Examine Safety and Immune Responses of GSK 257049 Vaccine When Administered to Infants Living in a Malaria-endemic Region

A Phase I/IIb Randomized, Double-blind, Controlled Study of the Safety, Immunogenicity and Proof-of-concept of RTS,S/AS02D, a Candidate Malaria Vaccine in Infants Living in a Malaria-endemic Region

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00197028

Enrollment

214

Registered

2005-09-20

Start date

2005-08-23

Completion date

2007-12-27

Last updated

2018-08-20

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Malaria

Brief summary

GSK Biologicals is developing in partnership with the Program for Appropriate Technology in Health (PATH) Malaria Vaccine Initiative a candidate malaria vaccine for the routine immunization of infants and children living in malaria endemic areas. The vaccine would offer protection against malaria disease due to the parasite Plasmodium falciparum. The vaccine would also provide protection against infection with hepatitis B virus (HBV). This trial is being carried out following the demonstration of efficacy of a previous version of the malaria candidate vaccine in children in Mozambique: there, the vaccine demonstrated approximately 30% efficacy against clinical episodes of malaria and approximately 58% efficacy against severe malaria disease. In order to integrate the malaria vaccine into the Expanded Program on Immunization (EPI) regimen, in malaria-endemic regions, for this trial, a 0.5 ml dose of GSK 257049 vaccine has been developed. The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.

Detailed description

All infants participating in this phase I/IIb study will receive TETRActHib (a licensed diphtheria-tetanus-pertussis Haemophilus influenzae vaccine manufactured by Aventis Pasteur) by IM injection in their right thigh at 8, 12, and 16 weeks; They will be randomized to receive either the candidate malaria vaccine, GSK 257049 vaccine (0.5 ml dose) or Engerix-B (a licensed hepatitis B vaccine manufactured by GSK Biologicals) by IM injection in their left thigh at 10, 14, 18 weeks. Infants will be followed-up daily for 7 days after each vaccine dose for evaluation of safety and reactogenicity. There will be a 14-day follow-up period after each dose of TETRActHib and after Dose 1 and Dose 2 of GSK 257049 vaccine or Engerix-B, and a one month follow-up period after Dose 3 of GSK 257049 vaccine or Engerix-B for reporting unsolicited symptoms. Serious adverse events will be recorded throughout the 14 month study period. A small amount of blood (2 ml = 1/2 teaspoon) will be obtained at four different time points to measure the immune response elicited by the vaccines administered during this study period. Preliminary indication of vaccine efficacy in this age group will be established by actively monitoring for infection with Plasmodium falciparum.

Interventions

BIOLOGICALRTS,S/AS02D

3-dose intramuscular injection in the thigh

BIOLOGICALTETRActHib™

3-dose intramuscular injection in the thigh.

BIOLOGICALEngerix-B®

3-dose intramuscular injection in the thigh.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

PREVENTION

Masking

TRIPLE (Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

6 Weeks to 12 Weeks

Healthy volunteers

Yes

Inclusion criteria

* A male or female infant of between 6 and 12 weeks of age at the time of first vaccination. * Written informed consent obtained from the parent(s) or guardian(s) of the subject * Free of obvious health problems as established by medical history and clinical examination before entering into the study. * Born to a mother who is hepatitis B surface antigen (HBsAg) negative and human immunodeficiency virus (HIV) negative. * Born after a normal gestation period (between 36 and 42 weeks). * Subjects who the investigator believes that their parents/guardians can and will comply with the requirements of the protocol should be enrolled in the study.

Exclusion criteria

* Bacillus Calmette-Guérin tuberculosis vaccine (BCG) administration within one week of proposed administration of a study vaccine. * Use of any investigational or non-registered drug or vaccine other than the study vaccines within 30 days preceding the first dose of study vaccine, or planned use during the study period. * Administration of immunoglobulins and/or any blood products since birth or planned administration during the study period. * Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs since birth * Any chronic drug therapy to be continued during the study period. * Previous vaccination with diphtheria, tetanus, pertussis, Haemophilus influenzae type b or hepatitis B vaccines. * Major congenital abnormality. * Serious acute or chronic illness determined by clinical, physical examination and laboratory screening tests * Any medically diagnosed or suspected immunodeficient condition based on medical history and physical examination * A family history of congenital or hereditary immunodeficiency. * History of allergic disease or reactions likely to be exacerbated by any component of the vaccine. * History of any neurological disorders or seizures. * Maternal death. * Hemoglobin \< 80 g/L * Simultaneous participation in any other clinical trial. * Same sex twin * Any other findings that the investigator feels would increase the risk of having an adverse outcome from participation in the trialModerate malnutrition at screening

Design outcomes

Primary

Measure	Time frame	Description
Number of Subjects With Serious Adverse Events (SAEs).	From Month 0 to Month 6	SAEs were defined as medical occurrences that resulted in death, were life threatening, required hospitalization or prolongation of hospitalization or resulted in disability/incapacity.

Secondary

Measure	Time frame	Description
Concentrations of Antibodies Against Hepatitis B (Anti-HB)	Prior to vaccination at Month 0 (PRE) and 1 month post Dose 3 of Engerix-B® or RTS,S/AS02D vaccine (Day 104).	Concentrations were expressed as geometric mean concentrations (GMCs) in milli-international unit per milliliter (mIU/mL). The seroprotection cut-off of the assay was 10 mIU/mL.
Concentrations of Anti-circumsporozoite Protein (Anti-CS) Antibodies.	Prior to vaccination at Month 0 (PRE), 1 month post Dose 3 of Engerix-B® or RTS,S/AS02D vaccine (Day 104) and 3½ months post Dose 3 of Engerix-B® or RTS,S/AS02D vaccine (Day 180).	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 seropositivity cut-off of the assay was 0.5 EL.U/mL.
Concentrations of Antibodies Against Anti-diphtheria (Anti-D)	At Day 90 (1 month post Dose 3 of TETRActHib™ vaccine)	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 seroprotection cut-off of the assay was 0.1 IU/mL.
Concentrations of Antibodies Against Tetanus (Anti-T)	At Day 90 (1 month post Dose 3 of TETRActHib™ vaccine)	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 seroprotection cut-off of the assay was 0.1 IU/mL.
Concentrations of Anti-Bordetella Pertussis Toxin Antibodies (Anti-BPT).	At Day 90 (1 month post Dose 3 of TETRActHib™ vaccine)	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 seropositivity cut-off of the assay was 15 EL.U/mL.
Concentrations of Anti-polyribosyl Ribitol Phosphate Antibodies (Anti-PRP).	At Day 90 (1 month post Dose 3 of TETRActHib™ vaccine)	Antibodies were measured by Enzyme-linked immunosorbent assay (ELISA). Concentrations were expressed as geometric mean concentrations (GMCs) in microgram per milliliter (µg/mL). The seroprotection cut-off of the assay was 0.15 µg/mL.
Number of Subjects With Serious Adverse Events (SAEs).	Throughout the entire study period (from Month 0 to Month 14)	SAEs were defined as medical occurrences that resulted in death, were life threatening, required hospitalization or prolongation of hospitalization or resulted in disability/incapacity.
Number of Subjects Prevalent for Plasmodium Falciparum (P. Falciparum)	At Month 6 (3½ months post Dose 3 of RTS,S/AS02D or Engerix-B® vaccine)	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.
Plasmodium Falciparum (P. Falciparum) Parasite Density in Subjects Prevalent for Parasitemia	At Month 6 (3½ months post Dose 3 of RTS,S/AS02D or Engerix-B® vaccine)	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 3 ½ months after administration of Dose 3 of RTS,S/AS02D or Engerix-B® vaccine (Month 6). Parasite density is expressed as mean, minimum and maximum density in parasite per µL.
Number of Subjects With Solicited Local Symptoms.	During the 7 day (Days 0-6) follow-up period after any vaccination with TETRActHib™ vaccine.	Assessed solicited local symptoms were pain and swelling at injection site.
Number of Subjects With Solicited General Symptoms.	During the 7 day (Days 0-6) follow-up period after any vaccination with TETRActHib™ vaccine	Assessed solicited general symptoms were drowsiness, fever, irritability and loss of appetite. Fever was defined as axillary temperature equal or above (≥) to 37.5 degrees Celsius (C).
Number of Subjects With Unsolicited Adverse Events (AEs).	During the 14 day (Days 0-13) follow-up period after any vaccination with of TETRActHib™ vaccine	An unsolicited AE is any AE (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.
Time to First Malaria Infection	Over the period starting 14 days after Dose 3 of RTS,S/AS02D or Engerix-B® vaccine and extending for 12 weeks thereafter (from Month 2.5 to Month 6)	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.

Countries

Mozambique

Participant flow

Pre-assignment details

The study comprised 2 phases, a double-blind vaccination phase from Month 0 to Month 6, and a single-blind phase (Month 7 to Month 14).

Participants by arm

Arm	Count
RTS,S/AS02D Group Subjects aged between 6 and 12 weeks at the time of first vaccination received by intramuscular injection a 3-dose vaccination course of RTS,S/AS02D at days 14, 44 and 74 and a 3-dose vaccination course of TETRActHib™ vaccine at days 0, 30 and 60. The RTS,S/AS02D vaccine was administered in the left anterolateral thigh, and the TETRActHib™ vaccine in the right anterolateral thigh.	107
Engerix-B Group Subjects aged between 6 and 12 weeks at the time of first vaccination received by intramuscular injection a 3-dose vaccination course of Engerix-B® vaccine at days 14, 44 and 74 and a 3-dose of TETRActHib™ vaccine at days 0, 30 and 60. The Engerix-B® vaccine was administered in the left anterolateral thigh, and the TETRActHib™ vaccine in the right anterolateral thigh.	107
Total	214

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	2	2
Overall Study	Lost to Follow-up	1	0
Overall Study	Other	3	6
Overall Study	Protocol Violation	2	1
Overall Study	Withdrawal by Subject	8	12

Baseline characteristics

Characteristic	RTS,S/AS02D Group	Engerix-B Group	Total
Age, Continuous	8.3 Weeks STANDARD_DEVIATION 1.42	8.3 Weeks STANDARD_DEVIATION 1.08	8.3 Weeks STANDARD_DEVIATION 1.25
Sex: Female, Male Female	48 Participants	59 Participants	107 Participants
Sex: Female, Male Male	59 Participants	48 Participants	107 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	107 / 107	107 / 107
serious Total, serious adverse events	35 / 107	34 / 107

Outcome results

Primary

Number of Subjects With Serious Adverse Events (SAEs).

SAEs were defined as medical occurrences that resulted in death, were life threatening, required hospitalization or prolongation of hospitalization or resulted in disability/incapacity.

Time frame: From Month 0 to Month 6

Population: The analysis was performed on the Total Vaccinated cohort, which included all vaccinated subjects for whom data were available.

Arm	Measure	Value (NUMBER)
RTS,S/AS02D Group	Number of Subjects With Serious Adverse Events (SAEs).	17 subjects
Engerix-B Group	Number of Subjects With Serious Adverse Events (SAEs).	17 subjects

Secondary

Concentrations of Antibodies Against Anti-diphtheria (Anti-D)

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 seroprotection cut-off of the assay was 0.1 IU/mL.

Time frame: At Day 90 (1 month post Dose 3 of TETRActHib™ vaccine)

Population: The analysis was performed on the According-to-Protocol cohort for immunogenicity, which included all evaluable subjects (i.e. those meeting all eligibility criteria, complying with the procedures defined in the protocol, with no elimination criteria during the study) for whom data concerning immunogenicity outcome variables were available.

Arm	Measure	Value (GEOMETRIC_MEAN)
RTS,S/AS02D Group	Concentrations of Antibodies Against Anti-diphtheria (Anti-D)	1.4 IU/mL
Engerix-B Group	Concentrations of Antibodies Against Anti-diphtheria (Anti-D)	1.4 IU/mL

Secondary

Concentrations of Antibodies Against Hepatitis B (Anti-HB)

Concentrations were expressed as geometric mean concentrations (GMCs) in milli-international unit per milliliter (mIU/mL). The seroprotection cut-off of the assay was 10 mIU/mL.

Time frame: Prior to vaccination at Month 0 (PRE) and 1 month post Dose 3 of Engerix-B® or RTS,S/AS02D vaccine (Day 104).

Arm	Measure	Group	Value (GEOMETRIC_MEAN)
RTS,S/AS02D Group	Concentrations of Antibodies Against Hepatitis B (Anti-HB)	Anti-HB, PRE [N=72;70]	14.0 mIU/mL
RTS,S/AS02D Group	Concentrations of Antibodies Against Hepatitis B (Anti-HB)	Anti-HB, Day 104 [N=68;64]	10081.6 mIU/mL
Engerix-B Group	Concentrations of Antibodies Against Hepatitis B (Anti-HB)	Anti-HB, PRE [N=72;70]	16.6 mIU/mL
Engerix-B Group	Concentrations of Antibodies Against Hepatitis B (Anti-HB)	Anti-HB, Day 104 [N=68;64]	392.4 mIU/mL

Secondary

Concentrations of Antibodies Against Tetanus (Anti-T)

Time frame: At Day 90 (1 month post Dose 3 of TETRActHib™ vaccine)

Arm	Measure	Value (GEOMETRIC_MEAN)
RTS,S/AS02D Group	Concentrations of Antibodies Against Tetanus (Anti-T)	6.2 IU/mL
Engerix-B Group	Concentrations of Antibodies Against Tetanus (Anti-T)	5.1 IU/mL

Secondary

Concentrations of Anti-Bordetella Pertussis Toxin Antibodies (Anti-BPT).

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 seropositivity cut-off of the assay was 15 EL.U/mL.

Time frame: At Day 90 (1 month post Dose 3 of TETRActHib™ vaccine)

Arm	Measure	Value (GEOMETRIC_MEAN)
RTS,S/AS02D Group	Concentrations of Anti-Bordetella Pertussis Toxin Antibodies (Anti-BPT).	104.4 EL.U/mL
Engerix-B Group	Concentrations of Anti-Bordetella Pertussis Toxin Antibodies (Anti-BPT).	106.8 EL.U/mL

Secondary

Concentrations of Anti-circumsporozoite Protein (Anti-CS) Antibodies.

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 seropositivity cut-off of the assay was 0.5 EL.U/mL.

Time frame: Prior to vaccination at Month 0 (PRE), 1 month post Dose 3 of Engerix-B® or RTS,S/AS02D vaccine (Day 104) and 3½ months post Dose 3 of Engerix-B® or RTS,S/AS02D vaccine (Day 180).

Arm	Measure	Group	Value (GEOMETRIC_MEAN)
RTS,S/AS02D Group	Concentrations of Anti-circumsporozoite Protein (Anti-CS) Antibodies.	Anti-CS, PRE [N=76;77]	0.4 EL.U/mL
RTS,S/AS02D Group	Concentrations of Anti-circumsporozoite Protein (Anti-CS) Antibodies.	Anti-CS, Day 104 [N=71;68]	199.9 EL.U/mL
RTS,S/AS02D Group	Concentrations of Anti-circumsporozoite Protein (Anti-CS) Antibodies.	Anti-CS, Day 180 [N=53;61]	58.8 EL.U/mL
Engerix-B Group	Concentrations of Anti-circumsporozoite Protein (Anti-CS) Antibodies.	Anti-CS, PRE [N=76;77]	0.4 EL.U/mL
Engerix-B Group	Concentrations of Anti-circumsporozoite Protein (Anti-CS) Antibodies.	Anti-CS, Day 104 [N=71;68]	0.3 EL.U/mL
Engerix-B Group	Concentrations of Anti-circumsporozoite Protein (Anti-CS) Antibodies.	Anti-CS, Day 180 [N=53;61]	0.4 EL.U/mL

Secondary

Concentrations of Anti-polyribosyl Ribitol Phosphate Antibodies (Anti-PRP).

Antibodies were measured by Enzyme-linked immunosorbent assay (ELISA). Concentrations were expressed as geometric mean concentrations (GMCs) in microgram per milliliter (µg/mL). The seroprotection cut-off of the assay was 0.15 µg/mL.

Time frame: At Day 90 (1 month post Dose 3 of TETRActHib™ vaccine)

Arm	Measure	Value (GEOMETRIC_MEAN)
RTS,S/AS02D Group	Concentrations of Anti-polyribosyl Ribitol Phosphate Antibodies (Anti-PRP).	22.1 µg/mL
Engerix-B Group	Concentrations of Anti-polyribosyl Ribitol Phosphate Antibodies (Anti-PRP).	17.9 µg/mL

Secondary

Number of Subjects Prevalent for Plasmodium Falciparum (P. Falciparum)

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.

Time frame: At Month 6 (3½ months post Dose 3 of RTS,S/AS02D or Engerix-B® vaccine)

Population: The analysis was performed on the According-to-Protocol cohort for efficacy, which included all evaluable subjects (i.e. those meeting all eligibility criteria, complying with the procedures defined in the protocol, with no elimination criteria during the study) for whom data concerning efficacy outcome variables were available.

Arm	Measure	Value (NUMBER)
RTS,S/AS02D Group	Number of Subjects Prevalent for Plasmodium Falciparum (P. Falciparum)	4 subjects
Engerix-B Group	Number of Subjects Prevalent for Plasmodium Falciparum (P. Falciparum)	7 subjects

Secondary

Number of Subjects With Serious Adverse Events (SAEs).

SAEs were defined as medical occurrences that resulted in death, were life threatening, required hospitalization or prolongation of hospitalization or resulted in disability/incapacity.

Time frame: Throughout the entire study period (from Month 0 to Month 14)

Population: The analysis was performed on the Total Vaccinated cohort, which included all vaccinated subjects for whom data were available.

Arm	Measure	Value (NUMBER)
RTS,S/AS02D Group	Number of Subjects With Serious Adverse Events (SAEs).	35 subjects
Engerix-B Group	Number of Subjects With Serious Adverse Events (SAEs).	34 subjects

Secondary

Number of Subjects With Solicited General Symptoms.

Assessed solicited general symptoms were drowsiness, fever, irritability and loss of appetite. Fever was defined as axillary temperature equal or above (≥) to 37.5 degrees Celsius (C).

Time frame: During the 7 day (Days 0-6) follow-up period after any vaccination with TETRActHib™ vaccine