Phase I Pediatric FMP2.1/AS02A Trial in Mali

Randomized, Controlled, Dose Escalation Phase I Clinical Trial to Evaluate the Safety and Immunogenicity of WRAIR's AMA-1 Malaria Vaccine (FMP2.1) Adjuvanted in GSKBio's AS02A Vs. Rabies Vaccine in 1-6 Year Old Children in Bandiagara, Mali

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00358332

Enrollment

100

Registered

2006-07-31

Start date

2006-11-30

Completion date

2007-12-31

Last updated

2011-10-24

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

Conditions

Plasmodium Falciparum Malaria

Keywords

malaria, vaccine, Mali, children

Brief summary

The purpose of this study is to test the safety and dosages of a malaria vaccine in 100 children, 1-6 years old, in Bandiagara, Mali. The study is testing the safety of the vaccine when it is given to people who are regularly exposed to malaria and it will provide information regarding optimal vaccine dosage. This study will compare 3 injections of different vaccine doses to a rabies vaccine that is already approved. During the study, the child's health will be checked in the clinic and during home visits. Children may participate for about 14 months, and blood will be taken from each child throughout the study. If the child becomes sick from malaria, he/she will be treated. Information from this study may be used to develop a malaria vaccine that will help control the disease.

Detailed description

This study is a randomized, controlled, dose-escalation, phase I trial of the FMP2.1/AS02A malaria vaccine, using rabies vaccine as a control. This study is linked to DMID protocol 07-0003. The primary objective of this study is to evaluate the safety and reactogenicity of FMP2.1/AS02A in children naturally exposed to P. falciparum malaria infection. The secondary objective is to measure the magnitude and duration of antibody response to FMP2.1 by enzyme-linked immunosorbent assay (ELISA). One hundred healthy children aged 1-6 years in Bandiagara, Mali, will be randomized to 1 of 3 possible groups. Twenty subjects will be enrolled in cohort 1 and 40 subjects each in cohorts 2 and 3. Children within each cohort will be randomized in a 3:1 ratio to receive 10, 25 or 50 micrograms of FMP2.1 (in cohorts 1, 2 and 3, respectively) adjuvanted with a proportionate volume of the AS02A, or rabies vaccine. Thus a total of 75 children will receive the malaria vaccine and 25 the rabies vaccine. Immunizations will be given on days 0, 30 and 60 in a staggered fashion, with the first administrations of the 25 and 50 microgram dose levels of FMP2.1 following the first administration of the 10 and 25 microgram dose levels, respectively, by 2-3 weeks. Solicited adverse events will be recorded on the days of immunization and days 1, 2, 3 and 7 after each immunization, and unsolicited adverse events will be recorded for 30 days after each immunization. Children will be followed for 1 year after the last immunization. Sera will be collected for anti-FMP2.1 antibody titers on the days of immunization and 14 days after each immunization as well as 3, 6, 9 and 12 months after the first immunization. Each child will participate in the study for up to 414 days, which includes the screening period. The primary outcome measures include: occurrence of solicited symptoms after each vaccination during a 7-day surveillance period (day of vaccination and days 1, 2, 3 and 7 after vaccination), occurrence of unsolicited symptoms after each vaccination during a 30-day surveillance period (day of vaccination and 30 subsequent days); and occurrence of serious adverse events throughout the study period. The secondary outcome measure is titers and activity of anti-FMP2.1 antibody at each time point where serology samples are analyzed, measured by ELISA.

Interventions

BIOLOGICALFMP2.1/AS02A

FMP2.1 will be reconstituted in AS02A adjuvant. Dosages: 10, 25, or 50 mcg of FMP2.1 or 0.1, 0.25 or 0.5 mL of FMP2.1/AS02A administered by intramuscular injection.

BIOLOGICALRabies vaccine (RabAvert)

RabAvert, white, freeze-dried vaccine for reconstitution with diluent. Dosage: 1.0 mL of rabies vaccine.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

PREVENTION

Masking

DOUBLE

Eligibility

Sex/Gender

ALL

Age

1 Years to 6 Years

Healthy volunteers

Yes

Inclusion criteria

* Age 1-6 years inclusive at the time of screening. * Residing in Bandiagara town. * Appear to be in generally good health based on clinical and laboratory investigation. * Separate written informed consent obtained from the parent/guardian before screening and study start, respectively. * Available to participate in follow-up for the duration of study (14 months).

Exclusion criteria

* Previous vaccination with an investigational vaccine or a rabies vaccine. * Use of a investigational or non-registered drug or vaccine other than the study vaccine(s) within 30 days preceding the first study immunization, or planned use up to 30 days after the third immunization. * Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs within six months prior to the first immunization. This includes any dose level of oral steroids or inhaled steroids, but not topical steroids. * Confirmed or suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection. * Confirmed or suspected autoimmune disease. * History of allergic reactions or anaphylaxis to immunizations or to any vaccine component. * History of serious allergic reactions to any substance, requiring hospitalization or emergent medical care. * History of allergy to tetracycline, doxycycline, nickel or Imidazole. * History of splenectomy. * Laboratory evidence of liver disease (alanine aminotransferase \[ALT\] greater than the upper limit of normal of the testing laboratory = 49.6 U/L). * Laboratory evidence of renal disease (serum creatinine greater than the upper limit of normal of the testing laboratory = 0.5 mg/dL (44.2 micromol/L), or more than trace protein or blood on urine dipstick testing). * Laboratory evidence of hematologic disease (absolute leukocyte count \<5,300/mm\^3 or \>15,300/mm\^3, absolute lymphocyte count \<2,300 mm\^3, platelet count \<133,000/mm\^3, or hemoglobin \<9.0 g/dL). * Chronic skin condition that could interfere with vaccine site reactogenicity assessment. * Administration of immunoglobulins and/or any blood products within the three months preceding the first study immunization or planned administration during the study period. * Simultaneous participation in any other interventional clinical trial. * Acute or chronic pulmonary, cardiovascular, hepatic, renal or neurological condition, severe malnutrition, or any other clinical findings that in the opinion of the Principal Investigator (PI) may increase the risk of participating in the study. * Other condition that in the opinion of the PI would jeopardize the safety or rights of a participant in the trial or would render the participant unable to comply with the protocol.

Design outcomes

Primary

Measure	Time frame	Description
Occurrence of Solicited Systemic Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	7 Days following any vaccination	The number of participants reporting drowsiness irritability/fussiness, loss of appetite, vomiting, and feverishness. Participants are counted only once but may have experienced symptoms on multiple occasions.
Occurrence of Unsolicited Symptoms During a 30-day Surveillance Period Following Vaccinations at Days 0, 30, and 60.	Day of vaccination and 30 subsequent days.	The number of participants spontaneously reporting any symptom (defined as any Adverse Event considered associated with the product) within 30 days of any vaccination. Participants are counted only once but may have experienced events on multiple occasions.
Number of Subjects Spontaneously Reporting Any Serious Adverse Event.	1 year after the last vaccination.	Any untoward medical occurrence that resulted in death, persistent/significant disability/incapacity, required in-patient hospitalization or prolongation thereof, was life threatening or a congenital anomaly/birth defect in offspring of a study subject; or may have jeopardized the participant or required intervention to prevent one of the outcomes.
Occurrence of Solicited Local Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	7 Days following any vaccination	The number of participants reporting pain, swelling and erythema. Participants are counted only once but may have experienced symptoms on multiple occasions.

Secondary

Measure	Time frame	Description
Anti-FMP2.1 Antibody Titers Measured by ELISA, at Day 180	Day 180 +/- 14 days	This outcome is the mean of the log anti-FMP2.1 antibody response measured by ELISA.
Anti-FMP2.1 Antibody Titers Measured by ELISA, at Day 0	Day 0	This outcome is the mean of the log anti-FMP2.1 antibody response measured by ELISA.
Anti-FMP2.1 Antibody Titers Measured by ELISA, at Day 364	Day 364 +/- 14 days	This outcome is the mean of the log anti-FMP2.1 antibody response measured by ELISA.
Anti-FMP2.1 Antibody Titers Measured by ELISA, at Day 272.	Day 272 +/- 14 days	This outcome is the mean of the log anti-FMP2.1 antibody response measured by ELISA.
Anti-FMP2.1 Antibody Titers Measured by ELISA, at Day 30	Day 30 +/- 7 days	This outcome is the mean of the log anti-FMP2.1 antibody response measured by ELISA.
Anti-FMP2.1 Antibody Titers Measured by ELISA, at Day 60	Day 60 +/- 7 days	This outcome is the mean of the log anti-FMP2.1 antibody response measured by ELISA.
Anti-FMP2.1 Antibody Titers Measured by ELISA, at Day 90	Day 90 +/- 10 days	This outcome is the mean of the log anti-FMP2.1 antibody response measured by ELISA.

Countries

Mali

Participant flow

Recruitment details

Parents in Bandiagara Mali were made aware of the study by a radio announcement and voluntarily brought their children to the Bandiagara Malaria Project (BMP) clinic on the campus of the Bandiagara District Hospital in Bandiagara, Mali. The first subject was enrolled on November 3, 2006 and the final subject was enrolled on December 12, 2006.

Participants by arm

Arm	Count
FMP2.1/AS02A 10 Mcg Subjects received FMP2.1/AS02A 10 mcg (Falciparum Malaria Protein 2.1 / Adjuvant System 2 of GlaxoSmithKline Biologicals without thimerosal) by intramuscular injection in the deltoid at study days 0, 30 and 60.	15
FMP2.1/AS02A 25 Mcg Subjects received FMP2.1/AS02A 25 mcg (Falciparum Malaria Protein 2.1 / Adjuvant System 2 without thimerosal) by intramuscular injection in the deltoid at study days 0, 30 and 60.	30
FMP2.1/AS02A 50 Mcg Subjects received FMP2.1/AS02A 50 mcg (Falciparum Malaria Protein 2.1 / Adjuvant System 2 without thimerosal) by intramuscular injection in the deltoid at study days 0, 30 and 60.	30
RabAvert(R) Subjects received RabAvert(R) rabies vaccine by intramuscular injection in the deltoid at study days 0, 30 and 60.	25
Total	100

Baseline characteristics

Characteristic	FMP2.1/AS02A 25 Mcg	FMP2.1/AS02A 50 Mcg	FMP2.1/AS02A 10 Mcg	RabAvert(R)	Total
Age, Categorical <=18 years	30 Participants	30 Participants	15 Participants	25 Participants	100 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age Continuous	3.5 years STANDARD_DEVIATION 1.7	3.6 years STANDARD_DEVIATION 1.7	3.5 years STANDARD_DEVIATION 1.8	3.2 years STANDARD_DEVIATION 1.9	3.4 years STANDARD_DEVIATION 1.8
Region of Enrollment Mali	30 participants	30 participants	15 participants	25 participants	100 participants
Sex: Female, Male Female	15 Participants	12 Participants	7 Participants	15 Participants	49 Participants
Sex: Female, Male Male	15 Participants	18 Participants	8 Participants	10 Participants	51 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	15 / 15	30 / 30	30 / 30	25 / 25
serious Total, serious adverse events	1 / 15	1 / 30	0 / 30	2 / 25

Outcome results

Primary

Number of Subjects Spontaneously Reporting Any Serious Adverse Event.

Any untoward medical occurrence that resulted in death, persistent/significant disability/incapacity, required in-patient hospitalization or prolongation thereof, was life threatening or a congenital anomaly/birth defect in offspring of a study subject; or may have jeopardized the participant or required intervention to prevent one of the outcomes.

Time frame: 1 year after the last vaccination.

Population: This outcome includes all enrolled subjects.

Arm	Measure	Value (NUMBER)
FMP2.1/AS02A 10 Mcg	Number of Subjects Spontaneously Reporting Any Serious Adverse Event.	1 Participants
FMP2.1/AS02A 25 Mcg	Number of Subjects Spontaneously Reporting Any Serious Adverse Event.	1 Participants
FMP2.1/AS02A 50 Mcg	Number of Subjects Spontaneously Reporting Any Serious Adverse Event.	0 Participants
RabAvert(R)	Number of Subjects Spontaneously Reporting Any Serious Adverse Event.	2 Participants

Primary

Occurrence of Solicited Local Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.

The number of participants reporting pain, swelling and erythema. Participants are counted only once but may have experienced symptoms on multiple occasions.

Time frame: 7 Days following any vaccination

Population: This outcome includes all enrolled subjects.

Arm	Measure	Group	Value (NUMBER)
FMP2.1/AS02A 10 Mcg	Occurrence of Solicited Local Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Site Pain	11 Participants
FMP2.1/AS02A 10 Mcg	Occurrence of Solicited Local Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Erythema	0 Participants
FMP2.1/AS02A 10 Mcg	Occurrence of Solicited Local Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Swelling	13 Participants
FMP2.1/AS02A 25 Mcg	Occurrence of Solicited Local Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Site Pain	27 Participants
FMP2.1/AS02A 25 Mcg	Occurrence of Solicited Local Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Erythema	0 Participants
FMP2.1/AS02A 25 Mcg	Occurrence of Solicited Local Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Swelling	28 Participants
FMP2.1/AS02A 50 Mcg	Occurrence of Solicited Local Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Swelling	30 Participants
FMP2.1/AS02A 50 Mcg	Occurrence of Solicited Local Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Site Pain	27 Participants
FMP2.1/AS02A 50 Mcg	Occurrence of Solicited Local Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Erythema	1 Participants
RabAvert(R)	Occurrence of Solicited Local Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Site Pain	6 Participants
RabAvert(R)	Occurrence of Solicited Local Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Erythema	0 Participants
RabAvert(R)	Occurrence of Solicited Local Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Swelling	11 Participants

Primary

Occurrence of Solicited Systemic Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.

The number of participants reporting drowsiness irritability/fussiness, loss of appetite, vomiting, and feverishness. Participants are counted only once but may have experienced symptoms on multiple occasions.

Time frame: 7 Days following any vaccination

Population: This outcome includes all enrolled subjects.

Arm	Measure	Group	Value (NUMBER)
FMP2.1/AS02A 10 Mcg	Occurrence of Solicited Systemic Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Vomiting	2 Participants
FMP2.1/AS02A 10 Mcg	Occurrence of Solicited Systemic Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Irritability/Fussiness	0 Participants
FMP2.1/AS02A 10 Mcg	Occurrence of Solicited Systemic Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Feverishness	3 Participants
FMP2.1/AS02A 10 Mcg	Occurrence of Solicited Systemic Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Loss of Appetite	3 Participants
FMP2.1/AS02A 10 Mcg	Occurrence of Solicited Systemic Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Drowsiness	0 Participants
FMP2.1/AS02A 25 Mcg	Occurrence of Solicited Systemic Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Loss of Appetite	0 Participants
FMP2.1/AS02A 25 Mcg	Occurrence of Solicited Systemic Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Vomiting	0 Participants
FMP2.1/AS02A 25 Mcg	Occurrence of Solicited Systemic Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Feverishness	17 Participants
FMP2.1/AS02A 25 Mcg	Occurrence of Solicited Systemic Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Irritability/Fussiness	0 Participants
FMP2.1/AS02A 25 Mcg	Occurrence of Solicited Systemic Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Drowsiness	0 Participants
FMP2.1/AS02A 50 Mcg	Occurrence of Solicited Systemic Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Loss of Appetite	1 Participants
FMP2.1/AS02A 50 Mcg	Occurrence of Solicited Systemic Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Drowsiness	0 Participants
FMP2.1/AS02A 50 Mcg	Occurrence of Solicited Systemic Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Irritability/Fussiness	0 Participants
FMP2.1/AS02A 50 Mcg	Occurrence of Solicited Systemic Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Vomiting	0 Participants
FMP2.1/AS02A 50 Mcg	Occurrence of Solicited Systemic Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Feverishness	16 Participants
RabAvert(R)	Occurrence of Solicited Systemic Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Vomiting	0 Participants
RabAvert(R)	Occurrence of Solicited Systemic Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Irritability/Fussiness	0 Participants
RabAvert(R)	Occurrence of Solicited Systemic Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Drowsiness	0 Participants
RabAvert(R)	Occurrence of Solicited Systemic Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Loss of Appetite	0 Participants
RabAvert(R)	Occurrence of Solicited Systemic Symptoms During a 7-day Surveillance Period (Systematically Collected) Following Vaccinations at Days 0, 30, and 60.	Feverishness	4 Participants

Primary

Occurrence of Unsolicited Symptoms During a 30-day Surveillance Period Following Vaccinations at Days 0, 30, and 60.

The number of participants spontaneously reporting any symptom (defined as any Adverse Event considered associated with the product) within 30 days of any vaccination. Participants are counted only once but may have experienced events on multiple occasions.

Time frame: Day of vaccination and 30 subsequent days.

Population: This outcome includes all enrolled subjects.

Arm	Measure	Value (NUMBER)
FMP2.1/AS02A 10 Mcg	Occurrence of Unsolicited Symptoms During a 30-day Surveillance Period Following Vaccinations at Days 0, 30, and 60.	4 Participants
FMP2.1/AS02A 25 Mcg	Occurrence of Unsolicited Symptoms During a 30-day Surveillance Period Following Vaccinations at Days 0, 30, and 60.	7 Participants
FMP2.1/AS02A 50 Mcg	Occurrence of Unsolicited Symptoms During a 30-day Surveillance Period Following Vaccinations at Days 0, 30, and 60.	10 Participants
RabAvert(R)	Occurrence of Unsolicited Symptoms During a 30-day Surveillance Period Following Vaccinations at Days 0, 30, and 60.	2 Participants

Secondary