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Study of Safety, Immunogenicity and Efficacy of a Candidate Malaria Vaccine in Tanzanian Infants

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00289185
First received: February 8, 2006
Last updated: July 3, 2014
Last verified: July 2014
  Purpose

GSK Biologicals in partnership with the Malaria Vaccine Initiative at PATH is developing a candidate malaria vaccine GSK 257049 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).

In order to integrate the malaria vaccine into the EPI regimen in malaria-endemic regions, a new variant RTS,S/AS02D (0.5 mL dose) has been developed.

The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.


Condition Intervention Phase
Malaria
Biological: RTS,S/AS02D
Biological: Engerix-B®
Biological: TETRActHib™
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: 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.

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Concentrations of Antibodies Against Hepatitis B (Anti-HB) [ Time Frame: Prior to vaccination at Week 0 (PRE), at Month 2 and at Month 3. ] [ Designated as safety issue: No ]
    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.

  • Number of Subjects With Serious Adverse Events (SAEs) [ Time Frame: From Week 0 to Month 9. ] [ Designated as safety issue: No ]
    SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.

  • Concentrations of Antibodies Against Diphtheria (Anti-D) [ Time Frame: Prior to vaccination at Week 0 (PRE), and at Month 3. ] [ Designated as safety issue: No ]
    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.

  • Concentrations of Antibodies Against Tetanus (Anti-T) [ Time Frame: Prior to vaccination at Week 0 (PRE), and at Month 3. ] [ Designated as safety issue: No ]
    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.

  • Concentrations of Anti-polyribosyl Ribitol Phosphate Antibodies (Anti-PRP). [ Time Frame: Prior to vaccination at Week 0 (PRE), and at Month 3. ] [ Designated as safety issue: No ]
    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.

  • Number of Subjects With Serious Adverse Events (SAEs) [ Time Frame: From Month 9 to Month 20. ] [ Designated as safety issue: No ]
    SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.

  • Concentrations of Anti-Bordetella Pertussis Toxin Antibodies (Anti-BPT). [ Time Frame: Prior to vaccination at Week 0 (PRE), and at Month 3. ] [ Designated as safety issue: No ]
    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.

  • Number of Subjects With Hepatitis B Antibody (Anti-HB) Concentrations Equal to or Above (>=) the Seroprotection Cut-off Value [ Time Frame: Prior to vaccination at Week 0 (PRE), at Month 2 and at Month 3. ] [ Designated as safety issue: No ]
    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.

  • Number of Subjects With Anti-diphtheria Antibody (Anti-D) Concentrations Equal to or Above (>=) the Seroprotection Cut-off Value [ Time Frame: Prior to vaccination at Week 0 (PRE), and at Month 3. ] [ Designated as safety issue: No ]
    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.

  • Number of Subjects With Anti-tetanus Antibody (Anti-T) Concentrations Equal to or Above (>=) the Seroprotection Cut-off Value [ Time Frame: Prior to vaccination at Week 0 (PRE), and at Month 3. ] [ Designated as safety issue: No ]
    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.

  • Number of Subjects With Anti-polyribosyl Ribitol Phosphate Antibody (Anti-PRP) Concentrations Equal to or Above (>=) the Seroprotection Cut-off Value [ Time Frame: Prior to vaccination at Week 0 (PRE), and at Month 3. ] [ Designated as safety issue: No ]
    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.

  • Number of Subjects With Anti-Bordetella Pertussis Toxin Antibody (Anti-BPT) Concentrations Equal to or Above (>=) the Seropositivity Cut-off Value [ Time Frame: Prior to vaccination at Week 0 (PRE), and at Month 3. ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Concentrations of Anti-Circumsporozoite Protein (Anti-CS) Antibodies [ Time Frame: Prior to vaccination at Week 0 (PRE), at Month 2, at Month 3 and at Month 9. ] [ Designated as safety issue: No ]
    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.

  • Number of Subjects With Solicited Local Symptoms. [ Time Frame: Within 7 days (Days 0-6) after vaccination with the RTS,S/AS02D or Engerix-B vaccine. ] [ Designated as safety issue: No ]
    Assessed solicited local symptoms were pain and swelling following vaccination with the RTS,S/AS02D or Engerix-B vaccine.

  • Number of Subjects With Solicited Local Symptoms. [ Time Frame: Within 7 days (Days 0-6) after vaccination with the TETRActHib vaccine. ] [ Designated as safety issue: No ]
    Assessed solicited local symptoms were pain and swelling following vaccination with the TETRActHib vaccine..

  • Number of Subjects With Solicited General Symptoms. [ Time Frame: Within 7 days (Days 0-6) after vaccination ] [ Designated as safety issue: No ]
    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).

  • Number of Subjects With Unsolicited Adverse Events (AEs). [ Time Frame: Within 30 days (Days 0-29) after vaccination ] [ Designated as safety issue: No ]
    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.

  • Number of Subjects With Serious Adverse Events (SAEs) [ Time Frame: Throughout the entire study, from Week 0 to Month 20. ] [ Designated as safety issue: No ]
    SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.

  • Time to First Malaria Infection [ Time Frame: 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). ] [ Designated as safety issue: No ]
    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.

  • Number of Subjects Prevalent for Parasitemia [ Time Frame: At Month 9 ] [ Designated as safety issue: No ]
    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 [ Time Frame: At Month 9 ] [ Designated as safety issue: No ]
    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 was assessed as prevalent for parasitemia.


Enrollment: 340
Study Start Date: September 2006
Study Completion Date: January 2009
Primary Completion Date: January 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: RTS,S/AS02D Group
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.
Biological: RTS,S/AS02D
3-dose intramuscular injection in the thigh
Other Names:
  • GSK 257146
  • RTS
  • S/AS02D
Biological: TETRActHib™
3-dose intramuscular injection in the thigh.
Other Name: DTPw/Hib
Active Comparator: Engerix-B Group
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..
Biological: Engerix-B®
3-dose intramuscular injection in the thigh.
Biological: TETRActHib™
3-dose intramuscular injection in the thigh.
Other Name: DTPw/Hib

Detailed Description:

This is a phase 2b trial designed to evaluate the safety and immunogenicity of RTS,S/AS02D when co-administered with a multivalent DTPw/Hib (Aventis Pasteur's TETRActHib vaccine). Infants randomized to the control group will receive a licensed hepatitis B vaccine, Engerix-B in place of RTS,S/AS02D.

Data pertaining to RTS,S/AS02D or Engerix-B will be collected in a double blinded manner; data relating to TETRActHib will be collected in an open fashion.

Oral polio vaccine (OPV) will be administered at birth, 8, 12, 16 weeks in co-administration with other vaccines and will not be administered as part of this protocol. Antibody titers to OPV will not be assessed as part of this protocol.

  Eligibility

Ages Eligible for Study:   6 Weeks to 10 Weeks
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion criteria:

  • A male or female infant between 6 and 10 weeks of age at the time of first vaccination.
  • Written or oral, signed or thumb-printed and witnessed informed consent obtained from the parent(s)/guardian(s) of the child.
  • Subjects who the investigator believes that their parents/guardians can and will comply with the requirements of the protocol (e.g. return for follow-up visits).
  • Born to a mother who is HBsAg negative & HIV negative.
  • Born after a normal gestation period (between 36 and 42 weeks).
  • Subjects who live within a 5 km radius of a dispensary.

Exclusion criteria:

  • Acute disease at the time of enrolment.
  • Serious acute or chronic illness determined by clinical or physical examination and laboratory screening tests.
  • Laboratory screening tests out of range for haemoglobin, total white cell count, platelets, ALT and creatinine.
  • Previous vaccination with diphtheria, tetanus, pertussis (whole-cell or acellular), Hemophilus influenzae type b or hepatitis B vaccines.
  • BCG administration within one week of proposed administration of a study vaccine.
  • Planned administration/administration of a vaccine not foreseen by the study protocol within 30 days of the first dose of vaccine(s).
  • Use of any investigational or non-registered drug or vaccine within 30 days preceding the first dose of study vaccine, or planned use during the study period.
  • Administration of immunoglobulins, blood transfusions or other blood products within the three months preceding the first dose of study vaccine or planned administration during the study period.
  • Chronic administration of immunosuppressants or other immune-modifying drugs within six months prior to the first vaccine dose.
  • Previous participation in any other malaria vaccine trial.
  • Simultaneous participation in any other clinical trial.
  • Same sex twin.
  • Maternal death.
  • History of allergic reactions (significant IgE-mediated events) or anaphylaxis to previous immunizations.
  • History of allergic disease or reactions likely to be exacerbated by any component of the vaccine.
  • Any other findings that the investigator feels would increase the risk of having an adverse outcome from participation in the trial.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00289185

Locations
Tanzania
GSK Investigational Site
Dar-es-Salaam, Tanzania
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Publications:
Abdulla S et al. (2008) Safety and immunogenicity of RTS,S/AS02D malaria vaccine in infants. N Engl J Med. 359(24):2533-2544.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00289185     History of Changes
Other Study ID Numbers: 104298
Study First Received: February 8, 2006
Results First Received: November 8, 2012
Last Updated: July 3, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
Coccidiosis
Parasitic Diseases
Malaria, Falciparum
Malaria

Additional relevant MeSH terms:
Malaria
Parasitic Diseases
Protozoan Infections

ClinicalTrials.gov processed this record on November 25, 2014