Malaria
Conditions
Keywords
Malaria, Prophylaxis, Atovaquone, Malarone, Challenge
Brief summary
The purpose of this study is to determine whether Malarone ®, which is a drug approved to prevent malaria when taken daily, will still effectively prevent malaria if taken weekly.
Detailed description
In this study, two groups of volunteers will be exposed to malaria through the bites of infected mosquitoes. In one group, volunteers will be randomly assigned to one of 5 arms. Each of these arms will receive a different dose of Malarone®, a drug known to prevent malaria when taken daily. Each of these doses will be lower than the maximum approved dose of this medicine. The other group will not be treated with any drug that could prevent symptoms or infection. After exposure, both groups will be monitored for a period of approximately 3 months to see if they develop symptoms of malaria. Any subjects who do so will be treated with appropriate medications. Subjects in both groups will have their blood checked regularly during this period for the presence of malaria parasites. At the completion of the study, results will be analyzed to determine whether any of the doses of Malarone might effectively prevent malaria if taken weekly rather than daily.
Interventions
Volunteers will receive doses of atovaquone/proguanil (Malarone) or matching sugar pills.
OTHERProcedure - malaria challenge
2\) Procedure- Malaria Challenge- Volunteers will be exposed to bites of infectious mosquitoes with the intention of causing malaria infection. Volunteers infected with malaria will undergo approved treatments for malaria.
Sponsors
U.S. Army Medical Research and Development Command
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* A male or non-pregnant, non-lactating female 18 to 50 years of age (inclusive) at the time of screening * Free of clinically significant health problems * Baseline ECG before entering into the study * Available to participate for duration of study (approximately 4 months, not including screening period) * If the participant is female, not pregnant or lactating and willing to use contraception to prevent pregnancy * BMI between 19 and 30
Exclusion criteria
* History of malaria or travel to a malarious country within the previous 12 months * History of participation in a study in which potential exposure to malaria or vaccination against malaria occurred. * Planned travel to malarious areas during the study period. * History of malaria chemoprophylaxis within 60 days prior to time of study entry. * Chronic use of antibiotics with anti-malarial effects * Chronic use (defined as more than 14 days)of immunosuppressants or other immune-modifying drugs within six months of study entry. * Any confirmed or suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection * Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by physical examination, ECG or laboratory screening tests * Significant unexplained anemia * History of sickle cell disease or sickle cell trait * Seropositive for hepatitis B or hepatitis C * History of splenectomy * Pregnant or lactating female, or female who intends to become pregnant during the study * Suspected or known current alcohol abuse as defined by the American Psychiatric Association in DSM IV * History of a neuropsychiatric disorder (anxiety, depression, psychosis, schizophrenia) * Chronic or active illicit and/or intravenous drug use * History of allergy to atovaquone, proguanil or chloroquine * History of psoriasis * Concurrent participation in other research studies
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Prophylactic Efficacy of 3 Different Doses of Atovaquone/Proguanil (Malarone@) Given 1 Week Before Infectious Sporozoite Challenge Using the P. Falciparum Human Challenge Model. | Days 6-20 | Number of participants with prophylactic efficacy was determined by the absence of cases of malaria parasitemia, defined as microscopically detectable parasitemia by Giemsa-stained thick smears, in those receiving any dose of Malarone as compared to the control (no treatment) group |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Measured Concentrations of Plasma Atovaquone With Determinations of T1/2. | 7, 6, 5, and 1 day prior to challenge; on the day of the challenge; 1, 4, 5, 6, 7, 8, 10and 14 days after the challenge; and on the day parasitemia develops., | Plasma concentrations (ng/ml) were used to determine the elimination half life (t1/2) of atovaquone (days). |
| Measured Concentrations of Plasma Atovaquone With Determinations of Area Under the Curve | 7, 6, 5, and 1 day prior to challenge; on the day of the challenge; 1, 4, 5, 6, 7, 8, 10and 14 days after the challenge; and on the day parasitemia develops., | Plasma concentrations were used to determine the pharmacokinetic curves with determinations of area under the curve (AUC).The smallest AUC Day 0-6.5 associated with protection from detectable parasitemia, and the highest AUC Day 0-6.5 observed in any cases of malaria (prophylactic failures) were to be reported. |
Countries
United States
Participant flow
Recruitment details
Study subjects were healthy male and non-pregnant or lactating females between the ages of 18 and 50 with a body mass index (BMI)between 19 and 30 for subject receiving the drug.
Participants by arm
| Arm | Count |
|---|---|
| Malarone Thirty (30) subjects were placed in the Malarone (treatment) Arm. The thirty subjects were then randomized into 5 treatment groups, each group receiving Malarone tablet(s) (250/100mg)prior to challenge. The groups received treatment as follows:
Group 1 - 1 tablet 1 day before challenge Group 2 - 1 tablet 4 days before challenge Group 3 - 1 tablet 7 days before challenge Group 4 - 2 tablets 7 days before challenge Group 5 - 4 tablets 7 days before challenge | 29 |
| Control The six (6) Control volunteers were enrolled in a open label arm and received no treatment prior to malaria challenge. | 6 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Malarone | Control | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 29 Participants | 6 Participants | 35 Participants |
| Region of Enrollment United States | 29 participants | 6 participants | 35 participants |
| Sex: Female, Male Female | 11 Participants | 1 Participants | 12 Participants |
| Sex: Female, Male Male | 18 Participants | 5 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 29 | 6 / 6 |
| serious Total, serious adverse events | 0 / 29 | 0 / 6 |
Outcome results
Primary
Prophylactic Efficacy of 3 Different Doses of Atovaquone/Proguanil (Malarone@) Given 1 Week Before Infectious Sporozoite Challenge Using the P. Falciparum Human Challenge Model.
Number of participants with prophylactic efficacy was determined by the absence of cases of malaria parasitemia, defined as microscopically detectable parasitemia by Giemsa-stained thick smears, in those receiving any dose of Malarone as compared to the control (no treatment) group
Time frame: Days 6-20
Population: Analysis population was According to Protocol which included participants meeting all eligibility criteria, not meeting any elimination criteria, complying with defined protocol procedures and for whom data are available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment Group 1 | Prophylactic Efficacy of 3 Different Doses of Atovaquone/Proguanil (Malarone@) Given 1 Week Before Infectious Sporozoite Challenge Using the P. Falciparum Human Challenge Model. | 6 participants with negative parasitemia |
| Treatment Group 2 | Prophylactic Efficacy of 3 Different Doses of Atovaquone/Proguanil (Malarone@) Given 1 Week Before Infectious Sporozoite Challenge Using the P. Falciparum Human Challenge Model. | 4 participants with negative parasitemia |
| Treatment Group 3 | Prophylactic Efficacy of 3 Different Doses of Atovaquone/Proguanil (Malarone@) Given 1 Week Before Infectious Sporozoite Challenge Using the P. Falciparum Human Challenge Model. | 3 participants with negative parasitemia |
| Treatment Group 4 | Prophylactic Efficacy of 3 Different Doses of Atovaquone/Proguanil (Malarone@) Given 1 Week Before Infectious Sporozoite Challenge Using the P. Falciparum Human Challenge Model. | 6 participants with negative parasitemia |
| Treatment Group 5 | Prophylactic Efficacy of 3 Different Doses of Atovaquone/Proguanil (Malarone@) Given 1 Week Before Infectious Sporozoite Challenge Using the P. Falciparum Human Challenge Model. | 5 participants with negative parasitemia |
| Control | Prophylactic Efficacy of 3 Different Doses of Atovaquone/Proguanil (Malarone@) Given 1 Week Before Infectious Sporozoite Challenge Using the P. Falciparum Human Challenge Model. | 0 participants with negative parasitemia |
Secondary
Measured Concentrations of Plasma Atovaquone With Determinations of Area Under the Curve
Plasma concentrations were used to determine the pharmacokinetic curves with determinations of area under the curve (AUC).The smallest AUC Day 0-6.5 associated with protection from detectable parasitemia, and the highest AUC Day 0-6.5 observed in any cases of malaria (prophylactic failures) were to be reported.
Time frame: 7, 6, 5, and 1 day prior to challenge; on the day of the challenge; 1, 4, 5, 6, 7, 8, 10and 14 days after the challenge; and on the day parasitemia develops.,
Population: Analysis was done on subjects who completed the study according to protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment Group 1 | Measured Concentrations of Plasma Atovaquone With Determinations of Area Under the Curve | 3595 ng*day/ml | Standard Deviation 2213 |
| Treatment Group 2 | Measured Concentrations of Plasma Atovaquone With Determinations of Area Under the Curve | 616 ng*day/ml | Standard Deviation 191 |
| Treatment Group 3 | Measured Concentrations of Plasma Atovaquone With Determinations of Area Under the Curve | 510 ng*day/ml | Standard Deviation 218 |
| Treatment Group 4 | Measured Concentrations of Plasma Atovaquone With Determinations of Area Under the Curve | 1434 ng*day/ml | Standard Deviation 664 |
| Treatment Group 5 | Measured Concentrations of Plasma Atovaquone With Determinations of Area Under the Curve | 2233 ng*day/ml | Standard Deviation 1895 |
Secondary
Measured Concentrations of Plasma Atovaquone With Determinations of T1/2.
Plasma concentrations (ng/ml) were used to determine the elimination half life (t1/2) of atovaquone (days).
Time frame: 7, 6, 5, and 1 day prior to challenge; on the day of the challenge; 1, 4, 5, 6, 7, 8, 10and 14 days after the challenge; and on the day parasitemia develops.,
Population: Population for analysis included According to Protocol Population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment Group 1 | Measured Concentrations of Plasma Atovaquone With Determinations of T1/2. | 3.3 Days | Standard Deviation 1.9 |
| Treatment Group 2 | Measured Concentrations of Plasma Atovaquone With Determinations of T1/2. | 3.3 Days | Standard Deviation 1.2 |
| Treatment Group 3 | Measured Concentrations of Plasma Atovaquone With Determinations of T1/2. | 3.3 Days | Standard Deviation 1.6 |
| Treatment Group 4 | Measured Concentrations of Plasma Atovaquone With Determinations of T1/2. | 5.6 Days | Standard Deviation 3.1 |
| Treatment Group 5 | Measured Concentrations of Plasma Atovaquone With Determinations of T1/2. | 3.7 Days | Standard Deviation 1.4 |