Clinical Trial Results:
A Phase IIb randomized, double-blind, controlled study of the safety, immunogenicity and proof-of-concept of RTS,S/AS02D, a candidate malaria vaccine, when incorporated into an Expanded Program on Immunization (EPI) regimen that includes DTPw/Hib in infants living in a malaria-endemic region.
Summary
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EudraCT number |
2015-001539-19 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
15 Jan 2009
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Results information
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Results version number |
v1 |
This version publication date |
11 May 2016
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First version publication date |
08 Jul 2015
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Other versions |
v2 , v3 |
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 |
104298
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00289185 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
IND number: 10514 | ||
Sponsors
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Sponsor organisation name |
GlaxoSmithKline Biologicals
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Sponsor organisation address |
Rue de l'Institut, 89, Rixensart, Belgium, B-1330
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Public contact |
Clinical Trials Call Center, GlaxoSmithKline Biologicals, 44 2089904466, GSKClinicalSupportHD@gsk.com
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Scientific contact |
Clinical Trials Call Center, GlaxoSmithKline Biologicals, 44 2089904466, GSKClinicalSupportHD@gsk.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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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 |
11 Dec 2009
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
15 Jan 2009
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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 describe the safety and reactogenicity of RTS,S/AS02D + TETRActHib (vaccine against diphtheria, tetanus, pertussis and Haemophilus influenzae type B) co-administered as 3 doses intramuscularly in separate thighs to infants at 8, 12 and 16 weeks of age.
-To demonstrate the non-inferiority of antibody responses to antigens D (diphteria), T (tetanus), Pw (whole-cell pertussis), Hib (Haemophilus influenzae type B) and HBs (hepatitis B), when administered as 3 doses of RTS,S/AS02D + TETRActHib at 8, 12 and 16 weeks of age compared to a regimen of 3 doses of Engerix-B (hepatitis B vaccine) + TETRActHib at the same age when assessed at 1 month post Dose 3.
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Protection of trial subjects |
Vaccinations took place the expanded program of immunization (EPI) clinic of the Bagamoyo District Hospital (BDH). All subjects were supervised closely for at least one hour following vaccination with appropriate medical treatment readily available to evaluate and treat any acute adverse events. Vaccines were administered by qualified and trained personnel. Vaccines were administered only to eligible subjects that had no contraindications to any components of the vaccines. Subjects were followed-up for one month (minimum 30 days) following administration of the last dose of study vaccines. Subjects who could not be vaccinated on the originally scheduled were vaccinated within 7 days and undergo all study procedures for the visit on the same day as vaccination. In the particular case of any child found to be febrile (axillary temperature 37.5C), a blood slide was taken to investigate for malaria. Children were treated as appropriate for their condition and were followed up until resolution of any symptoms and vaccinated if their clinical symptoms resolved within 7 days.
Those who could not be re-vaccinated within 7 days of their scheduled date continued all study procedures apart from receiving further study vaccinations. The parent(s)/guardian(s) of infants who are withdrawn from the study will be advised on an appropriate method of completing the infants’ vaccination regimen. In addition to above, subjects were followed-up for post-vaccination adverse events (AEs) and serious AEs (SAEs) according to the following timeframes: 7-day (Days 0-6) and 21-day (Days 0-20) periods post vaccination for solicited symptoms and unsolicited AES, respectively; SAEs were assessed throughout the entire study period, from Week 0 to Month 20.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
27 Sep 2006
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
11 Months | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
Tanzania, United Republic of: 340
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Worldwide total number of subjects |
340
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EEA total number of subjects |
0
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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) |
340
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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 |
A total of 340 subjects were enrolled for this study. The study comprised 2 phases, a double-blind phase, from Week 0 to Month 9 (2 months after the administration of the last vaccine dose), followed by a single-blind safety phase, from Month 9 to study end at Month 20. | ||||||||||||||||||||||||
Pre-assignment
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Screening details |
Screening included the following: routine antenatal care to counsel/test for HIV infection in pregnancy, check for inclusion/exclusion criteria, vaccination contraindications/precautions & subjects’ medical history, & signing informed consent forms. | ||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Period
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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, Monitor, Subject, Carer, Assessor | ||||||||||||||||||||||||
Blinding implementation details |
The study was run as a double blind to Month 9, then as a single blind to Month 20. To Month 9, data pertaining to RTS,S/AS02D or Engerix-B were collected in a double blinded manner and data relating to TETRActHib in an open fashion. ‘Double blinded’ meant that the vaccine recipient and their parent(s)/guardian(s) as well as those responsible for the evaluation of safety, immunogenicity and efficacy endpoints were unaware which treatment, RTS,S/AS02D or Engerix-B, was administered to a subject.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Engerix-B Group | ||||||||||||||||||||||||
Arm description |
Subjects aged between 6 and 10 weeks at the time of first vaccination received by intramuscular injection a 3-dose vaccination course of Engerix-B® vaccine co-administered with the TETRActHib™ vaccine at Week 0, Week 4 (Month 1) and Week 8 (Month 2). The Engerix-B® vaccine was administered in the left anterolateral thigh, and the TETRActHib™ vaccine in the right anterolateral thigh.. | ||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||
Investigational medicinal product name |
Engerix-B Junior
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Investigational medicinal product code |
HBV Paediatric 10
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Other name |
HBV, Engerix-B
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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 |
3-dose intramuscular injection in the thigh.
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Investigational medicinal product name |
TETRActHib
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Investigational medicinal product code |
DTPw+Hib
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Other name |
DTPw/Hib
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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 |
3-dose intramuscular injection in the thigh.
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Arm title
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RTS,S/AS02D Group | ||||||||||||||||||||||||
Arm description |
Subjects aged between 6 and 10 weeks at the time of first vaccination received by intramuscular injection a 3-dose vaccination course of the RTS,S/AS02D vaccine co-administered with the TETRActHib™ vaccine at Week 0, Week 4 (Month 1) and Week 8 (Month 2). The RTS,S/AS02D vaccine was administered in the left anterolateral thigh, and the TETRActHib™ vaccine in the right anterolateral thigh. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
TETRActHib
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Investigational medicinal product code |
DTPw+Hib
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Other name |
DTPw/Hib
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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 |
3-dose intramuscular injection in the thigh.
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Investigational medicinal product name |
Candidate Plasmodium falciparum Malaria vaccines
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Investigational medicinal product code |
RTS,S/AS02D
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Other name |
GSK 257146; RTS,S/AS02D
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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 |
3-dose intramuscular injection in the thigh
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Baseline characteristics reporting groups
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Reporting group title |
Engerix-B Group
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Reporting group description |
Subjects aged between 6 and 10 weeks at the time of first vaccination received by intramuscular injection a 3-dose vaccination course of Engerix-B® vaccine co-administered with the TETRActHib™ vaccine at Week 0, Week 4 (Month 1) and Week 8 (Month 2). The Engerix-B® vaccine was administered in the left anterolateral thigh, and the TETRActHib™ vaccine in the right anterolateral thigh.. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
RTS,S/AS02D Group
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Reporting group description |
Subjects aged between 6 and 10 weeks at the time of first vaccination received by intramuscular injection a 3-dose vaccination course of the RTS,S/AS02D vaccine co-administered with the TETRActHib™ vaccine at Week 0, Week 4 (Month 1) and Week 8 (Month 2). The RTS,S/AS02D vaccine was administered in the left anterolateral thigh, and the TETRActHib™ vaccine in the right anterolateral thigh. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Engerix-B Group
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Reporting group description |
Subjects aged between 6 and 10 weeks at the time of first vaccination received by intramuscular injection a 3-dose vaccination course of Engerix-B® vaccine co-administered with the TETRActHib™ vaccine at Week 0, Week 4 (Month 1) and Week 8 (Month 2). The Engerix-B® vaccine was administered in the left anterolateral thigh, and the TETRActHib™ vaccine in the right anterolateral thigh.. | ||
Reporting group title |
RTS,S/AS02D Group
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Reporting group description |
Subjects aged between 6 and 10 weeks at the time of first vaccination received by intramuscular injection a 3-dose vaccination course of the RTS,S/AS02D vaccine co-administered with the TETRActHib™ vaccine at Week 0, Week 4 (Month 1) and Week 8 (Month 2). The RTS,S/AS02D vaccine was administered in the left anterolateral thigh, and the TETRActHib™ vaccine in the right anterolateral thigh. |
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End point title |
Concentrations of antibodies against hepatitis B (Anti-HB) [1] | |||||||||||||||||||||
End point description |
Concentrations were expressed as geometric mean concentrations (GMCs) in milli-international unit per milliliter (mIU/mL). The cut-off of the assay was the seroprotection cut-off of 10 mIU/mL. Month 3 results are the specific results for this primary outcome measure.
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End point type |
Primary
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End point timeframe |
Prior to vaccination at Week 0 (PRE), at Month 2 and at Month 3.
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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: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed. |
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No statistical analyses for this end point |
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End point title |
Number of subjects with serious adverse events (SAEs) [2] | |||||||||
End point description |
SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.
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End point type |
Primary
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End point timeframe |
From Week 0 to Month 9.
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Notes [2] - 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: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed. |
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No statistical analyses for this end point |
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End point title |
Concentrations of antibodies against diphtheria (Anti-D) [3] | ||||||||||||||||||
End point description |
Antibodies were measured by Enzyme-linked immunosorbent assay (ELISA). Concentrations were expressed as geometric mean concentrations (GMCs) in international unit per milliliter (IU/mL). The cut-off of the assay was the seroprotection cut-off of 0.1 IU/mL. Month 3 results are the specific results for this primary outcome measure.
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End point type |
Primary
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End point timeframe |
Prior to vaccination at Week 0 (PRE), and at Month 3.
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Notes [3] - 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: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed. |
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No statistical analyses for this end point |
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End point title |
Concentrations of antibodies against tetanus (Anti-T) [4] | ||||||||||||||||||
End point description |
Antibodies were measured by Enzyme-linked immunosorbent assay (ELISA). Concentrations were expressed as geometric mean concentrations (GMCs) in international unit per milliliter (IU/mL). The cut-off of the assay was the seroprotection cut-off of 0.1 IU/mL. Month 3 results are the specific results for this primary outcome measure.
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End point type |
Primary
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End point timeframe |
Prior to vaccination at Week 0 (PRE), and at Month 3.
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Notes [4] - 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: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed. |
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No statistical analyses for this end point |
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End point title |
Concentrations of anti-polyribosyl ribitol phosphate antibodies (Anti-PRP). [5] | ||||||||||||||||||
End point description |
Concentrations were expressed as geometric mean concentrations (GMCs) in microgram per milliliter (µg/mL). The cut-off of the assay is the seroprotection cut-off value of 0.15 µg/mL. Month 3 results are the specific results for this primary outcome measure.
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End point type |
Primary
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End point timeframe |
Prior to vaccination at Week 0 (PRE), and at Month 3.
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Notes [5] - 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: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed. |
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No statistical analyses for this end point |
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End point title |
Number of subjects with serious adverse events (SAEs) [6] | |||||||||
End point description |
SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.
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End point type |
Primary
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End point timeframe |
From Month 9 to Month 20.
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Notes [6] - 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: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed. |
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No statistical analyses for this end point |
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End point title |
Concentrations of anti-Bordetella pertussis toxin antibodies (Anti-BPT). | ||||||||||||||||||
End point description |
Antibodies were measured by Enzyme-linked immunosorbent assay (ELISA). Concentrations were expressed as geometric mean concentrations (GMCs) in ELISA unit per milliliter (EL.U/mL). The cut-off of the assay was the seropositivity cut-off of 15 EL.U/mL. Month 3 results are the specific results for this primary outcome measure.
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End point type |
Primary
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End point timeframe |
Prior to vaccination at Week 0 (PRE), and at Month 3.
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Statistical analysis title |
Non-inferiority - Anti-BPT immune response | ||||||||||||||||||
Statistical analysis description |
The aim was to test the non-inferiority (NI) of 3 doses of RTS,S/AS02D vs 3 doses of HBV, both co-administered with DTPw/Hib, as regards antigens for HBs, D, T, PRP and BPT. NI was demonstrated if - ALL criteria to be met: 1) difference between groups in percent of seroprotection (SPR) < 10% for anti-HB, -D, -T and PRP antibodies AND 2) geometric mean concentration (GMC) ratio between groups < 1.5 for anti-BPT antibodies.
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Comparison groups |
Engerix-B Group v RTS,S/AS02D Group
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Number of subjects included in analysis |
327
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [7] | ||||||||||||||||||
Method |
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Parameter type |
GMC ratio | ||||||||||||||||||
Point estimate |
1.23
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Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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lower limit |
1.08 | ||||||||||||||||||
upper limit |
1.4 | ||||||||||||||||||
Notes [7] - This analysis concerns the NI assessment for anti-PBT immune response. GMC ratio between groups (Engerix-B over RTS,S/AS02D) as anti BPT antibody concentrations (expressed in %) was calculated as well as the 95% CI (standardized asymptotic) (criteria for success = lower limit of 95% CI of GMC ratio between groups < 1.5). Results from this analysis are to be combined with those for NI assessment for antigens for HB, D, T, PRP and BPT to obtain an overall assessment of NI. |
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End point title |
Number of subjects with hepatitis B antibody (Anti-HB) concentrations equal to or above (>=) the seroprotection cut-off value | ||||||||||||||||||
End point description |
The seroprotection cut-off value was 10 milli-international units per milliliter (mIU/mL). Blood samples were collected prior to vaccination at Week 0 (PRE), at Month 2 and at Month 3. Month 3 results are the specific results for this primary outcome measure.
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End point type |
Primary
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End point timeframe |
Prior to vaccination at Week 0 (PRE), at Month 2 and at Month 3.
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Statistical analysis title |
Non-inferiority - Anti-HB SPR immune response | ||||||||||||||||||
Statistical analysis description |
The aim was to test the non-inferiority (NI) of 3 doses of RTS,S/AS02D vs 3 doses of HBV, both co-administered with DTPw/Hib, as regards antigens for HB, D, T, PRP and BPT as assessed at Month 3. NI was demonstrated if - ALL criteria to be met: 1) difference between groups in percent of seroprotection (SPR) < 10% for anti-HB, -D, -T and PRP antibodies AND 2) geometric mean concentration (GMC) ratio between groups < 1.5 for anti-BPT antibodies.
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Comparison groups |
Engerix-B Group v RTS,S/AS02D Group
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Number of subjects included in analysis |
297
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [8] | ||||||||||||||||||
Method |
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Parameter type |
Difference in % | ||||||||||||||||||
Point estimate |
-5.67
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Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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lower limit |
-10.8 | ||||||||||||||||||
upper limit |
2.9 | ||||||||||||||||||
Notes [8] - This analysis assesses NI as regards anti-HB immune response. The difference between groups (Engerix-B minus RTS,S/AS02D) as regards SPR (expressed in %) was calculated as well as the 95% CI (standardized asymptotic) around this difference (criteria for success = lower limit of 95% CI of difference between groups in percent of SPR < 10%). Results from this analysis are to be combined with those for NI assessment for antigens for HB, D, T, PRP and BPT to obtain an overall assessment of NI. |
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End point title |
Number of subjects with anti-diphtheria antibody (Anti-D) concentrations equal to or above (>=) the seroprotection cut-off value | |||||||||||||||
End point description |
Antibodies were measured by Enzyme-linked immunosorbent assay (ELISA). The seroprotection cut-off value was 0.1 international unit per milliliter (IU/mL). Blood samples were collected prior to vaccination at Week 0 (PRE), and at Month 3. Month 3 results are the specific results for this primary outcome measure.
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End point type |
Primary
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End point timeframe |
Prior to vaccination at Week 0 (PRE), and at Month 3.
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Statistical analysis title |
Non-inferiority - Anti-D SPR immune response | |||||||||||||||
Statistical analysis description |
The aim was to test the non-inferiority (NI) of 3 doses of RTS,S/AS02D vs 3 doses of HBV, both co-administered with DTPw/Hib, as regards antigens for HB, D, T, PRP and BPT as assessed at Month 3. NI was demonstrated if - ALL criteria to be met: 1) difference between groups in percent of seroprotection (SPR) < 10% for anti-HB, -D, -T and PRP antibodies AND 2) geometric mean concentration (GMC) ratio between groups < 1.5 for anti-BPT antibodies.
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Comparison groups |
Engerix-B Group v RTS,S/AS02D Group
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Number of subjects included in analysis |
327
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [9] | |||||||||||||||
Method |
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Parameter type |
Difference in % | |||||||||||||||
Point estimate |
-1.32
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
-5.09 | |||||||||||||||
upper limit |
1.9 | |||||||||||||||
Notes [9] - This analysis assesses NI as regards anti-D immune response. The difference between groups (Engerix-B minus RTS,S/AS02D) as regards SPR (expressed in %) was calculated as well as the 95% CI (standardized asymptotic) around this difference (criteria for success = lower limit of 95% CI of difference between groups in percent of SPR < 10%). Results from this analysis are to be combined with those for NI assessment for antigens for HB, D, T, PRP and BPT to obtain an overall assessment of NI. |
|
||||||||||||||||
End point title |
Number of subjects with anti-tetanus antibody (Anti-T) concentrations equal to or above (>=) the seroprotection cut-off value | |||||||||||||||
End point description |
Antibodies were measured by Enzyme-linked immunosorbent assay (ELISA). The seroprotection cut-off value was 0.1 international unit per milliliter (IU/mL). Blood samples were collected prior to vaccination at Week 0 (PRE), and at Month 3. Month 3 results are the specific results for this primary outcome measure.
|
|||||||||||||||
End point type |
Primary
|
|||||||||||||||
End point timeframe |
Prior to vaccination at Week 0 (PRE), and at Month 3.
|
|||||||||||||||
|
||||||||||||||||
Statistical analysis title |
Non-inferiority - Anti-T SPR immune response | |||||||||||||||
Statistical analysis description |
The aim was to test the non-inferiority (NI) of 3 doses of RTS,S/AS02D vs 3 doses of HBV, both co-administered with DTPw/Hib, as regards antigens for HB, D, T, PRP and BPT as assessed at Month 3. NI was demonstrated if - ALL criteria to be met: 1) difference between groups in percent of seroprotection (SPR) < 10% for anti-HB, -D, -T and PRP antibodies AND 2) geometric mean concentration (GMC) ratio between groups < 1.5 for anti-BPT antibodies.
|
|||||||||||||||
Comparison groups |
Engerix-B Group v RTS,S/AS02D Group
|
|||||||||||||||
Number of subjects included in analysis |
327
|
|||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||
Analysis type |
non-inferiority [10] | |||||||||||||||
Method |
||||||||||||||||
Parameter type |
Difference in % | |||||||||||||||
Point estimate |
0
|
|||||||||||||||
Confidence interval |
||||||||||||||||
level |
95% | |||||||||||||||
sides |
2-sided
|
|||||||||||||||
lower limit |
-2.48 | |||||||||||||||
upper limit |
2.51 | |||||||||||||||
Notes [10] - This analysis assesses NI as regards anti-T immune response. The difference between groups (Engerix-B minus RTS,S/AS02D) as regards SPR (expressed in %) was calculated as well as the 95% CI (standardized asymptotic) around this difference (criteria for success = lower limit of 95% CI of difference between groups in percent of SPR < 10%). Results from this analysis are to be combined with those for NI assessment for antigens for HB, D, T, PRP and BPT to obtain an overall assessment of NI. |
|
||||||||||||||||
End point title |
Number of subjects with anti-polyribosyl ribitol phosphate antibody (Anti-PRP) concentrations equal to or above (>=) the seroprotection cut-off value | |||||||||||||||
End point description |
Antibodies were measured by Enzyme-linked immunosorbent assay (ELISA). The seroprotection cut-off value was 0.15 microgram per milliliter (µg/mL). Blood samples were collected prior to vaccination at Week 0 (PRE), and at Month 3. Month 3 results are the specific results for this primary outcome measure.
|
|||||||||||||||
End point type |
Primary
|
|||||||||||||||
End point timeframe |
Prior to vaccination at Week 0 (PRE), and at Month 3.
|
|||||||||||||||
|
||||||||||||||||
Statistical analysis title |
Non-inferiority - Anti-PRP SPR immune response | |||||||||||||||
Statistical analysis description |
The aim was to test the non-inferiority (NI) of 3 doses of RTS,S/AS02D vs 3 doses of HBV, both co-administered with DTPw/Hib, as regards antigens for HB, D, T, PRP and BPT as assessed at Month 3. NI was demonstrated if - ALL criteria to be met: 1) difference between groups in percent of seroprotection (SPR) < 10% for anti-HB, -D, -T and PRP antibodies AND 2) geometric mean concentration (GMC) ratio between groups < 1.5 for anti-BPT antibodies.
|
|||||||||||||||
Comparison groups |
Engerix-B Group v RTS,S/AS02D Group
|
|||||||||||||||
Number of subjects included in analysis |
327
|
|||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||
Analysis type |
non-inferiority [11] | |||||||||||||||
Method |
||||||||||||||||
Parameter type |
Difference in % | |||||||||||||||
Point estimate |
0.01
|
|||||||||||||||
Confidence interval |
||||||||||||||||
level |
95% | |||||||||||||||
sides |
2-sided
|
|||||||||||||||
lower limit |
-3.04 | |||||||||||||||
upper limit |
3.12 | |||||||||||||||
Notes [11] - This analysis assesses NI as regards anti-PRP immune response. The difference between groups (Engerix-B minus RTS,S/AS02D) as regards SPR (expressed in %) was calculated as well as the 95% CI (standardized asymptotic) around this difference (criteria for success = lower limit of 95% CI of difference between groups in percent of SPR < 10%). Results from this analysis are to be combined with those for NI assessment for antigens for HB, D, T, PRP and BPT to obtain an overall assessment of NI. |
|
||||||||||||||||
End point title |
Number of subjects with anti-Bordetella pertussis toxin antibody (Anti-BPT) concentrations equal to or above (>=) the seropositivity cut-off value [12] | |||||||||||||||
End point description |
Antibodies were measured by Enzyme-linked immunosorbent assay (ELISA). The seropositivity cut-off value was 15 ELISA units per milliliter (EL.U/mL). Blood samples were collected prior to vaccination at Week 0 (PRE), and at Month 3. Month 3 results are the specific results for this primary outcome measure.
|
|||||||||||||||
End point type |
Primary
|
|||||||||||||||
End point timeframe |
Prior to vaccination at Week 0 (PRE), and at Month 3.
|
|||||||||||||||
Notes [12] - 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: The analysis of the primary endpoint was descriptive i.e. no statistical hypothesis test was performed. |
||||||||||||||||
|
||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||
End point title |
Concentrations of anti-Circumsporozoite protein (Anti-CS) antibodies | ||||||||||||||||||||||||
End point description |
Antibodies were measured by Enzyme-linked immunosorbent assay (ELISA). Concentrations are expressed as geometric mean concentrations (GMCs) in ELISA unit per milliliter (EL.U/mL). The cut-off of the assay was the seropositivity cut-off value of 0.5 EL.U/mL.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Prior to vaccination at Week 0 (PRE), at Month 2, at Month 3 and at Month 9.
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||
End point title |
Number of subjects with solicited local symptoms. | |||||||||||||||
End point description |
Assessed solicited local symptoms were pain and swelling following vaccination with the RTS,S/AS02D or Engerix-B vaccine.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
Within 7 days (Days 0-6) after vaccination with the RTS,S/AS02D or Engerix-B vaccine.
|
|||||||||||||||
|
||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||
End point title |
Number of subjects with solicited local symptoms. | |||||||||||||||
End point description |
Assessed solicited local symptoms were pain and swelling following vaccination with the TETRActHib vaccine.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
Within 7 days (Days 0-6) after vaccination with the TETRActHib vaccine.
|
|||||||||||||||
|
||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||
End point title |
Number of subjects with solicited general symptoms. | |||||||||||||||||||||
End point description |
Assessed solicited general symptoms were drowsiness, fever, irritability, and loss of appetite. Fever was defined as axillary temperature above or equal to (>=) 37.5 degrees Celsius (°C).
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Within 7 days (Days 0-6) after vaccination
|
|||||||||||||||||||||
|
||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Number of subjects with unsolicited adverse events (AEs). | |||||||||
End point description |
An unsolicited adverse event is any adverse event (i.e. any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product) reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Within 30 days (Days 0–29) after vaccination
|
|||||||||
|
||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Number of subjects with serious adverse events (SAEs) | |||||||||
End point description |
SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Throughout the entire study, from Week 0 to Month 20.
|
|||||||||
|
||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Time to first malaria infection | ||||||||||||
End point description |
Malaria infection by Plasmodium falciparum (P. falciparum) was detected by active detection of infection (ADI) and passive case detection (PCD), and was defined as the presence of P. falciparum asexual parasitemia above 0 per microliter (µL) on Giemsa stained thick blood films. The time to first malaria infection is expressed in terms of rate of first malaria infection, that is, the number of malaria infection events reported (n) over the period elapsed until the event occurred (i.e. events per Persons Year at Risk [PYAR]) for each group.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Over the period starting 14 days after Dose 3 of RTS,S or HBV vaccine and extending for 6 months thereafter (from Month 2.5 up to Month 9).
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Number of subjects prevalent for parasitemia | |||||||||
End point description |
Subjects prevalent for P. falciparum parasitemia were defined as subjects with the presence of P. falciparum asexual parasitemia above 0 per microliter (µL) on Giemsa stained thick blood films.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
At Month 9
|
|||||||||
|
||||||||||
No statistical analyses for this end point |
|
|||||||||
End point title |
Plasmodium falciparum (P. falciparum) parasite density in subjects prevalent for parasitemia [13] | ||||||||
End point description |
The parasite density in subjects prevalent for P. falciparum parasitemia (subjects with the presence of P. falciparum asexual parasitemia above 0 per microliter (µL) on Giemsa stained thick blood films), was detected at a cross sectional time point 7 months after administration of Dose 3 of RTS,S or HBV vaccine (Month 9). Parasite density is expressed as mean, minimum and maximum density in parasite per µL. This outcome for solely assessed in the Engerix-B Group, as no subject in the RTS,S/AS02D Group was assessed as prevalent for parasitemia.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
At Month 9
|
||||||||
Notes [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This outcome for solely assessed in the Engerix-B Group, as no subject in the RTS,S/AS02D Group was assessed as prevalent for parasitemia. |
|||||||||
|
|||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
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Timeframe for reporting adverse events |
Time frames for adverse events (AEs) reporting were the 7-day (Days 0-6) and 30-day (Days 0-29) periods post vaccination for solicited symptoms and unsolicited AES, respectively. Serious adverse events were assessed throughout, from Week 0 to Month 20.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
The occurrence of reported AEs (all/related) was not available and is encoded as equal to the number of subjects affected.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
12.1
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Engerix-B Group
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects aged between 6 and 10 weeks at the time of first vaccination received by intramuscular injection a 3-dose vaccination course of Engerix-B® vaccine co-administered with the TETRActHib™ vaccine at Week 0, Week 4 (Month 1) and Week 8 (Month 2). The Engerix-B® vaccine was administered in the left anterolateral thigh, and the TETRActHib™ vaccine in the right anterolateral thigh. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
RTS,S/AS02D Group
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects aged between 6 and 10 weeks at the time of first vaccination received by intramuscular injection a 3-dose vaccination course of the RTS,S/AS02D vaccine co-administered with the TETRActHib vaccine at Week 0, Week 4 (Month 1) and Week 8 (Month 2). The RTS,S/AS02D vaccine was administered in left anterolateral thigh, and the TETRActHib vaccine in the right anterolateral thigh. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
02 May 2006 |
At the request of National Institute of Medical Research (NIMR) and Malaria Vaccine Initiative (MVI) at Program for Appropriate Technology in Health (PATH), a number of operational and administrative details were made to the protocol. A number of errors in the final version of the protocol were corrected. |
||
15 Sep 2006 |
Capillary puncture for obtaining blood samples was added as an alternative method to venous extraction with a needle and syringe in order to increase compliance with obtaining blood samples at the required visits. The minimum volume of blood to be obtained at each visit was also reviewed and decreased where appropriate. |
||
20 Aug 2007 |
The study protocol was amended due to the low transmission rates observed in the community which would have resulted in an under-powered study to reach the efficacy objective. Efficacy data will be collected to 18 months post Dose 3 (Month 20) by passive case detection. It was proposed not to prolong active detection of infection visits given their intrusive nature for the families. Assessment of SAEs will be conducted for the duration of the study. |
||
Interruptions (globally) |
|||
Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |