Clinical Trial Results:
A Phase III Randomized, Double-Blind, Active-Comparator Controlled Clinical Trial to Study the Safety, Tolerability, and Immunogenicity of V419 in Healthy Infants When Given at 2, 4, and 11 to 12 Months
Summary
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EudraCT number |
2010-021491-28 |
Trial protocol |
FI SE IT |
Global end of trial date |
09 Oct 2013
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Results information
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Results version number |
v1 |
This version publication date |
27 Apr 2016
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First version publication date |
02 Aug 2015
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Other versions |
v2 |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
V419-008
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01480258 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Sanofi Pasteur MSD S.N.C.
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Sponsor organisation address |
162 avenue Jean Jaurès - CS 50712, Lyon Cedex 07, France, 69367
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Public contact |
Clinical Trials Disclosure, Sanofi Pasteur MSD S.N.C., ClinicalTrialsDisclosure@spmsd.com
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Scientific contact |
Clinical Trials Disclosure, Sanofi Pasteur MSD S.N.C., ClinicalTrialsDisclosure@spmsd.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-000394-PIP01-08 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
09 Oct 2013
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
09 Oct 2013
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Global end of trial reached? |
Yes
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Global end of trial date |
09 Oct 2013
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate the immunogenicity of PR5I when given at 2, 4, and 11 to 12 months of age.
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Protection of trial subjects |
This study was conducted in healthy infants.
Subjects with known or suspected hypersensitivity to any of the vaccine components or history of a life-threatening reaction to a vaccine containing the same substances as the study vaccines or concomitant vaccines were excluded.
Vaccines were administered by qualified study personnel.
After each vaccination, subjects were kept under observation for 30 minutes to ensure their safety.
Adequate treatment provisions, including epinephrine, were available for immediate use in case of
anaphylactic or anaphylactoid reactions occurring during or immediately following vaccination.
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Background therapy |
- | ||
Evidence for comparator |
This study was conducted in healthy infants to assess the safety, tolerability, and immunogenicity of 3 doses of the hexavalent PR5I vaccine when given at 2, 4 and 11 to 12 months of age. INFANRIX™ hexa was chosen as the active comparator because it was the only hexavalent pediatric vaccine licensed in Europe at the time this study was conducted. | ||
Actual start date of recruitment |
23 Nov 2011
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Sweden: 132
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Country: Number of subjects enrolled |
Finland: 919
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Country: Number of subjects enrolled |
Italy: 264
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Worldwide total number of subjects |
1315
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EEA total number of subjects |
1315
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
1315
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Study subjects were enrolled from 23 November 2011 (first subject entered) in 23 active centres in 3 European countries (Finland, Italy, and Sweden). | |||||||||||||||||||||||||||
Pre-assignment
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Screening details |
1325 subjects were screened. 1315 subjects were randomised. 1312 subjects were vaccinated. 1300 subjects received the 2 doses of the infant series (period 1). 1281 subjects received the toddler dose (period 2). | |||||||||||||||||||||||||||
Period 1
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Period 1 title |
Infant Series
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||||||||
Roles blinded |
Investigator, Subject | |||||||||||||||||||||||||||
Blinding implementation details |
The parent(s)/legal representative of the subject, the Investigator, laboratory testing personnel, and sponsor/sponsor representative personnel (except for an unblinded sponsor representative) were blinded to the vaccination group assigned.
Because INFANRIX™ hexa is to be reconstituted and PR5I is ready to use, an unblinded individual at each study site who was otherwise not involved in the conduct of the study was required to prepare study vaccines to maintain the study blind.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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PR5I | |||||||||||||||||||||||||||
Arm description |
# Subjects received at 2 and 4 months of age 1 dose of PR5I (DTaP-HB-IPV-Hib = Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated), and Haemophilus influenzae type b conjugate vaccine (adsorbed)) by intramuscular route (IM) + 1 dose of Prevenar 13 (PCV-13 = Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed)) by IM route (opposite leg). # Subjects also received either 1 dose of Rotarix (live human rotavirus RIX4414 strain) at 2 and 4 months of age (in Italy & Sweden) or 1 dose of RotaTeq (pentavalent combination live vaccine of 5 human-bovine reassortant rotavirus strains) at 2, 4, and 5 months of age (in Finland), both by oral route. # Blood samples were collected on Day 0 (D0) before any vaccination and at Month 5 (M5), i.e. 1 month after the 2nd dose of infant series. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
PR5I vaccine
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Investigational medicinal product code |
DTaP-HB-IPV-Hib
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Other name |
V419
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Pharmaceutical forms |
Suspension for injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
0.5 mL, intramuscular route (upper anterolateral thigh, separate limb from the concomitant vaccine), one dose at 2 and 4 months of age.
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Investigational medicinal product name |
Prevenar 13™
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Investigational medicinal product code |
PCV-13
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Other name |
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Pharmaceutical forms |
Suspension for injection in pre-filled syringe
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Routes of administration |
Intramuscular use
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Dosage and administration details |
0.5 mL, intramuscular route (upper anterolateral thigh, separate limb from hexavalent vaccine), one dose at 2 and 4 months of age.
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Investigational medicinal product name |
Rotarix™
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Investigational medicinal product code |
Rotarix
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Other name |
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Pharmaceutical forms |
Oral liquid, Oral solution, Powder and solvent for oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
1.5 mL, oral route, one dose at 2 and 4 months of age.
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Investigational medicinal product name |
RotaTeq™
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Investigational medicinal product code |
RotaTeq
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Other name |
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Pharmaceutical forms |
Oral solution in single-dose container
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Routes of administration |
Oral use
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Dosage and administration details |
2 mL, oral route, one dose at 2, 4 and 5 months of age.
Note: The 3rd dose of RotaTeq was to be given to subjects at least 4 weeks after the 2nd dose and no later than 26 weeks of age.
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Arm title
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INFANRIX hexa | |||||||||||||||||||||||||||
Arm description |
# Subjects received at 2 and 4 months of age 1 dose of INFANRIX hexa (DTaP-HBV-IPV-Hib = Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated), and Haemophilus influenzae type b conjugate vaccine (adsorbed)) by intramuscular route (IM) + 1 dose of Prevenar 13 (PCV-13 = Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed)) by IM route (opposite leg). # Subjects also received either 1 dose of Rotarix (live human rotavirus RIX4414 strain) at 2 and 4 months of age (in Italy & Sweden) or 1 dose of RotaTeq (pentavalent combination live vaccine of 5 human-bovine reassortant rotavirus strains) at 2, 4, and 5 months of age (in Finland), both by oral route. # Blood samples were collected on Day 0 (D0) before any vaccination and at Month 5 (M5), i.e. 1 month after the 2nd dose of infant series. | |||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||
Investigational medicinal product name |
INFANRIX™ hexa
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Investigational medicinal product code |
DTaP-HBV-IPV-Hib
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Other name |
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Pharmaceutical forms |
Powder and suspension for suspension for injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
0.5 mL, intramuscular route (upper anterolateral thigh, separate limb from the concomitant vaccine), one dose at 2 and 4 months of age.
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Investigational medicinal product name |
Prevenar 13™
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Investigational medicinal product code |
PCV-13
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Other name |
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Pharmaceutical forms |
Suspension for injection in pre-filled syringe
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Routes of administration |
Intramuscular use
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Dosage and administration details |
0.5 mL, intramuscular route (upper anterolateral thigh, separate limb from hexavalent vaccine), one dose at 2 and 4 months of age.
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Investigational medicinal product name |
Rotarix™
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Investigational medicinal product code |
Rotarix
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Other name |
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Pharmaceutical forms |
Oral liquid, Oral solution, Powder and solvent for oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
1.5 mL, oral route, one dose at 2 and 4 months of age.
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Investigational medicinal product name |
RotaTeq™
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Investigational medicinal product code |
RotaTeq
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Other name |
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Pharmaceutical forms |
Oral solution in single-dose container
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Routes of administration |
Oral use
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Dosage and administration details |
2 mL, oral route, one dose at 2, 4 and 5 months of age.
Note: The 3rd dose of RotaTeq was to be given to subjects at least 4 weeks after the 2nd dose and no later than 26 weeks of age.
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Period 2
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Period 2 title |
Toddler Dose
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Is this the baseline period? |
No | |||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator | |||||||||||||||||||||||||||
Blinding implementation details |
The parent(s)/legal representative of the subject, the Investigator, laboratory testing personnel, and sponsor/sponsor representative personnel (except for an unblinded sponsor representative) were blinded to the vaccination group assigned.
Because INFANRIX™ hexa is to be reconstituted and PR5I is ready to use, an unblinded individual at each study site who was otherwise not involved in the conduct of the study was required to prepare study vaccines to maintain the study blind.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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PR5I | |||||||||||||||||||||||||||
Arm description |
# Subjects (arm 1 - period 1) received at 11 to 12 months of age 1 dose of PR5I (DTaP-HB-IPV-Hib = Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated), and Haemophilus influenzae type b conjugate vaccine (adsorbed)) by intramuscular route (IM) + 1 dose of Prevenar 13 (PCV-13 = Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed)) by IM route (opposite leg). # Blood samples were collected at Month 11 or 12 before any Toddler dose and 1 month (28 to 37 days) after Toddler dose. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
PR5I vaccine
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Investigational medicinal product code |
DTaP-HB-IPV-Hib
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Other name |
V419
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Pharmaceutical forms |
Suspension for injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
0.5 mL, intramuscular route (upper anterolateral thigh, separate limb from the concomitant vaccine), one dose at 11 to 12 months of age.
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Investigational medicinal product name |
Prevenar 13™
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Investigational medicinal product code |
PCV-13
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Other name |
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Pharmaceutical forms |
Suspension for injection in pre-filled syringe
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Routes of administration |
Intramuscular use
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Dosage and administration details |
0.5 mL, intramuscular route (upper anterolateral thigh, separate limb from hexavalent vaccine), one dose at 11 to 12 months of age.
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Arm title
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INFANRIX hexa | |||||||||||||||||||||||||||
Arm description |
# Subjects (arm 2 - period 1) received at 12 months of age 1 dose of INFANRIX hexa (DTaP-HBV-IPV-Hib = Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated), and Haemophilus influenzae type b conjugate vaccine (adsorbed)) by intramuscular route (IM) + 1 dose of Prevenar 13 (PCV-13 = Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed)) by IM route (opposite leg). # Blood samples were collected at Month 11 or 12 before any Toddler dose and 1 month (28 to 37 days) after Toddler dose. | |||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||
Investigational medicinal product name |
INFANRIX™ hexa
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Investigational medicinal product code |
DTaP-HBV-IPV-Hib
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Other name |
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Pharmaceutical forms |
Powder and suspension for suspension for injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
0.5 mL, intramuscular route (upper anterolateral thigh, separate limb from the concomitant vaccine), one dose at 11 to 12 months of age.
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Investigational medicinal product name |
Prevenar 13™
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Investigational medicinal product code |
PCV-13
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Other name |
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Pharmaceutical forms |
Suspension for injection in pre-filled syringe
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Routes of administration |
Intramuscular use
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Dosage and administration details |
0.5 mL, intramuscular route (upper anterolateral thigh, separate limb from hexavalent vaccine), one dose at 11 to 12 months of age.
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Notes [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: # In the PR5I arm, 10 subjects discontinued the study between the Infant Series and Toddler Dose: 1 "physician decision" and 9 "consent withdrawn by subject". # In the INFANRIX hexa arm, 9 subjects discontinued the study between the Infant Series and Toddler Dose: 2 "lost to follow-up", 1 "protocol deviation", and 6 "consent withdrawn by subject". |
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Baseline characteristics reporting groups
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Reporting group title |
PR5I
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Reporting group description |
# Subjects received at 2 and 4 months of age 1 dose of PR5I (DTaP-HB-IPV-Hib = Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated), and Haemophilus influenzae type b conjugate vaccine (adsorbed)) by intramuscular route (IM) + 1 dose of Prevenar 13 (PCV-13 = Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed)) by IM route (opposite leg). # Subjects also received either 1 dose of Rotarix (live human rotavirus RIX4414 strain) at 2 and 4 months of age (in Italy & Sweden) or 1 dose of RotaTeq (pentavalent combination live vaccine of 5 human-bovine reassortant rotavirus strains) at 2, 4, and 5 months of age (in Finland), both by oral route. # Blood samples were collected on Day 0 (D0) before any vaccination and at Month 5 (M5), i.e. 1 month after the 2nd dose of infant series. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
INFANRIX hexa
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Reporting group description |
# Subjects received at 2 and 4 months of age 1 dose of INFANRIX hexa (DTaP-HBV-IPV-Hib = Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated), and Haemophilus influenzae type b conjugate vaccine (adsorbed)) by intramuscular route (IM) + 1 dose of Prevenar 13 (PCV-13 = Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed)) by IM route (opposite leg). # Subjects also received either 1 dose of Rotarix (live human rotavirus RIX4414 strain) at 2 and 4 months of age (in Italy & Sweden) or 1 dose of RotaTeq (pentavalent combination live vaccine of 5 human-bovine reassortant rotavirus strains) at 2, 4, and 5 months of age (in Finland), both by oral route. # Blood samples were collected on Day 0 (D0) before any vaccination and at Month 5 (M5), i.e. 1 month after the 2nd dose of infant series. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
PR5I
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Reporting group description |
# Subjects received at 2 and 4 months of age 1 dose of PR5I (DTaP-HB-IPV-Hib = Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated), and Haemophilus influenzae type b conjugate vaccine (adsorbed)) by intramuscular route (IM) + 1 dose of Prevenar 13 (PCV-13 = Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed)) by IM route (opposite leg). # Subjects also received either 1 dose of Rotarix (live human rotavirus RIX4414 strain) at 2 and 4 months of age (in Italy & Sweden) or 1 dose of RotaTeq (pentavalent combination live vaccine of 5 human-bovine reassortant rotavirus strains) at 2, 4, and 5 months of age (in Finland), both by oral route. # Blood samples were collected on Day 0 (D0) before any vaccination and at Month 5 (M5), i.e. 1 month after the 2nd dose of infant series. | ||
Reporting group title |
INFANRIX hexa
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Reporting group description |
# Subjects received at 2 and 4 months of age 1 dose of INFANRIX hexa (DTaP-HBV-IPV-Hib = Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated), and Haemophilus influenzae type b conjugate vaccine (adsorbed)) by intramuscular route (IM) + 1 dose of Prevenar 13 (PCV-13 = Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed)) by IM route (opposite leg). # Subjects also received either 1 dose of Rotarix (live human rotavirus RIX4414 strain) at 2 and 4 months of age (in Italy & Sweden) or 1 dose of RotaTeq (pentavalent combination live vaccine of 5 human-bovine reassortant rotavirus strains) at 2, 4, and 5 months of age (in Finland), both by oral route. # Blood samples were collected on Day 0 (D0) before any vaccination and at Month 5 (M5), i.e. 1 month after the 2nd dose of infant series. | ||
Reporting group title |
PR5I
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Reporting group description |
# Subjects (arm 1 - period 1) received at 11 to 12 months of age 1 dose of PR5I (DTaP-HB-IPV-Hib = Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated), and Haemophilus influenzae type b conjugate vaccine (adsorbed)) by intramuscular route (IM) + 1 dose of Prevenar 13 (PCV-13 = Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed)) by IM route (opposite leg). # Blood samples were collected at Month 11 or 12 before any Toddler dose and 1 month (28 to 37 days) after Toddler dose. | ||
Reporting group title |
INFANRIX hexa
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Reporting group description |
# Subjects (arm 2 - period 1) received at 12 months of age 1 dose of INFANRIX hexa (DTaP-HBV-IPV-Hib = Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated), and Haemophilus influenzae type b conjugate vaccine (adsorbed)) by intramuscular route (IM) + 1 dose of Prevenar 13 (PCV-13 = Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed)) by IM route (opposite leg). # Blood samples were collected at Month 11 or 12 before any Toddler dose and 1 month (28 to 37 days) after Toddler dose. | ||
Subject analysis set title |
PR5I - Rotarix
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
# Subjects (arm 1 - period 1 - sub-group Rotarix) received 1 dose of PR5I (DTaP-HB-IPV-Hib) by intramuscular route (IM) + 1 dose of Prevenar 13 (PCV-13) by IM route (opposite leg) + 1 dose of Rotarix (in Italy & Sweden) by oral route at 2 and 4 months of age.
# Blood samples were collected on Day 0 (D0) before any vaccination and at Month 5 (M5), i.e. 1 month after the 2nd dose of infant series.
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Subject analysis set title |
INFANRIX hexa - Rotarix
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
# Subjects (arm 2 - period 1 - sub-group Rotarix) received 1 dose of INFANRIX hexa (DTaP-HBV-IPV-Hib) by intramuscular route (IM) + 1 dose of Prevenar 13 (PCV-13) by IM route (opposite leg) + 1 dose of Rotarix (in Italy & Sweden) by oral route at 2 and 4 months of age.
# Blood samples were collected on Day 0 (D0) before any vaccination and at Month 5 (M5), i.e. 1 month after the 2nd dose of infant series.
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End point title |
Acceptability of antibody (Ab) response or seroresponse rates to all antigens contained in PR5I vaccine one month after the Toddler dose of PR5I (11 to 12 months of age) [1] | ||||||||||||||||||||||||||||||
End point description |
% of subjects with an Ab titre ≥1.0 μg/mL for Haemophilus influenzae type b (Hib) (polyribosylribitol phosphate, PRP); ≥10 mIU/mL for Hepatitis B (HBsAg); ≥0.1 IU/mL for diphtheria & tetanus; ≥8 (1/dil) for IPV1, 2 & 3, and % of pertussis seroresponder subjects (Pertussis toxoid (PT), Filamentous haemagglutinin (FHA), Fimbriae types 2 & 3 (FIM) & Pertactin (PRN)) 1 month Post-Toddler dose of PR5I.
Seroresponse was defined: (1) If pre-Dose 1 Ab concentration (cc) was <LLOQ (lower limit of quantitation), postvaccination Ab cc was ≥LLOQ, (2) If pre-Dose 1 Ab cc was ≥LLOQ, postvaccination Ab cc was ≥prevaccination levels.
Ab titres were measured by Radioimmunoassay (RIA) for PRP, enhanced Chemiluminescence assay (ECi) for HBsAg, Micrometabolic inhibition test (MIT) for diphtheria & poliovirus, and Enzyme-Linked Immunosorbent Assay (ELISA) for PT, FHA, FIM, PRN & tetanus.
Analysis was done on the Per Protocol Revised Windows (PP-RW) population.
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End point type |
Primary
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End point timeframe |
1 month after the Toddler dose of PR5I (Post-Toddler Dose).
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This endpoint includes only one arm. The immune response to PR5I vaccine was considered as acceptable if the lower bounds of the 2-sided 95% CI for the response rates were greater than the predetermined lower limits: 75% for PRP, PT, FHA, FIM & PRN, 80% for diphtheria, and 90% for HBsAg, tetanus and IPV1, 2 & 3. Acceptability criteria were met for all PR5I antigens. Note: (N=***) represents the number of assessed subjects. |
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No statistical analyses for this end point |
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End point title |
Non-inferiority of antibody (Ab) response rate to Haemophilus influenzae type b (PRP) one month after the 2nd dose of PR5I (4 months of age) as compared with INFANRIX hexa | |||||||||||||||
End point description |
Percentage of subjects with an Ab titre ≥1.0 μg/mL for Hib (polyribosylribitol phosphate, PRP) measured by RIA 1 month Post-Dose 2 of PR5I or INFANRIX hexa.
Analysis was done on the Per Protocol Revised Windows (PP-RW) population, i.e. PP population using a blood draw sample window of Days 28 to 51 Post-Dose 2 or Post-Toddler dose.
Note: (N=***, ***) represents the number of assessed subjects in the PR5I and INFANRIX hexa groups, respectively.
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End point type |
Secondary
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End point timeframe |
1 month after the 2nd dose of PR5I or INFANRIX hexa (Post-Dose 2).
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Statistical analysis title |
Non-inferiority for PRP | |||||||||||||||
Statistical analysis description |
The estimate of the difference between PR5I & INFANRIX hexa groups in PRP response rate (based on Ab titre ≥1.0 µg/mL) was calculated with its 1-sided P-value & 2-sided 95% confidence interval (CI). If the lower bound of the 95% CI was greater than -10% (non-inferiority margin), it was concluded that PR5I group response rate was non-inferior to INFANRIX hexa group response rate.
Analysis was done on the PP-RW population: N=609, 592 (PR5I group, INFANRIX hexa group).
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Comparison groups |
PR5I v INFANRIX hexa
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Number of subjects included in analysis |
1300
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [2] | |||||||||||||||
P-value |
< 0.001 | |||||||||||||||
Method |
Miettinen & Nurminen with stratification | |||||||||||||||
Parameter type |
Difference in percentages of subjects | |||||||||||||||
Point estimate |
46.2
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Confidence interval |
||||||||||||||||
level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
41.05 | |||||||||||||||
upper limit |
51.06 | |||||||||||||||
Notes [2] - Statistical analysis was based on the Miettinen & Nurminen method stratified by country. |
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End point title |
Superiority of antibody (Ab) response rates to Haemophilus influenzae type b (PRP) one month after the 2nd dose of PR5I (4 months of age) as compared with INFANRIX hexa | |||||||||||||||
End point description |
Percentage of subjects with an Ab titre ≥1.0 μg/mL for Hib (polyribosylribitol phosphate, PRP) measured by RIA 1 month Post-Dose 2 of PR5I or INFANRIX hexa.
Analysis was done on the PP-RW population.
Note: (N=***, ***) represents the number of assessed subjects in the PR5I and INFANRIX hexa groups, respectively.
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End point type |
Secondary
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End point timeframe |
1 month after the 2nd dose of PR5I or INFANRIX hexa (Post-Dose 2).
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Statistical analysis title |
Superiority for PRP | |||||||||||||||
Statistical analysis description |
The estimate of the difference between PR5I & INFANRIX hexa groups in PRP response rate (based on Ab titre ≥1.0 µg/mL) was calculated with its 1-sided P-value & 2-sided 95% confidence interval (CI). If the lower bound of the 95% CI was greater than 0, it was concluded that PR5I group response rate was superior to INFANRIX hexa group response rate.
Analysis was done on the PP-RW population: N=609, 592 (PR5I group, INFANRIX hexa group).
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Comparison groups |
PR5I v INFANRIX hexa
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Number of subjects included in analysis |
1300
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Analysis specification |
Pre-specified
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Analysis type |
superiority [3] | |||||||||||||||
P-value |
< 0.001 | |||||||||||||||
Method |
Miettinen & Nurminen with stratification | |||||||||||||||
Parameter type |
Difference in percentages of subjects | |||||||||||||||
Point estimate |
46.2
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Confidence interval |
||||||||||||||||
level |
95% | |||||||||||||||
sides |
2-sided
|
|||||||||||||||
lower limit |
41.05 | |||||||||||||||
upper limit |
51.06 | |||||||||||||||
Notes [3] - Statistical analysis was based on the Miettinen & Nurminen method stratified by country. |
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End point title |
Non-inferiority of antibody (Ab) response rates to PR5I antigens one month after the Toddler dose of PR5I (11 to 12 months of age) as compared with INFANRIX hexa | ||||||||||||||||||||||||||||||||||||||||||
End point description |
% of subjects with an Ab titre ≥1.0 μg/mL for Hib (PRP); ≥10 mIU/mL for Hepatitis B (HBsAg); ≥0.1 IU/mL for diphtheria & tetanus; ≥8 (1/dil) for IPV1, 2 & 3, and % of pertussis seroresponder subjects (Pertussis toxoid (PT), Filamentous haemagglutinin (FHA) & Pertactin (PRN)) 1 month Post-Toddler dose of PR5I.
Seroresponse was defined: (1) If pre-Dose 1 Ab concentration (cc) was <LLOQ (lower limit of quantitation), postvaccination Ab cc was ≥LLOQ, (2) If pre-Dose 1 Ab cc was ≥LLOQ, postvaccination Ab cc was ≥prevaccination levels.
Ab titres were measured by RIA for PRP, ECi for HBsAg, MIT for diphtheria & poliovirus, and ELISA for PT, FHA, PRN & tetanus.
Analysis was done on the PP-RW population.
Note: (N=***, ***) represents the number of assessed subjects in the PR5I and INFANRIX hexa groups, respectively.
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End point type |
Secondary
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End point timeframe |
1 month after the Toddler dose of PR5I or INFANRIX hexa (Post-Toddler Dose).
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Statistical analysis title |
Non-inferiority for PRP | ||||||||||||||||||||||||||||||||||||||||||
Statistical analysis description |
The estimate of the difference between PR5I & INFANRIX hexa groups in PRP response rate (based on Ab titre ≥1.0 µg/mL) was calculated with its 1-sided P-value & 2-sided 95% confidence interval (CI). If the lower bound of the 95% CI was greater than -10% (non-inferiority margin), it was concluded that PR5I group response rate was non-inferior to INFANRIX hexa group response rate.
Analysis was done on the PP-RW population: N=454, 478 (PR5I group, INFANRIX hexa group).
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Comparison groups |
PR5I v INFANRIX hexa
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Number of subjects included in analysis |
1280
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Analysis specification |
Pre-specified
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||||||||||||||||||||||||||||||||||||||||||
Analysis type |
non-inferiority [4] | ||||||||||||||||||||||||||||||||||||||||||
P-value |
< 0.001 | ||||||||||||||||||||||||||||||||||||||||||
Method |
Miettinen & Nurminen with stratification | ||||||||||||||||||||||||||||||||||||||||||
Parameter type |
Difference in percentages of subjects | ||||||||||||||||||||||||||||||||||||||||||
Point estimate |
-1.27
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Confidence interval |
|||||||||||||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||||||||||||
lower limit |
-5.13 | ||||||||||||||||||||||||||||||||||||||||||
upper limit |
2.52 | ||||||||||||||||||||||||||||||||||||||||||
Notes [4] - Statistical analysis was based on the Miettinen & Nurminen method stratified by country. |
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Statistical analysis title |
Non-inferiority for HBsAg | ||||||||||||||||||||||||||||||||||||||||||
Statistical analysis description |
The estimate of the difference between PR5I & INFANRIX hexa groups in HBsAg response rate (based on Ab titre ≥10 mIU/mL) was calculated with its 1-sided P-value & 2-sided 95% confidence interval (CI). If the lower bound of the 95% CI was greater than -10% (non-inferiority margin), it was concluded that PR5I group response rate was non-inferior to INFANRIX hexa group response rate.
Analysis was done on the PP-RW population: N=377, 391 (PR5I group, INFANRIX hexa group).
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Comparison groups |
PR5I v INFANRIX hexa
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Number of subjects included in analysis |
1280
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||||||||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||||||||||||
Analysis type |
non-inferiority [5] | ||||||||||||||||||||||||||||||||||||||||||
P-value |
< 0.001 | ||||||||||||||||||||||||||||||||||||||||||
Method |
Miettinen & Nurminen with stratification | ||||||||||||||||||||||||||||||||||||||||||
Parameter type |
Difference in percentages of subjects | ||||||||||||||||||||||||||||||||||||||||||
Point estimate |
-0.59
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Confidence interval |
|||||||||||||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||||||||||||
lower limit |
-2.66 | ||||||||||||||||||||||||||||||||||||||||||
upper limit |
1.35 | ||||||||||||||||||||||||||||||||||||||||||
Notes [5] - Statistical analysis was based on the Miettinen & Nurminen method stratified by country. |
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Statistical analysis title |
Non-inferiority for Diphtheria | ||||||||||||||||||||||||||||||||||||||||||
Statistical analysis description |
The estimate of the difference between PR5I & INFANRIX hexa groups in Diphtheria response rate (based on Ab titre ≥0.1 IU/mL) was calculated with its 1-sided P-value & 2-sided 95% confidence interval (CI). If the lower bound of the 95% CI was greater than -10% (non-inferiority margin), it was concluded that PR5I group response rate was non-inferior to INFANRIX hexa group response rate.
Analysis was done on the PP-RW population: N=590, 578 (PR5I group, INFANRIX hexa group).
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Comparison groups |
PR5I v INFANRIX hexa
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||||||||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
1280
|
||||||||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||||||||||||
Analysis type |
non-inferiority [6] | ||||||||||||||||||||||||||||||||||||||||||
P-value |
< 0.001 | ||||||||||||||||||||||||||||||||||||||||||
Method |
Miettinen & Nurminen with stratification | ||||||||||||||||||||||||||||||||||||||||||
Parameter type |
Difference in percentages of subjects | ||||||||||||||||||||||||||||||||||||||||||
Point estimate |
-1.21
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Confidence interval |
|||||||||||||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||||||||||||
lower limit |
-2.54 | ||||||||||||||||||||||||||||||||||||||||||
upper limit |
-0.22 | ||||||||||||||||||||||||||||||||||||||||||
Notes [6] - Statistical analysis was based on the Miettinen & Nurminen method stratified by country. |
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Statistical analysis title |
Non-inferiority for Tetanus | ||||||||||||||||||||||||||||||||||||||||||
Statistical analysis description |
The estimate of the difference between PR5I & INFANRIX hexa groups in Tetanus response rate (based on Ab titre ≥0.1 IU/mL) was calculated with its 1-sided P-value & 2-sided 95% confidence interval (CI). If the lower bound of the 95% CI was greater than -5% (non-inferiority margin), it was concluded that PR5I group response rate was non-inferior to INFANRIX hexa group response rate.
Analysis was done on the PP-RW population: N=589, 577 (PR5I group, INFANRIX hexa group).
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Comparison groups |
PR5I v INFANRIX hexa
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||||||||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
1280
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||||||||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||||||||||||
Analysis type |
non-inferiority [7] | ||||||||||||||||||||||||||||||||||||||||||
P-value |
< 0.001 | ||||||||||||||||||||||||||||||||||||||||||
Method |
Miettinen & Nurminen with stratification | ||||||||||||||||||||||||||||||||||||||||||
Parameter type |
Difference in percentages of subjects | ||||||||||||||||||||||||||||||||||||||||||
Point estimate |
-0.17
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||||||||||||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||||||||||||
lower limit |
-0.95 | ||||||||||||||||||||||||||||||||||||||||||
upper limit |
0.5 | ||||||||||||||||||||||||||||||||||||||||||
Notes [7] - Statistical analysis was based on the Miettinen & Nurminen method stratified by country. |
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Statistical analysis title |
Non-inferiority for PT | ||||||||||||||||||||||||||||||||||||||||||
Statistical analysis description |
The estimate of the difference between PR5I & INFANRIX hexa groups in the percentage of seroresponder subjects for PT was calculated with its 1-sided P-value & 2-sided 95% confidence interval (CI). If the lower bound of the 95% CI was greater than -10% (non-inferiority margin), it was concluded that PR5I group response rate was non-inferior to INFANRIX hexa group response rate.
Analysis was done on the PP-RW population: N=566, 561 (PR5I group, INFANRIX hexa group).
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Comparison groups |
PR5I v INFANRIX hexa
|
||||||||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
1280
|
||||||||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||||||||||||
Analysis type |
non-inferiority [8] | ||||||||||||||||||||||||||||||||||||||||||
P-value |
< 0.001 | ||||||||||||||||||||||||||||||||||||||||||
Method |
Miettinen & Nurminen with stratification | ||||||||||||||||||||||||||||||||||||||||||
Parameter type |
Difference in percentages of subjects | ||||||||||||||||||||||||||||||||||||||||||
Point estimate |
-0.54
|
||||||||||||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||||||||||||
lower limit |
-1.75 | ||||||||||||||||||||||||||||||||||||||||||
upper limit |
0.49 | ||||||||||||||||||||||||||||||||||||||||||
Notes [8] - Statistical analysis was based on the Miettinen & Nurminen method stratified by country. |
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Statistical analysis title |
Non-inferiority for FHA | ||||||||||||||||||||||||||||||||||||||||||
Statistical analysis description |
The estimate of the difference between PR5I & INFANRIX hexa groups in the percentage of seroresponder subjects for FHA was calculated with its 1-sided P-value & 2-sided 95% confidence interval (CI). If the lower bound of the 95% CI was greater than -10% (non-inferiority margin), it was concluded that PR5I group response rate was non-inferior to INFANRIX hexa group response rate.
Analysis was done on the PP-RW population: N=582, 571 (PR5I group, INFANRIX hexa group).
|
||||||||||||||||||||||||||||||||||||||||||
Comparison groups |
PR5I v INFANRIX hexa
|
||||||||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
1280
|
||||||||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||||||||||||
Analysis type |
non-inferiority [9] | ||||||||||||||||||||||||||||||||||||||||||
P-value |
< 0.001 | ||||||||||||||||||||||||||||||||||||||||||
Method |
Miettinen & Nurminen with stratification | ||||||||||||||||||||||||||||||||||||||||||
Parameter type |
Difference in percentages of subjects | ||||||||||||||||||||||||||||||||||||||||||
Point estimate |
-1.73
|
||||||||||||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||||||||||||
lower limit |
-3.47 | ||||||||||||||||||||||||||||||||||||||||||
upper limit |
-0.26 | ||||||||||||||||||||||||||||||||||||||||||
Notes [9] - Statistical analysis was based on the Miettinen & Nurminen method stratified by country. |
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Statistical analysis title |
Non-inferiority for PRN | ||||||||||||||||||||||||||||||||||||||||||
Statistical analysis description |
The estimate of the difference between PR5I & INFANRIX hexa groups in the percentage of seroresponder subjects for PRN was calculated with its 1-sided P-value & 2-sided 95% confidence interval (CI). If the lower bound of the 95% CI was greater than -10% (non-inferiority margin), it was concluded that PR5I group response rate was non-inferior to INFANRIX hexa group response rate.
Analysis was done on the PP-RW population: N=582, 572 (PR5I group, INFANRIX hexa group).
|
||||||||||||||||||||||||||||||||||||||||||
Comparison groups |
PR5I v INFANRIX hexa
|
||||||||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
1280
|
||||||||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||||||||||||
Analysis type |
non-inferiority [10] | ||||||||||||||||||||||||||||||||||||||||||
P-value |
< 0.001 | ||||||||||||||||||||||||||||||||||||||||||
Method |
Miettinen & Nurminen with stratification | ||||||||||||||||||||||||||||||||||||||||||
Parameter type |
Difference in percentages of subjects | ||||||||||||||||||||||||||||||||||||||||||
Point estimate |
-1.42
|
||||||||||||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||||||||||||
lower limit |
-3.42 | ||||||||||||||||||||||||||||||||||||||||||
upper limit |
0.39 | ||||||||||||||||||||||||||||||||||||||||||
Notes [10] - Statistical analysis was based on the Miettinen & Nurminen method stratified by country. |
|||||||||||||||||||||||||||||||||||||||||||
Statistical analysis title |
Non-inferiority for IPV1 | ||||||||||||||||||||||||||||||||||||||||||
Statistical analysis description |
The estimate of the difference between PR5I & INFANRIX hexa groups in IPV1 response rate (based on Ab titre ≥8 (1/dil)) was calculated with its 1-sided P-value & 2-sided 95% confidence interval (CI). If the lower bound of the 95% CI was greater than -5% (non-inferiority margin), it was concluded that PR5I group response rate was non-inferior to INFANRIX hexa group response rate.
Analysis was done on the PP-RW population: N=591, 580 (PR5I group, INFANRIX hexa group).
|
||||||||||||||||||||||||||||||||||||||||||
Comparison groups |
PR5I v INFANRIX hexa
|
||||||||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
1280
|
||||||||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||||||||||||
Analysis type |
non-inferiority [11] | ||||||||||||||||||||||||||||||||||||||||||
P-value |
< 0.001 | ||||||||||||||||||||||||||||||||||||||||||
Method |
Miettinen & Nurminen with stratification | ||||||||||||||||||||||||||||||||||||||||||
Parameter type |
Difference in percentages of subjects | ||||||||||||||||||||||||||||||||||||||||||
Point estimate |
-0.51
|
||||||||||||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||||||||||||
lower limit |
-1.59 | ||||||||||||||||||||||||||||||||||||||||||
upper limit |
0.34 | ||||||||||||||||||||||||||||||||||||||||||
Notes [11] - Statistical analysis was based on the Miettinen & Nurminen method stratified by country. |
|||||||||||||||||||||||||||||||||||||||||||
Statistical analysis title |
Non-inferiority for IPV2 | ||||||||||||||||||||||||||||||||||||||||||
Statistical analysis description |
The estimate of the difference between PR5I & INFANRIX hexa groups in IPV2 response rate (based on Ab titre ≥8 (1/dil)) was calculated with its 1-sided P-value & 2-sided 95% confidence interval (CI). If the lower bound of the 95% CI was greater than -5% (non-inferiority margin), it was concluded that PR5I group response rate was non-inferior to INFANRIX hexa group response rate.
Analysis was done on the PP-RW population: N=591, 579 (PR5I group, INFANRIX hexa group).
|
||||||||||||||||||||||||||||||||||||||||||
Comparison groups |
PR5I v INFANRIX hexa
|
||||||||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
1280
|
||||||||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||||||||||||
Analysis type |
non-inferiority [12] | ||||||||||||||||||||||||||||||||||||||||||
P-value |
< 0.001 | ||||||||||||||||||||||||||||||||||||||||||
Method |
Miettinen & Nurminen with stratification | ||||||||||||||||||||||||||||||||||||||||||
Parameter type |
Difference in percentages of subjects | ||||||||||||||||||||||||||||||||||||||||||
Point estimate |
-0.17
|
||||||||||||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||||||||||||
lower limit |
-0.96 | ||||||||||||||||||||||||||||||||||||||||||
upper limit |
0.49 | ||||||||||||||||||||||||||||||||||||||||||
Notes [12] - Statistical analysis was based on the Miettinen & Nurminen method stratified by country. |
|||||||||||||||||||||||||||||||||||||||||||
Statistical analysis title |
Non-inferiority for IPV3 | ||||||||||||||||||||||||||||||||||||||||||
Statistical analysis description |
The estimate of the difference between PR5I & INFANRIX hexa groups in IPV3 response rate (based on Ab titre ≥8 (1/dil)) was calculated with its 1-sided P-value & 2-sided 95% confidence interval (CI). If the lower bound of the 95% CI was greater than -5% (non-inferiority margin), it was concluded that PR5I group response rate was non-inferior to INFANRIX hexa group response rate.
Analysis was done on the PP-RW population: N=590, 579 (PR5I group, INFANRIX hexa group).
|
||||||||||||||||||||||||||||||||||||||||||
Comparison groups |
PR5I v INFANRIX hexa
|
||||||||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
1280
|
||||||||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||||||||||||
Analysis type |
non-inferiority [13] | ||||||||||||||||||||||||||||||||||||||||||
P-value |
< 0.001 | ||||||||||||||||||||||||||||||||||||||||||
Method |
Miettinen & Nurminen with stratification | ||||||||||||||||||||||||||||||||||||||||||
Parameter type |
Difference in percentages of subjects | ||||||||||||||||||||||||||||||||||||||||||
Point estimate |
-0.16
|
||||||||||||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||||||||||||
lower limit |
-1.2 | ||||||||||||||||||||||||||||||||||||||||||
upper limit |
0.82 | ||||||||||||||||||||||||||||||||||||||||||
Notes [13] - Statistical analysis was based on the Miettinen & Nurminen method stratified by country. |
|
||||||||||||||||
End point title |
Non-inferiority of Rotavirus response (geometric mean titer, GMT) one month after the 2nd dose of Rotarix (4 months of age) administered concomitantly with PR5I versus INFANRIX hexa | |||||||||||||||
End point description |
Antibody titres expressed in units/mL were measured for Rotavirus IgA by Enzyme Immunoassay (EIA), 1 month after the 2nd dose of Rotarix, administered concomitantly with PR5I or INFANRIX hexa (Post-Dose 2).
Analysis was done on the PP-RW population, subgroups "PR5I - Rotarix" and "INFANRIX hexa - Rotarix".
Note: (N=***, ***) represents the number of assessed subjects in the PR5I and INFANRIX hexa groups, respectively.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
1 month after the 2nd dose of Rotarix, administered concomitantly with PR5I or INFANRIX hexa (Post-Dose 2).
|
|||||||||||||||
|
||||||||||||||||
Statistical analysis title |
Non-inferiority for Rotavirus IgA | |||||||||||||||
Statistical analysis description |
The estimate for anti-rotavirus IgA GMT ratio (PR5I group/INFANRIX hexa group) was calculated with its 1-sided P-value and 2-sided 95% CI. If the lower bound of the 95% CI for GMT ratio was greater than 0.50 (non-inferiority margin), it was concluded that the Rotarix antigen response in the PR5I group was not inferior to the Rotarix antigen response in the INFANRIX hexa group.
Analysis was done on the PP-RW population, Subgroups Rotarix: N=160, 171 (PR5I group, INFANRIX hexa group).
|
|||||||||||||||
Comparison groups |
PR5I - Rotarix v INFANRIX hexa - Rotarix
|
|||||||||||||||
Number of subjects included in analysis |
331
|
|||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||
Analysis type |
non-inferiority [14] | |||||||||||||||
P-value |
= 0.011 | |||||||||||||||
Method |
ANCOVA | |||||||||||||||
Parameter type |
Geometric Mean Titer (GMT) ratio | |||||||||||||||
Point estimate |
0.8
|
|||||||||||||||
Confidence interval |
||||||||||||||||
level |
95% | |||||||||||||||
sides |
2-sided
|
|||||||||||||||
lower limit |
0.54 | |||||||||||||||
upper limit |
1.2 | |||||||||||||||
Notes [14] - Statistical analysis was based on an ANCOVA model. |
|
|||||||||||||||||||||||||||||||||||||
End point title |
Global safety from D1 to D15 after any vaccination | ||||||||||||||||||||||||||||||||||||
End point description |
Injection-site and systemic adverse events (AEs) were reported daily on the Vaccination Report Card (VRC) by the parent(s) or legal representative from Day 1 (D1) to D15 after each vaccination.
Solicited injection-site and systemic AEs were reported daily from D1 to D5 after each vaccination.
AEs at injection sites were always considered as vaccine-related (V-related) (Injection-Site Reactions (ISRs)).
The investigator had to assess whether systemic AEs were related or not to the vaccine.
All AEs (related and unrelated) are displayed here.
Analysis was done on the All Subjects as Treated (ASaT) population, i.e. all randomised subjects (N=1312) who received at least 1 vaccination and who had safety follow-up.
|
||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||
End point timeframe |
From Day 1 (D1) to D15 after any vaccination.
|
||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
Statistical analysis title |
ISRs or systemic AEs | ||||||||||||||||||||||||||||||||||||
Statistical analysis description |
The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate an overall trend and not any specific difference. If 0.0 was excluded from the 95% CI, the trend could not be ruled out.
Analysis was done on the All Subjects as Treated (ASaT) population.
|
||||||||||||||||||||||||||||||||||||
Comparison groups |
PR5I v INFANRIX hexa
|
||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
1312
|
||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||||||
Analysis type |
other | ||||||||||||||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||||||||||||||
Parameter type |
Risk difference (RD) | ||||||||||||||||||||||||||||||||||||
Point estimate |
0.3
|
||||||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||||||
lower limit |
-0.7 | ||||||||||||||||||||||||||||||||||||
upper limit |
1.4 | ||||||||||||||||||||||||||||||||||||
Statistical analysis title |
ISRs or vaccine-related systemic AEs | ||||||||||||||||||||||||||||||||||||
Statistical analysis description |
The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate an overall trend and not any specific difference. If 0.0 was excluded from the 95% CI, the trend could not be ruled out.
Analysis was done on the All Subjects as Treated (ASaT) population.
|
||||||||||||||||||||||||||||||||||||
Comparison groups |
PR5I v INFANRIX hexa
|
||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
1312
|
||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||||||
Analysis type |
other | ||||||||||||||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||||||||||||||
Parameter type |
Risk difference (RD) | ||||||||||||||||||||||||||||||||||||
Point estimate |
0.8
|
||||||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||||||
lower limit |
-0.3 | ||||||||||||||||||||||||||||||||||||
upper limit |
2 | ||||||||||||||||||||||||||||||||||||
Statistical analysis title |
At least 1 ISR | ||||||||||||||||||||||||||||||||||||
Statistical analysis description |
The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate an overall trend and not any specific difference. If 0.0 was excluded from the 95% CI, the trend could not be ruled out.
Analysis was done on the All Subjects as Treated (ASaT) population.
|
||||||||||||||||||||||||||||||||||||
Comparison groups |
PR5I v INFANRIX hexa
|
||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
1312
|
||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||||||
Analysis type |
other | ||||||||||||||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||||||||||||||
Parameter type |
Risk difference (RD) | ||||||||||||||||||||||||||||||||||||
Point estimate |
2.6
|
||||||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||||||
lower limit |
-0.7 | ||||||||||||||||||||||||||||||||||||
upper limit |
6 | ||||||||||||||||||||||||||||||||||||
Statistical analysis title |
At least 1 solicited ISR | ||||||||||||||||||||||||||||||||||||
Statistical analysis description |
The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate an overall trend and not any specific difference. If 0.0 was excluded from the 95% CI, the trend could not be ruled out.
Analysis was done on the All Subjects as Treated (ASaT) population.
|
||||||||||||||||||||||||||||||||||||
Comparison groups |
PR5I v INFANRIX hexa
|
||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
1312
|
||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||||||
Analysis type |
other | ||||||||||||||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||||||||||||||
Parameter type |
Risk difference (RD) | ||||||||||||||||||||||||||||||||||||
Point estimate |
2.5
|
||||||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||||||
lower limit |
-0.9 | ||||||||||||||||||||||||||||||||||||
upper limit |
5.9 | ||||||||||||||||||||||||||||||||||||
Statistical analysis title |
At least 1 systemic AE | ||||||||||||||||||||||||||||||||||||
Statistical analysis description |
The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate an overall trend and not any specific difference. If 0.0 was excluded from the 95% CI, the trend could not be ruled out.
Analysis was done on the All Subjects as Treated (ASaT) population.
|
||||||||||||||||||||||||||||||||||||
Comparison groups |
PR5I v INFANRIX hexa
|
||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
1312
|
||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||||||
Analysis type |
other | ||||||||||||||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||||||||||||||
Parameter type |
Risk difference (RD) | ||||||||||||||||||||||||||||||||||||
Point estimate |
0.1
|
||||||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||||||
lower limit |
-1.1 | ||||||||||||||||||||||||||||||||||||
upper limit |
1.4 | ||||||||||||||||||||||||||||||||||||
Statistical analysis title |
At least 1 vaccine-related systemic AE | ||||||||||||||||||||||||||||||||||||
Statistical analysis description |
The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate an overall trend and not any specific difference. If 0.0 was excluded from the 95% CI, the trend could not be ruled out.
Analysis was done on the All Subjects as Treated (ASaT) population.
|
||||||||||||||||||||||||||||||||||||
Comparison groups |
PR5I v INFANRIX hexa
|
||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
1312
|
||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||||||
Analysis type |
other | ||||||||||||||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||||||||||||||
Parameter type |
Risk difference (RD) | ||||||||||||||||||||||||||||||||||||
Point estimate |
0.8
|
||||||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||||||
lower limit |
-0.5 | ||||||||||||||||||||||||||||||||||||
upper limit |
2.2 | ||||||||||||||||||||||||||||||||||||
Statistical analysis title |
At least 1 solicited systemic AE | ||||||||||||||||||||||||||||||||||||
Statistical analysis description |
The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate an overall trend and not any specific difference. If 0.0 was excluded from the 95% CI, the trend could not be ruled out.
Analysis was done on the All Subjects as Treated (ASaT) population.
|
||||||||||||||||||||||||||||||||||||
Comparison groups |
PR5I v INFANRIX hexa
|
||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
1312
|
||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||||||
Analysis type |
other | ||||||||||||||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||||||||||||||
Parameter type |
Risk difference (RD) | ||||||||||||||||||||||||||||||||||||
Point estimate |
0.8
|
||||||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||||||
lower limit |
-0.5 | ||||||||||||||||||||||||||||||||||||
upper limit |
2.2 | ||||||||||||||||||||||||||||||||||||
Statistical analysis title |
At least 1 vaccine-related solicited systemic AE | ||||||||||||||||||||||||||||||||||||
Statistical analysis description |
The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate an overall trend and not any specific difference. If 0.0 was excluded from the 95% CI, the trend could not be ruled out.
Analysis was done on the All Subjects as Treated (ASaT) population.
|
||||||||||||||||||||||||||||||||||||
Comparison groups |
PR5I v INFANRIX hexa
|
||||||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
1312
|
||||||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||||||
Analysis type |
other | ||||||||||||||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||||||||||||||
Parameter type |
Risk difference (RD) | ||||||||||||||||||||||||||||||||||||
Point estimate |
0.9
|
||||||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||||||
lower limit |
-0.4 | ||||||||||||||||||||||||||||||||||||
upper limit |
2.3 |
|
||||||||||||||||||||||
End point title |
Proportion of subjects reporting solicited ISRs from D1 to D5 after any vaccination | |||||||||||||||||||||
End point description |
Adverse events at injection sites were always considered as related to vaccine (Injection-Site Reactions (ISRs)).
Solicited ISRs were defined as injection-site erythema, injection-site pain, and injection-site swelling occurring from Day 1 (D1) to D5 after vaccination.
Analysis was done on the All Subjects as Treated (ASaT) population, i.e. all randomised subjects (N=1312) who received at least 1 vaccination and who had safety follow-up.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
From Day 1 (D1) to D5 after any vaccination.
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
Injection-site erythema | |||||||||||||||||||||
Statistical analysis description |
The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate whether an overall trend of risk differences existed. If the 95% CI for the risk differences included 0.0, the numerical differences were not considered significant.
Analysis was done on the All Subjects as Treated (ASaT) population.
|
|||||||||||||||||||||
Comparison groups |
PR5I v INFANRIX hexa
|
|||||||||||||||||||||
Number of subjects included in analysis |
1312
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
other [15] | |||||||||||||||||||||
Method |
||||||||||||||||||||||
Parameter type |
Risk difference (RD) | |||||||||||||||||||||
Point estimate |
8.2
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
3 | |||||||||||||||||||||
upper limit |
13.3 | |||||||||||||||||||||
Notes [15] - Injection-site erythema: the 95% CI of the difference between the PR5I and INFANRIX™ hexa groups excluded 0 and was therefore statistically significant. The difference was not considered to be clinically significant as none of these events were considered serious or led to study discontinuation, and the majority were mild or moderate in intensity. |
||||||||||||||||||||||
Statistical analysis title |
Injection-site pain | |||||||||||||||||||||
Statistical analysis description |
The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate whether an overall trend of risk differences existed. If the 95% CI for the risk differences included 0.0, the numerical differences were not considered significant.
Analysis was done on the All Subjects as Treated (ASaT) population.
|
|||||||||||||||||||||
Comparison groups |
PR5I v INFANRIX hexa
|
|||||||||||||||||||||
Number of subjects included in analysis |
1312
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
other | |||||||||||||||||||||
Method |
||||||||||||||||||||||
Parameter type |
Risk difference (RD) | |||||||||||||||||||||
Point estimate |
3.4
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-1.5 | |||||||||||||||||||||
upper limit |
8.3 | |||||||||||||||||||||
Statistical analysis title |
Injection-site swelling | |||||||||||||||||||||
Statistical analysis description |
The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate whether an overall trend of risk differences existed. If the 95% CI for the risk differences included 0.0, the numerical differences were not considered significant.
Analysis was done on the All Subjects as Treated (ASaT) population.
|
|||||||||||||||||||||
Comparison groups |
PR5I v INFANRIX hexa
|
|||||||||||||||||||||
Number of subjects included in analysis |
1312
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
other [16] | |||||||||||||||||||||
Method |
||||||||||||||||||||||
Parameter type |
Risk difference (RD) | |||||||||||||||||||||
Point estimate |
7.5
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
2.1 | |||||||||||||||||||||
upper limit |
12.9 | |||||||||||||||||||||
Notes [16] - Injection-site swelling: the 95% CI of the difference between the PR5I and INFANRIX™ hexa groups excluded 0 and was therefore statistically significant. The difference was not considered to be clinically significant as none of these events were considered serious or led to study discontinuation, and the majority were mild or moderate in intensity. |
|
||||||||||||||||||||||||||||
End point title |
Proportion of subjects reporting unsolicited ISRs from D1 to D15 after any vaccination | |||||||||||||||||||||||||||
End point description |
Adverse events at injection sites were always considered as related to vaccine (Injection-Site Reactions (ISRs)).
Unsolicited ISRs occurring from Day 1 (D1) to D15 after any vaccination were reported daily on the VRC by the parent(s) or legal representative.
Unsolicited ISRs with incidence ≥1% are reported below.
Analysis was done on the All Subjects as Treated (ASaT) population, i.e. all randomised subjects (N=1312) who received at least 1 vaccination and who had safety follow-up.
|
|||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||
End point timeframe |
From Day 1 (D1) to D15 after any vaccination.
|
|||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||
Statistical analysis title |
Injection-site bruising | |||||||||||||||||||||||||||
Statistical analysis description |
The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate an overall trend and not any specific difference. If 0.0 was excluded from the 95% CI, the trend could not be ruled out.
Analysis was done on the All Subjects as Treated (ASaT) population.
|
|||||||||||||||||||||||||||
Comparison groups |
PR5I v INFANRIX hexa
|
|||||||||||||||||||||||||||
Number of subjects included in analysis |
1312
|
|||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||||||||
Analysis type |
other | |||||||||||||||||||||||||||
Method |
||||||||||||||||||||||||||||
Parameter type |
Risk difference (RD) | |||||||||||||||||||||||||||
Point estimate |
-1.1
|
|||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||
level |
95% | |||||||||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||||||||
lower limit |
-2.5 | |||||||||||||||||||||||||||
upper limit |
0.3 | |||||||||||||||||||||||||||
Statistical analysis title |
Injection-site haemorrhage | |||||||||||||||||||||||||||
Statistical analysis description |
The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate an overall trend and not any specific difference. If 0.0 was excluded from the 95% CI, the trend could not be ruled out.
Analysis was done on the All Subjects as Treated (ASaT) population.
|
|||||||||||||||||||||||||||
Comparison groups |
PR5I v INFANRIX hexa
|
|||||||||||||||||||||||||||
Number of subjects included in analysis |
1312
|
|||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||||||||
Analysis type |
other | |||||||||||||||||||||||||||
Method |
||||||||||||||||||||||||||||
Parameter type |
Risk difference (RD) | |||||||||||||||||||||||||||
Point estimate |
0
|
|||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||
level |
95% | |||||||||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||||||||
lower limit |
-1.5 | |||||||||||||||||||||||||||
upper limit |
1.6 | |||||||||||||||||||||||||||
Statistical analysis title |
Injection-site induration | |||||||||||||||||||||||||||
Statistical analysis description |
The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate an overall trend and not any specific difference. If 0.0 was excluded from the 95% CI, the trend could not be ruled out.
Analysis was done on the All Subjects as Treated (ASaT) population.
|
|||||||||||||||||||||||||||
Comparison groups |
PR5I v INFANRIX hexa
|
|||||||||||||||||||||||||||
Number of subjects included in analysis |
1312
|
|||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||||||||
Analysis type |
other | |||||||||||||||||||||||||||
Method |
||||||||||||||||||||||||||||
Parameter type |
Risk difference (RD) | |||||||||||||||||||||||||||
Point estimate |
2.6
|
|||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||
level |
95% | |||||||||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||||||||
lower limit |
-1.2 | |||||||||||||||||||||||||||
upper limit |
6.4 | |||||||||||||||||||||||||||
Statistical analysis title |
Injection-site nodule | |||||||||||||||||||||||||||
Statistical analysis description |
The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate an overall trend and not any specific difference. If 0.0 was excluded from the 95% CI, the trend could not be ruled out.
Analysis was done on the All Subjects as Treated (ASaT) population.
|
|||||||||||||||||||||||||||
Comparison groups |
PR5I v INFANRIX hexa
|
|||||||||||||||||||||||||||
Number of subjects included in analysis |
1312
|
|||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||||||||
Analysis type |
other | |||||||||||||||||||||||||||
Method |
||||||||||||||||||||||||||||
Parameter type |
Risk difference (RD) | |||||||||||||||||||||||||||
Point estimate |
0.3
|
|||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||
level |
95% | |||||||||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||||||||
lower limit |
-0.8 | |||||||||||||||||||||||||||
upper limit |
1.5 | |||||||||||||||||||||||||||
Statistical analysis title |
Injection-site warmth | |||||||||||||||||||||||||||
Statistical analysis description |
The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate an overall trend and not any specific difference. If 0.0 was excluded from the 95% CI, the trend could not be ruled out.
Analysis was done on the All Subjects as Treated (ASaT) population.
|
|||||||||||||||||||||||||||
Comparison groups |
PR5I v INFANRIX hexa
|
|||||||||||||||||||||||||||
Number of subjects included in analysis |
1312
|
|||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||||||||
Analysis type |
other | |||||||||||||||||||||||||||
Method |
||||||||||||||||||||||||||||
Parameter type |
Risk difference (RD) | |||||||||||||||||||||||||||
Point estimate |
1.1
|
|||||||||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||||||||
level |
95% | |||||||||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||||||||
lower limit |
-0.4 | |||||||||||||||||||||||||||
upper limit |
2.7 |
|
|||||||||||||||||||||||||||||||
End point title |
Proportion of subjects reporting solicited systemic adverse events (AEs) from D1 to D5 after any vaccination | ||||||||||||||||||||||||||||||
End point description |
Solicited systemic AEs were defined as crying, decreased appetite, irritability, pyrexia (rectal temperature ≥38.0°C), somnolence, and vomiting occurring from Day 1 (D1) to D5 after vaccination.
The investigator had to assess whether these systemic AEs were related or not to the vaccines. All (related and unrelated) are displayed here.
Analysis was done on the All Subjects as Treated (ASaT) population, i.e. all randomised subjects (N=1312) who received at least 1 vaccination and who had safety follow-up.
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
From Day 1 (D1) to D5 after any vaccination.
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
Statistical analysis title |
Crying | ||||||||||||||||||||||||||||||
Statistical analysis description |
The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate whether an overall trend of risk differences existed. If the 95% CI for the risk differences included 0.0, the numerical differences were not considered significant.
|
||||||||||||||||||||||||||||||
Comparison groups |
PR5I v INFANRIX hexa
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
1312
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
other | ||||||||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||||||||
Parameter type |
Risk difference (RD) | ||||||||||||||||||||||||||||||
Point estimate |
2.2
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-1.3 | ||||||||||||||||||||||||||||||
upper limit |
5.7 | ||||||||||||||||||||||||||||||
Statistical analysis title |
Decreased appetite | ||||||||||||||||||||||||||||||
Statistical analysis description |
The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate whether an overall trend of risk differences existed. If the 95% CI for the risk differences included 0.0, the numerical differences were not considered significant.
|
||||||||||||||||||||||||||||||
Comparison groups |
PR5I v INFANRIX hexa
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
1312
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
other | ||||||||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||||||||
Parameter type |
Risk difference (RD) | ||||||||||||||||||||||||||||||
Point estimate |
3.6
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-1.6 | ||||||||||||||||||||||||||||||
upper limit |
8.8 | ||||||||||||||||||||||||||||||
Statistical analysis title |
Irritability | ||||||||||||||||||||||||||||||
Statistical analysis description |
The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate whether an overall trend of risk differences existed. If the 95% CI for the risk differences included 0.0, the numerical differences were not considered significant.
|
||||||||||||||||||||||||||||||
Comparison groups |
PR5I v INFANRIX hexa
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
1312
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
other | ||||||||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||||||||
Parameter type |
Risk difference (RD) | ||||||||||||||||||||||||||||||
Point estimate |
2.2
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-1 | ||||||||||||||||||||||||||||||
upper limit |
5.4 | ||||||||||||||||||||||||||||||
Statistical analysis title |
Pyrexia | ||||||||||||||||||||||||||||||
Statistical analysis description |
The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate whether an overall trend of risk differences existed. If the 95% CI for the risk differences included 0.0, the numerical differences were not considered significant.
|
||||||||||||||||||||||||||||||
Comparison groups |
PR5I v INFANRIX hexa
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
1312
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
other [17] | ||||||||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||||||||
Parameter type |
Risk difference (RD) | ||||||||||||||||||||||||||||||
Point estimate |
6.4
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
1.5 | ||||||||||||||||||||||||||||||
upper limit |
11.3 | ||||||||||||||||||||||||||||||
Notes [17] - Pyrexia: the 95% CI of the difference between PR5I and INFANRIX™ hexa groups excluded 0 and was statistically significant. The difference was not considered to be clinically significant as the majority were of mild to moderate intensity and did not result in any study discontinuations. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Somnolence | ||||||||||||||||||||||||||||||
Statistical analysis description |
The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate whether an overall trend of risk differences existed. If the 95% CI for the risk differences included 0.0, the numerical differences were not considered significant.
|
||||||||||||||||||||||||||||||
Comparison groups |
PR5I v INFANRIX hexa
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
1312
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
other [18] | ||||||||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||||||||
Parameter type |
Risk difference (RD) | ||||||||||||||||||||||||||||||
Point estimate |
5.8
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
1.7 | ||||||||||||||||||||||||||||||
upper limit |
9.8 | ||||||||||||||||||||||||||||||
Notes [18] - The 95% CI of the difference between PR5I and INFANRIX™ hexa groups excluded 0 and was statistically significant. The difference was not considered to be clinically significant as the majority were of mild to moderate intensity and did not result in any study discontinuations. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Vomiting | ||||||||||||||||||||||||||||||
Statistical analysis description |
The risk differences between groups (PR5I group – INFANRIX hexa group) and their 2-sided 95% confidence interval (CI) were calculated for the above criteria based on the unstratified Miettinen & Nurminen method. The aim of the 95% CI was to investigate whether an overall trend of risk differences existed. If the 95% CI for the risk differences included 0.0, the numerical differences were not considered significant.
|
||||||||||||||||||||||||||||||
Comparison groups |
PR5I v INFANRIX hexa
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
1312
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
other | ||||||||||||||||||||||||||||||
Method |
|||||||||||||||||||||||||||||||
Parameter type |
Risk difference (RD) | ||||||||||||||||||||||||||||||
Point estimate |
1.8
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-3.2 | ||||||||||||||||||||||||||||||
upper limit |
6.9 |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Unsolicited non-serious and serious adverse events (AEs) were collected from D1 to D15 after each hexavalent vaccination.
Vaccine-related serious AEs and deaths were collected for the duration of the study.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Analysis of AEs was done on the All Subjects as Treated (ASaT) population, i.e. all randomised subjects (N=1312) who received at least 1 vaccination and who had safety follow-up.
Unsolicited non-serious systemic AEs (vaccine-related or not) with incidence ≥2.5% are presented hereafter.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Non-systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16.1
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Reporting groups
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Reporting group title |
PR5I
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Reporting group description |
# Subjects received 1 dose of PR5I (DTaP-HB-IPV-Hib) by intramuscular route (IM) + 1 dose of Prevenar 13 (PCV-13) by IM route (opposite leg) at 2 and 4 months of age. # Subjects also received either 1 dose of Rotarix at 2 and 4 months of age (in Italy & Sweden) or 1 dose of RotaTeq at 2, 4, and 5 months of age (in Finland), both by oral route. # Respectively, 342 (52.4%) subjects reported at least 1 unsolicited non-serious systemic AE, and 172 (26.3%) subjects reported at least 1 vaccine-related unsolicited non-serious systemic AE within 15 days after any vaccination. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
INFANRIX hexa
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Reporting group description |
# Subjects received 1 dose of INFANRIX hexa (DTaP-HBV-IPV-Hib) by intramuscular route (IM) + 1 dose of Prevenar 13 (PCV-13) by IM route (opposite leg) at 2 and 4 months of age. # Subjects also received either 1 dose of Rotarix at 2 and 4 months of age (in Italy & Sweden) or 1 dose of RotaTeq at 2, 4, and 5 months of age (in Finland), both by oral route. # Respectively, 319 (48.4%) subjects reported at least 1 unsolicited non-serious systemic AE, and 149 (22.6%) subjects reported at least 1 vaccine-related unsolicited non-serious systemic AE within 15 days after any vaccination. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 2.5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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01 Apr 2011 |
Protocol Amendment submitted to the regulatory authority in Finland only.
# This amendment was in response to the change in Rotarix™ availability in some EU countries. This amendment allowed for subsets of subjects to receive 1 of 2 available rotavirus vaccines, either Rotarix™ or RotaTeq™. The specific primary changes were as follows:
1. Designation that a subset of subjects were to receive Rotarix™ concomitantly with PR5I or INFANRIX™ hexa, while another subset of subjects were to receive
RotaTeq™ concomitantly with PR5I or INFANRIX™ hexa. Vaccine designation was to be site specific.
2. Revision of the power statement for the secondary hypothesis for Rotarix™ immunogenicity since Rotarix™ was to be administered to a subset of subjects,
and not the entire study population as the original protocol indicated.
3. Indication that RotaTeq™ was to be administered at 2, 4, and 5 months of age. This dosing schedule was consistent with the product label.
# In addition, the text in all relevant sections was updated to reflect a change in timing of when non-study vaccines could be received during the study; non-study licensed pediatric vaccines were not to be administered within 30 days before or after any dose of study vaccine, except for inactivated influenza vaccine, which was not to be administered within 14 days before or after any dose of study vaccine. |
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13 May 2011 |
Protocol Amendment submitted to the regulatory authority in Finland, Italy and Sweden.
This amendment stated that RotaTeq™, a vaccine administered concomitantly with PR5I that was not evaluated for immunogenicity, was to be supplied centrally by the Sponsor Representative (it was originally planned to be sourced locally by study sites, but local sourcing was not operationally feasible). This was also to have the additional benefit of greater control over vaccine accountability and cold-chain.
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20 Jan 2012 |
Country-specific protocol amendment for Finland.
This amendment allowed the 1st dose of RotaTeq™ to be given in Finland prior to Visit 1 outside the study, as RotaTeq™ is recommended to be given as early
as 6 weeks of age in the Finnish pediatric vaccination schedule. This amendment was to allow for flexibility for study entry within the full prespecified age range (46 to 89 days), even if a subject had received RotaTeq™ through the Finnish national vaccine program. |
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25 Apr 2013 |
Country-specific protocol amendment for Finland.
# Section 2.7.1, Immunogenicity of PR5I:
- Addition of a new primary statistical analysis method for all GMT analyses (i.e., MI ANCOVA) to account for missing baseline titers due to limited serum volumes obtained from 2-month old infant subjects at study entry.
- Addition of a second PP population (referred to as PP-RW) in addition to the existing PP population (referred to as PP-OW) to account for subjects who received study vaccinations and/or blood draws outside of narrow protocol-defined visit windows. The success of the hypothesis test will be based on the results from the PP-RW population. PP-RW is defined as the PP population using a blood draw sample window of Days 28 to 51 following Dose 2 or the Toddler dose. PP-OW is defined as the PP population using a blood draw sample window of Days 28 to 44 following Dose 2 or the Toddler dose. The change to the SAP was introduced into all 4 Phase III studies (V419-005, V419-006, V419-007, and V419-008).
# Section 3.5, SAP:
- Addition of 2 sensitivity analyses: (1) analysis of GMT endpoints with no baseline adjustment and (2) analysis of GMT endpoints based on data from subjects with both baseline and postvaccination titers to support the ANCOVA MI primary analysis for GMT endpoints. |
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26 Apr 2013 |
Protocol Amendment applicable only to Italy and Sweden.
Same as Protocol Amendment 4 (issued on 25 April 2013) which was only applicable to Finland. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |