/mL with increase of at least four times pre-booster concentration one month post-booster initially sero+ with pre-booster antibody concentration ≥20.0 EL.U/mL with an increase of at least two times the pre-booster antibody concentration one month post-booster

3. Geometric Mean Titers (GMTs) for Antibodies to Poliovirus Types 1, 2 and 3 [One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.]

   Titers are expressed as GMTs.

Secondary Outcome Measures

1. Number of Subjects With Anti-D and Anti-T Antibody Concentrations Above Cut-off Value [One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.]

   Cut-off value was defined as greater than or equal to 1.0 international units per milliliter (IU/mL).

2. Geometric Mean Concentrations (GMCs) for Anti-D and Anti-T Antibodies [One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.]

   Concentrations were expressed as GMCs in IU/mL.

3. GMCs for Anti-PT, Anti-FHA, Anti-PRN Antibodies [One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.]

   Concentrations are expressed as GMCs in Enzyme-Linked Immunosorbent Assay (ELISA) Units per milliliter (EL.U/mL).

4. Number of Subjects With an Anti-polio 1, 2, 3 Booster Response [One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.]

   Anti-poliovirus 1, anti-poliovirus 2 and anti-poliovirus 3 booster response: initially seronegative subjects (pre-booster antibody titer below cut-off of 8 ED50) with an antibody titer ≥ 32 ED50 one month after vaccination initially seropositive subjects (pre-booster antibody titers ≥ 8 ED50) with an increase at least four times the pre-booster antibody titer one month after vaccination. ED50 is defined here as the reverse of the dilution resulting in 50% inhibition. The lowest dilution at which serum samples were tested is 1:8 from which a test was considered positive.

5. Number of Subjects Seroprotected Against Diphteria and Tetanus [One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.]

   Seroprotection status was defined as: anti-D antibody concentration greater than or equal to 0.1 IU/mL anti-T antibody concentration greater than or equal to 0.1 IU/mL

6. Number of Subjects Protected Against Poliovirus 1, 2 and 3 [One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.]

   Seroprotection was defined: * anti-poliovirus type 1, 2 or 3 antibody titer greater than or equal to 8 ED50. ED50 is defined here as the reverse of the dilution resulting in 50% inhibition.

7. Number of Subjects Seropositive for Anti-PT, Anti-FHA and Anti-PRN Antibodies [One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.]

   Seropositivity was defined as a concentration greater than or equal to 5.0 EL.U/mL

8. Number of Subjects With Any Solicited Local Symptoms [Within 4 days (Day 0 to 3) after booster immunization * for Kinrix + M-M-R II -> Varivax Group before vaccination with Varivax]

   Solicited local symptoms included pain, redness and swelling at the injection site. Any was defined as incidence of a particular symptom regardless of intensity grade.

9. Number of Subjects With Any Solicited General Symptoms [Within 4 days (Day 0 to 3) after booster immunization * for Kinrix + M-M-R II -> Varivax Group before vaccination with Varivax]

   Solicited general symptoms included fever [temperature equal to or greater than 37.5 degrees Celsius (°C)], drowsiness and loss of appetite. Any was defined as incidence of a particular symptom regardless of intensity grade.

10. Number of Subjects With Unsolicited Adverse Events [Up to 31 days (Day 0 through Day 30) after booster vaccination * for Kinrix + M-M-R II -> Varivax Group before vaccination with Varivax]

    An unsolicited adverse event is any adverse event (i.e. any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product) reported in addition to those solicited during the clinical study. Also any "solicited" symptom with onset outside the specified period of follow-up for solicited symptoms will be reported as an unsolicited adverse event.

11. Number of Subjects With Serious Adverse Events (SAEs) [During the entire study period (from Day 0 to 6 months post-vaccination)]

    Serious adverse events are medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 4 Years to 6 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Subjects for whom the investigator believes that their parents/ guardians can and will comply with the requirements of the protocol.

• A male or female child between 4 and 6 years of age, inclusive.

• Written informed consent obtained from the parent or guardian of the subject.

• Healthy subjects as established by medical history and clinical examination before entering into the study.

• Having received 4 doses of (Diphtheria, Tetanus Acellular Pertussis) DTaP vaccine using Pediarix and/or Infanrix, and 3 doses of poliovirus vaccine using Pediarix and/or (inactivated poliovirus vaccine, Aventis Pasteur) IPOL in the first 2 years of life.

• Previously received 1 dose of M-M-RII and Varivax (separate or combined) in the second year of life.

Exclusion Criteria:

• Use of any investigational or non-registered drug or vaccine other than the study vaccines within 30 days preceding the administration of study vaccines, or planned use during the study period.

• Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or non-investigational product or device.

• History of previous or intercurrent diphtheria, tetanus, pertussis, polio, measles, mumps, rubella or varicella disease, or of vaccination against these diseases given after the second year of life.

• Known exposure to diphtheria, tetanus, pertussis, or polio, prior to vaccination.

• Poliovirus vaccination with one or more doses of (oral polio virus) OPV vaccine.

• Administration or planned administration of a vaccine not foreseen by the study protocol within 30 days of study vaccination and ending at Day 30.

• Chronic administration or planned administration of immunosuppressants or other immune modifying drugs within six months prior to study vaccination or planned administration during the study period ending at Day 30.

• Administration of immunoglobulins and/or any blood products at any time prior to study vaccination or planned administration during the study period ending at Day 30.

• Any confirmed or suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection.

• History of seizures or progressive neurological disorder, including infantile spasms, uncontrolled epilepsy or progressive encephalopathy.

• Major congenital defects or serious chronic illness.

• Acute disease at the time of enrolment.

• History of allergic disease or reactions likely to be exacerbated by any component of the vaccine(s).

• History of anaphylactic reaction to egg proteins or previous doses of the vaccine(s).

• Encephalopathy within 7 days of administration of previous dose of Infanrix or Pediarix.

• Fever >=40.5°C or 104.9°F (rectal temperature) (39.5°C or 103.1°F, oral/axillary) within 48 hours of previous dose of Infanrix or Pediarix not due to another identifiable cause.

• Collapse or shock-like state within 48 hours of previous dose of DTaP or DTaP-containing vaccine.

• Persistent, severe, inconsolable screaming or crying lasting ³3 hours occurring within 48 hours of administration of previous dose of DTaP or DTaP-containing vaccine.

• Thrombocytopenia following a previous dose of M-M-RII or its component vaccines

• Inability to contact a parent/guardian of the subject by telephone.

• Blood dyscrasias, leukemia, lymphomas or other malignant neoplasms affecting the bone marrow or lymphatic systems.

• Family history of congenital or hereditary immunodeficiency, unless the immune competence of the subject has been demonstrated.

• Residence in the same household as the following persons:

• New-born infants (0-4 weeks of age).

• Pregnant mother/women without documented positive history of chickenpox disease or laboratory evidence of prior varicella vaccination.

• Pregnant women at or beyond 28 weeks gestation regardless of varicella vaccination status or varicella disease history.

• Persons with known immunodeficiency.

• Active untreated tuberculosis.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Antioch	California	United States	94509
2	GSK Investigational Site	Daly City	California	United States	94015
3	GSK Investigational Site	Hayward	California	United States	94545
4	GSK Investigational Site	Redwood City	California	United States	94063
5	GSK Investigational Site	Roseville	California	United States	95661
6	GSK Investigational Site	Sacramento	California	United States	95815
7	GSK Investigational Site	Sacramento	California	United States	95823
8	GSK Investigational Site	San Jose	California	United States	95119
9	GSK Investigational Site	Santa Rosa	California	United States	95403
10	GSK Investigational Site	Vallejo	California	United States	94589
11	GSK Investigational Site	Walnut Creek	California	United States	94596

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Publications

• Klein NP, Weston WM, Kuriyakose S, Kolhe D, Howe B, Friedland LR, Van Der Meeren O. An open-label, randomized, multi-center study of the immunogenicity and safety of DTaP-IPV (Kinrix™) co-administered with MMR vaccine with or without varicella vaccine in healthy pre-school age children. Vaccine. 2012 Jan 11;30(3):668-74. doi: 10.1016/j.vaccine.2011.10.065. Epub 2011 Nov 4.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT00871117
• Other Study ID Numbers: 111852
• First Posted: Mar 30, 2009
• Last Update Posted: Aug 22, 2018
• Last Verified: Jun 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by GlaxoSmithKline: Co-administration; Immunization; Preschool; Booster
• Additional relevant MeSH terms: Diphtheria

Study Results

Participant Flow

Pre-assignment Detail	478 subjects were enrolled, but 2 subjects who received a subject number were not vaccinated. Therefore the total amount of subjects used for the analysis was 476.

Arm/Group Title	Kinrix + M-M-R II + Varivax	Kinrix + M-M-R II -> Varivax
Arm/Group Description	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II and Varivax each, subcutaneously in the deltoid of the right upper and lower arm, respectively.	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II, subcutaneously in the deltoid of the right upper arm. At Day 30 they received one dose of Varivax subcutaneously in the deltoid region of the right upper arm.
Period Title: Overall Study
STARTED	239	237
COMPLETED	234	227
NOT COMPLETED	5	10

Baseline Characteristics

Arm/Group Title	Kinrix + M-M-R II + Varivax	Kinrix + M-M-R II -> Varivax	Total
Arm/Group Description	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II and Varivax each, subcutaneously in the deltoid of the right upper and lower arm, respectively.	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II, subcutaneously in the deltoid of the right upper arm. At Day 30 they received one dose of Varivax subcutaneously in the deltoid region of the right upper arm.	Total of all reporting groups
Overall Participants	239	237	476
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	4.2 (0.41)	4.2 (0.37)	4.2 (0.39)
Sex: Female, Male (Count of Participants)
Female	129 54%	123 51.9%	252 52.9%
Male	110 46%	114 48.1%	224 47.1%
Race/Ethnicity, Customized (Count of Participants)
African Heritage / African American	27 11.3%	23 9.7%	50 10.5%
American Indian or Alaskan Native	35 14.6%	33 13.9%	68 14.3%
Asian - Central/South Asian Heritage	7 2.9%	11 4.6%	18 3.8%
Asian - East Asian Heritage	3 1.3%	5 2.1%	8 1.7%
Asian - South East Asian Heritage	13 5.4%	17 7.2%	30 6.3%
Native Hawaiian or Other Pacific Islander	2 0.8%	3 1.3%	5 1.1%
White - Arabic / North African Heritage	1 0.4%	6 2.5%	7 1.5%
White - Caucasian / European Heritage	109 45.6%	107 45.1%	216 45.4%
Unspecified	42 17.6%	32 13.5%	74 15.5%

Outcome Measures

1. Primary Outcome

Title	Number of Subjects With Booster Responses to Diphteria and Tetanus
Description	Anti-diphteria (anti-D) and anti-tetanus (anti-T) booster response was defined as: initially seronegative subjects (sero-) (pre-booster antibody concentration below cut-off of < 0.1 international units per milliliter (IU/mL)) with an increase of at least four times the cut-off one month after vaccination (post-booster antibody concentration ≥0.4 IU/mL) initially seropositive subjects (sero+) (pre-booster antibody concentration ≥0.1 IU/mL) with an increase of at least four times the pre-booster antibody concentration one month after vaccination
Time Frame	One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.

Outcome Measure Data

Analysis Population Description

Analysis was performed on the according-to-protocol (ATP) cohort for immunogenicity, which included all evaluable subjects for whom immunogenicity data were available for antibodies against at least one study vaccine antigen component after vaccination.

Arm/Group Title	Kinrix + M-M-R II + Varivax	Kinrix + M-M-R II -> Varivax
Arm/Group Description	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II and Varivax each, subcutaneously in the deltoid of the right upper and lower arm, respectively.	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II, subcutaneously in the deltoid of the right upper arm. At Day 30 they received one dose of Varivax subcutaneously in the deltoid region of the right upper arm.
Measure Participants	211	209
Anti-D	209 87.4%	207 87.3%
Anti-T	208 87%	203 85.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Kinrix + M-M-R II + Varivax, Kinrix + M-M-R II -> Varivax
	Comments	To demonstrate the non-inferiority of DTaP-IPV vaccine co-administered with Varicella and MMR vaccines compared to DTaP-IPV vaccine co-administered with MMR only in terms of diphtheria (D) booster response one month after vaccination with DTaP-IPV vaccine.
	Type of Statistical Test	Non-Inferiority
	Comments	Lower limit of the standardized asymptotic 95% confidence interval (CI) for the between-group differences in booster response to diphtheria was greater than or equal to (≥)-10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in booster response rates
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -2.54 to 2.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Kinrix + M-M-R II + Varivax, Kinrix + M-M-R II -> Varivax
	Comments	To demonstrate the non-inferiority of DTaP-IPV vaccine co-administered with Varicella and MMR vaccines compared to DTaP-IPV vaccine co-administered with MMR only in terms of tetanus (T) booster response one month after vaccination with DTaP-IPV vaccine.
	Type of Statistical Test	Non-Inferiority
	Comments	Lower limit of the standardized asymptotic 95% CI for the between-group differences in booster response to tetanus was ≥ -10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in booster response rates
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95%; -1.99 to 4.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Number of Subjects With Anti-pertussis Toxoid (Anti-PT), Anti-filamentous Hemagglutinin (FHA) and Anti-pertactin (Anti-PRN) Booster Responses, Measured in Enzyme-Linked Immunosorbent Assay Units Per Milliliter (EL.U/mL)
Description	anti-PT, anti-FHA and anti-PRN booster response : initially sero- (pre-booster antibody concentration below cut-off < 5.0 EL.U/mL) with increase of at least four times cut-off one month after vaccination (concentration post-booster ≥20.0 EL.U/mL) initially sero+ with pre-booster antibody concentration ≥5.0 EL.U/mL and < 20.0 EL.U/mL with increase of at least four times pre-booster concentration one month post-booster initially sero+ with pre-booster antibody concentration ≥20.0 EL.U/mL with an increase of at least two times the pre-booster antibody concentration one month post-booster
Time Frame	One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.

Outcome Measure Data

Analysis Population Description

Analysis was performed on the according-to-protocol (ATP) cohort for immunogenicity, which included all evaluable subjects for whom immunogenicity data were available for antibodies against at least one study vaccine antigen component after vaccination.

Arm/Group Title	Kinrix + M-M-R II + Varivax	Kinrix + M-M-R II -> Varivax
Arm/Group Description	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II and Varivax each, subcutaneously in the deltoid of the right upper and lower arm, respectively.	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II, subcutaneously in the deltoid of the right upper arm. At Day 30 they received one dose of Varivax subcutaneously in the deltoid region of the right upper arm.
Measure Participants	220	212
Anti-PT	207 86.6%	201 84.8%
Anti-FHA	213 89.1%	209 88.2%
Anti-PRN	220 92.1%	209 88.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Kinrix + M-M-R II + Varivax, Kinrix + M-M-R II -> Varivax
	Comments	To demonstrate the non-inferiority of DTaP-IPV vaccine co-administered with Varicella and MMR vaccines compared to DTaP-IPV vaccine co-administered with MMR only in terms of pertussis toxoid (PT) booster response one month after vaccination with DTaP-IPV vaccine.
	Type of Statistical Test	Non-Inferiority
	Comments	Lower limit of the standardized asymptotic 95% CI for the between-group differences in booster response to PT was ≥ -10%
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in booster response rates
	Estimated Value	-0.76
	Confidence Interval	(2-Sided) 95%; -5.07 to 3.51
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Kinrix + M-M-R II + Varivax, Kinrix + M-M-R II -> Varivax
	Comments	To demonstrate the non-inferiority of DTaP-IPV vaccine co-administered with Varicella and MMR vaccines compared to DTaP-IPV vaccine co-administered with MMR only in terms of filamentous hemagglutinin (FHA) booster response one month after vaccination with DTaP-IPV vaccine.
	Type of Statistical Test	Non-Inferiority
	Comments	Lower limit of the standardized asymptotic 95% CI for the between-group differences in booster response to FHA was ≥ -10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in booster response rates
	Estimated Value	-0.91
	Confidence Interval	(2-Sided) 95%; -3.59 to 1.39
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Kinrix + M-M-R II + Varivax, Kinrix + M-M-R II -> Varivax
	Comments	To demonstrate the non-inferiority of DTaP-IPV vaccine co-administered with Varicella and MMR vaccines compared to DTaP-IPV vaccine co-administered with MMR only in terms of pertactin (PRN) booster response one month after vaccination with DTaP-IPV vaccine.
	Type of Statistical Test	Non-Inferiority
	Comments	Lower limit of the standardized asymptotic 95% CI for the between-group differences in booster response to PRN, was ≥ -10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in booster response rates
	Estimated Value	1.42
	Confidence Interval	(2-Sided) 95%; -0.32 to 4.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Geometric Mean Titers (GMTs) for Antibodies to Poliovirus Types 1, 2 and 3
Description	Titers are expressed as GMTs.
Time Frame	One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.

Outcome Measure Data

Analysis Population Description

Analysis was performed on the according-to-protocol (ATP) cohort for immunogenicity, which included all evaluable subjects for whom immunogenicity data were available for antibodies against at least one study vaccine antigen component after vaccination.

Arm/Group Title	Kinrix + M-M-R II + Varivax	Kinrix + M-M-R II -> Varivax
Arm/Group Description	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II and Varivax each, subcutaneously in the deltoid of the right upper and lower arm, respectively.	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II, subcutaneously in the deltoid of the right upper arm. At Day 30 they received one dose of Varivax subcutaneously in the deltoid region of the right upper arm.
Measure Participants	219	212
Anti-Polio 1	1638.4	1789.9
Anti-Polio 2	1572.9	1902.6
Anti-Polio 3	2588.4	3189.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Kinrix + M-M-R II + Varivax, Kinrix + M-M-R II -> Varivax
	Comments	To demonstrate the non-inferiority of DTaP-IPV vaccine co-administered with Varicella and MMR vaccines compared to DTaP-IPV vaccine co-administered with MMR only in terms of poliovirus type 1 geometric mean titers (GMTs), one month after vaccination with DTaP-IPV vaccine.
	Type of Statistical Test	Non-Inferiority
	Comments	Lower limit of the 95% CI for the GMT ratios for poliovirus type 1 antigens was ≥ 0.67.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted GMT ratio
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 95%; 0.76 to 1.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Kinrix + M-M-R II + Varivax, Kinrix + M-M-R II -> Varivax
	Comments	To demonstrate the non-inferiority of DTaP-IPV vaccine co-administered with Varicella and MMR vaccines compared to DTaP-IPV vaccine co-administered with MMR only in terms of poliovirus type 2 geometric mean titers (GMTs), one month after vaccination with DTaP-IPV vaccine.
	Type of Statistical Test	Non-Inferiority
	Comments	Lower limit of the 95% CI for the GMT ratios of poliovirus type 2 antigens was ≥ 0.67.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted GMT ratio
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95%; 0.7 to 0.99
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Kinrix + M-M-R II + Varivax, Kinrix + M-M-R II -> Varivax
	Comments	To demonstrate the non-inferiority of DTaP-IPV vaccine co-administered with Varicella and MMR vaccines compared to DTaP-IPV vaccine co-administered with MMR only in terms of poliovirus type 3 geometric mean titers (GMTs), one month after vaccination with DTaP-IPV vaccine.
	Type of Statistical Test	Non-Inferiority
	Comments	Lower limit of the 95% CI for the GMT ratios of poliovirus type 3 antigens was ≥ 0.67.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted GMT ratio
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.71 to 1.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Number of Subjects With Anti-D and Anti-T Antibody Concentrations Above Cut-off Value
Description	Cut-off value was defined as greater than or equal to 1.0 international units per milliliter (IU/mL).
Time Frame	One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.

Outcome Measure Data

Analysis Population Description

Analysis was performed on the according-to-protocol (ATP) cohort for immunogenicity, which included all evaluable subjects for whom immunogenicity data were available for antibodies against at least one study vaccine antigen component after vaccination.

Arm/Group Title	Kinrix + M-M-R II + Varivax	Kinrix + M-M-R II -> Varivax
Arm/Group Description	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II and Varivax each, subcutaneously in the deltoid of the right upper and lower arm, respectively.	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II, subcutaneously in the deltoid of the right upper arm. At Day 30 they received one dose of Varivax subcutaneously in the deltoid region of the right upper arm.
Measure Participants	217	212
Anti-D	217 90.8%	212 89.5%
Anti-T	217 90.8%	209 88.2%

5. Secondary Outcome

Title	Geometric Mean Concentrations (GMCs) for Anti-D and Anti-T Antibodies
Description	Concentrations were expressed as GMCs in IU/mL.
Time Frame	One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.

Outcome Measure Data

Analysis Population Description

Analysis was performed on the according-to-protocol (ATP) cohort for immunogenicity, which included all evaluable subjects for whom immunogenicity data were available for antibodies against at least one study vaccine antigen component after vaccination.

Arm/Group Title	Kinrix + M-M-R II + Varivax	Kinrix + M-M-R II -> Varivax
Arm/Group Description	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II and Varivax each, subcutaneously in the deltoid of the right upper and lower arm, respectively.	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II, subcutaneously in the deltoid of the right upper arm. At Day 30 they received one dose of Varivax subcutaneously in the deltoid region of the right upper arm.
Measure Participants	217	212
Anti-D	14.273	14.809
Anti-T	8.658	8.138

6. Secondary Outcome

Title	GMCs for Anti-PT, Anti-FHA, Anti-PRN Antibodies
Description	Concentrations are expressed as GMCs in Enzyme-Linked Immunosorbent Assay (ELISA) Units per milliliter (EL.U/mL).
Time Frame	One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.

Outcome Measure Data

Analysis Population Description

Analysis was performed on the according-to-protocol (ATP) cohort for immunogenicity, which included all evaluable subjects for whom immunogenicity data were available for antibodies against at least one study vaccine antigen component after vaccination.

Arm/Group Title	Kinrix + M-M-R II + Varivax	Kinrix + M-M-R II -> Varivax
Arm/Group Description	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II and Varivax each, subcutaneously in the deltoid of the right upper and lower arm, respectively.	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II, subcutaneously in the deltoid of the right upper arm. At Day 30 they received one dose of Varivax subcutaneously in the deltoid region of the right upper arm.
Measure Participants	220	212
Anti-PT	96.5	101.3
Anti-FHA	968.9	968.2
Anti-PRN	627.1	620.4

7. Secondary Outcome

Title	Number of Subjects With an Anti-polio 1, 2, 3 Booster Response
Description	Anti-poliovirus 1, anti-poliovirus 2 and anti-poliovirus 3 booster response: initially seronegative subjects (pre-booster antibody titer below cut-off of 8 ED50) with an antibody titer ≥ 32 ED50 one month after vaccination initially seropositive subjects (pre-booster antibody titers ≥ 8 ED50) with an increase at least four times the pre-booster antibody titer one month after vaccination. ED50 is defined here as the reverse of the dilution resulting in 50% inhibition. The lowest dilution at which serum samples were tested is 1:8 from which a test was considered positive.
Time Frame	One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.

Outcome Measure Data

Analysis Population Description

Analysis was performed on the according-to-protocol (ATP) cohort for immunogenicity, which included all evaluable subjects for whom immunogenicity data were available for antibodies against at least one study vaccine antigen component after vaccination.

Arm/Group Title	Kinrix + M-M-R II + Varivax	Kinrix + M-M-R II -> Varivax
Arm/Group Description	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II and Varivax each, subcutaneously in the deltoid of the right upper and lower arm, respectively.	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II, subcutaneously in the deltoid of the right upper arm. At Day 30 they received one dose of Varivax subcutaneously in the deltoid region of the right upper arm.
Measure Participants	215	211
Anti-polio 1	211 88.3%	202 85.2%
Anti-polio 2	204 85.4%	207 87.3%
Anti-polio 3	213 89.1%	207 87.3%

8. Secondary Outcome

Title	Number of Subjects Seroprotected Against Diphteria and Tetanus
Description	Seroprotection status was defined as: anti-D antibody concentration greater than or equal to 0.1 IU/mL anti-T antibody concentration greater than or equal to 0.1 IU/mL
Time Frame	One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.

Outcome Measure Data

Analysis Population Description

Analysis was performed on the according-to-protocol (ATP) cohort for immunogenicity, which included all evaluable subjects for whom immunogenicity data were available for antibodies against at least one study vaccine antigen component after vaccination.

Arm/Group Title	Kinrix + M-M-R II + Varivax	Kinrix + M-M-R II -> Varivax
Arm/Group Description	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II and Varivax each, subcutaneously in the deltoid of the right upper and lower arm, respectively.	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II, subcutaneously in the deltoid of the right upper arm. At Day 30 they received one dose of Varivax subcutaneously in the deltoid region of the right upper arm.
Measure Participants	217	212
Anti-D	217 90.8%	212 89.5%
Anti-T	217 90.8%	212 89.5%

9. Secondary Outcome

Title	Number of Subjects Protected Against Poliovirus 1, 2 and 3
Description	Seroprotection was defined: * anti-poliovirus type 1, 2 or 3 antibody titer greater than or equal to 8 ED50. ED50 is defined here as the reverse of the dilution resulting in 50% inhibition.
Time Frame	One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.

Outcome Measure Data

Analysis Population Description

Analysis was performed on the according-to-protocol (ATP) cohort for immunogenicity, which included all evaluable subjects for whom immunogenicity data were available for antibodies against at least one study vaccine antigen component after vaccination.

Arm/Group Title	Kinrix + M-M-R II + Varivax	Kinrix + M-M-R II -> Varivax
Arm/Group Description	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II and Varivax each, subcutaneously in the deltoid of the right upper and lower arm, respectively.	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II, subcutaneously in the deltoid of the right upper arm. At Day 30 they received one dose of Varivax subcutaneously in the deltoid region of the right upper arm.
Measure Participants	219	212
Anti-Polio 1	219 91.6%	211 89%
Anti-Polio 2	218 91.2%	212 89.5%
Anti-Polio 3	219 91.6%	212 89.5%

10. Secondary Outcome

Title	Number of Subjects Seropositive for Anti-PT, Anti-FHA and Anti-PRN Antibodies
Description	Seropositivity was defined as a concentration greater than or equal to 5.0 EL.U/mL
Time Frame	One month after Kinrix vaccination (Month 1), prior to Varivax vaccination for Kinrix + M-M-R II -> Varivax Group.

Outcome Measure Data

Analysis Population Description

Analysis was performed on the according-to-protocol (ATP) cohort for immunogenicity, which included all evaluable subjects for whom immunogenicity data were available for antibodies against at least one study vaccine antigen component after vaccination.

Arm/Group Title	Kinrix + M-M-R II + Varivax	Kinrix + M-M-R II -> Varivax
Arm/Group Description	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II and Varivax each, subcutaneously in the deltoid of the right upper and lower arm, respectively.	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II, subcutaneously in the deltoid of the right upper arm. At Day 30 they received one dose of Varivax subcutaneously in the deltoid region of the right upper arm.
Measure Participants	220	212
anti-PT	220 92.1%	212 89.5%
anti-FHA	220 92.1%	212 89.5%
anti-PRN	220 92.1%	212 89.5%

11. Secondary Outcome

Title	Number of Subjects With Any Solicited Local Symptoms
Description	Solicited local symptoms included pain, redness and swelling at the injection site. Any was defined as incidence of a particular symptom regardless of intensity grade.
Time Frame	Within 4 days (Day 0 to 3) after booster immunization * for Kinrix + M-M-R II -> Varivax Group before vaccination with Varivax

Outcome Measure Data

Analysis Population Description

The analysis was performed on the total vaccinated cohort, which included subjects with at least one vaccine administration documented, only on subjects with their symptom sheets completed.

Arm/Group Title	Kinrix + M-M-R II + Varivax	Kinrix + M-M-R II -> Varivax
Arm/Group Description	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II and Varivax each, subcutaneously in the deltoid of the right upper and lower arm, respectively.	Subjects received at Day 0 one dose of Kinrix,intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II, subcutaneously in the deltoid of the right upper arm. At Day 30 they received one dose of Varivax subcutaneously in the deltoid region of the right upper arm.
Measure Participants	230	230
Any Pain	156 65.3%	166 70%
Any Redness	115 48.1%	114 48.1%
Any Swelling	95 39.7%	84 35.4%

12. Secondary Outcome

Title	Number of Subjects With Any Solicited General Symptoms
Description	Solicited general symptoms included fever [temperature equal to or greater than 37.5 degrees Celsius (°C)], drowsiness and loss of appetite. Any was defined as incidence of a particular symptom regardless of intensity grade.
Time Frame	Within 4 days (Day 0 to 3) after booster immunization * for Kinrix + M-M-R II -> Varivax Group before vaccination with Varivax

Outcome Measure Data

Analysis Population Description

The analysis was performed on the total vaccinated cohort, which included subjects with at least one vaccine administration documented, only on subjects with their symptom sheets completed.

Arm/Group Title	Kinrix + M-M-R II + Varivax	Kinrix + M-M-R II -> Varivax
Arm/Group Description	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II and Varivax each, subcutaneously in the deltoid of the right upper and lower arm, respectively.	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II, subcutaneously in the deltoid of the right upper arm. At Day 30 they received one dose of Varivax subcutaneously in the deltoid region of the right upper arm.
Measure Participants	230	230
Any Drowsiness	61 25.5%	66 27.8%
Any Loss of appetite	60 25.1%	57 24.1%
Any Temperature (Axillary)	58 24.3%	68 28.7%

13. Secondary Outcome

Title	Number of Subjects With Unsolicited Adverse Events
Description	An unsolicited adverse event is any adverse event (i.e. any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product) reported in addition to those solicited during the clinical study. Also any "solicited" symptom with onset outside the specified period of follow-up for solicited symptoms will be reported as an unsolicited adverse event.
Time Frame	Up to 31 days (Day 0 through Day 30) after booster vaccination * for Kinrix + M-M-R II -> Varivax Group before vaccination with Varivax

Outcome Measure Data

Analysis Population Description

Analysis was performed on the total vaccinated cohort, which included all subjects with at least one vaccine administration documented and for whom data was available.

Arm/Group Title	Kinrix + M-M-R II + Varivax	Kinrix + M-M-R II -> Varivax
Arm/Group Description	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II and Varivax each, subcutaneously in the deltoid of the right upper and lower arm, respectively.	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II, subcutaneously in the deltoid of the right upper arm. At Day 30 they received one dose of Varivax subcutaneously in the deltoid region of the right upper arm.
Measure Participants	239	237
Count of Participants [Participants]	75 31.4%	72 30.4%

14. Secondary Outcome

Title	Number of Subjects With Serious Adverse Events (SAEs)
Description	Serious adverse events are medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject.
Time Frame	During the entire study period (from Day 0 to 6 months post-vaccination)

Outcome Measure Data

Analysis Population Description

Analysis was performed on the total vaccinated cohort, which included all subjects with at least one vaccine administration documented and for whom data was available.

Arm/Group Title	Kinrix + M-M-R II + Varivax	Kinrix + M-M-R II -> Varivax
Arm/Group Description	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II and Varivax each, subcutaneously in the deltoid of the right upper and lower arm, respectively.	Subjects received at Day 0 one dose of Kinrix, intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II, subcutaneously in the deltoid of the right upper arm. At Day 30 they received one dose of Varivax subcutaneously in the deltoid region of the right upper arm.
Measure Participants	239	237
Count of Participants [Participants]	0 0%	1 0.4%

Adverse Events

Time Frame	Solicited local/general Adverse Events (AEs) during the first 4 days (Day 0-3) post vaccination ; unsolicited AEs during the 31 days (Days 0-30) post vaccination and SAEs during the entire study period (from Day 0 to 6 months post-vaccination).
Adverse Event Reporting Description	Solicited local/general Adverse Events (AEs) were only collected from subjects with their symptom sheets completed.
Arm/Group Title	Kinrix + M-M-R II + Varivax		Kinrix + M-M-R II -> Varivax
Arm/Group Description	Subjects received at Day 0 one dose of Kinrix,intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II, subcutaneously in the deltoid of the right upper arm, and one dose of Varivax subcutaneously in the deltoid region of the right lower arm.		Subjects received at Day 0 one dose of Kinrix,intramuscularly in the deltoid region of the left upper arm, co-administered with one dose of M-M-R II, subcutaneously in the deltoid of the right upper arm. At Day 30 they received one dose of Varivax subcutaneously in the deltoid region of the right upper arm.
All Cause Mortality
	Kinrix + M-M-R II + Varivax		Kinrix + M-M-R II -> Varivax
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/239 (0%)		0/237 (0%)
Serious Adverse Events
	Kinrix + M-M-R II + Varivax		Kinrix + M-M-R II -> Varivax
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/239 (0%)		1/237 (0.4%)
Infections and infestations
Croup infectious	0/239 (0%)		1/237 (0.4%)
Other (Not Including Serious) Adverse Events
	Kinrix + M-M-R II + Varivax		Kinrix + M-M-R II -> Varivax
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	228/230 (99.1%)		230/230 (100%)
General disorders
Pain	156/230 (67.8%)		166/230 (72.2%)
Redness	115/230 (50%)		114/230 (49.6%)
Swelling	95/230 (41.3%)		84/230 (36.5%)
Drowsiness	61/230 (26.5%)		66/230 (28.7%)
Loss of appetite	60/230 (26.1%)		57/230 (24.8%)
Fever	58/230 (25.2%)		68/230 (29.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.