Malaria
Conditions
Keywords
Uncomplicated Malaria, GMP artesunate
Brief summary
The purpose of this study is to determine how GMP IV Artesunate is metabolized and cleared by individuals with uncomplicated malaria infection and to determine how fast it eliminates malaria infection from the body.
Detailed description
This is an unblinded non-randomized phase II pharmacokinetic study of a new GMP formulation of intravenous artesunate. Artesunate has been used throughout Asia and Africa for many years. Its overall efficacy associated with the ability to lower parasitemia is well established. To date, pharmacokinetic studies have not been done in Africa using GMP (Good Manufacturing Practices)-produced drug. The objective of this study is to show that GMP IV artesunate rapidly clears parasites in Adult Kenyan populations with malaria and that the pharmacokinetic profile of the drug approximates other populations of adults tested (Asians and North Americans).
Interventions
DRUGArtesunate
Intravenous Artesunate (2.4 mg/kg) once a day for three days
DRUGMalarone
(proguanil/atovaquone) follow-on therapy (4 tablets once daily for three days)
Sponsors
Military Infectious Diseases Research Program (MIDRP)
U.S. Army Medical Research and Development Command
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Adult male & non-pregnant females, 18-65 years * Fever, defined as \>37.5ºC, during the current illness, or history (within the last 48 hours) of fever. * Diagnosis of falciparum malaria, greater than or equal to 200 parasites/uL * Able to communicate well with the investigator and to comply with the requirements of the entire study. * Willing to be admitted for the period of drug administration and/or to follow up (return to hospital) * Provision of the written informed consent to participate as shown by a signature on the informed consent form.
Exclusion criteria
* Administration of any investigational drug in the period 0 to 16 weeks before entry to the study. * The use of any medication during the period 0 to 14 days (prescribed drugs) or 0 to 5 days (OTC) before entry to the study (including herbal or dietary supplements), except those deemed by the principal investigator / clinical investigator not to interfere with the outcome of the study. * Existence of any surgical or medical condition that, in the judgment of the clinical investigator, might interfere with the distribution, metabolism or excretion of the drug. * History of serious adverse reaction or hypersensitivity to study drug or follow on treatment. * Mixed malaria infection (malaria other than falciparum malaria mono-infection as detected by screening blood smear) * Severe falciparum malaria (as defined by the WHO; Attachment 1). * Donation or loss of greater than 400 ml of blood in the period 0 to 12 weeks before entry to the study, * Transfusion of blood within past 30 days. * Refusal to prevent pregnancy during the 14 days of the trial * Pregnancy as defined clinically or by a positive urine BHCG at the time of screening, or nursing mothers. * Laboratory evidence or history of significant cardiovascular, liver or renal functional abnormality, which in the opinion of the investigator would place them at increased risk. Specifically, the following will serve as exclusionary lab values: * Creatinine \>1.4 x ULN (\>2.0 mg/dL) * Glucose \<LLN (65mg/dL) * AST, ALT \>3x ULN (120 U/L)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Percentage of Parasites Detected at 48 Hours | 48 hours | Change in Percentage of Parasites Detected at 48 Hours. With positive numbers to represent increases and negative numbers to represent decreases |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Fever Clearance | Within 48 hours post dose | Temperature is measured by oral digital thermometers, and fever clearance time is defined as the first time with resolution of fever (\<37.5C) sustained for 24 hours |
| Safety - Severity of Adverse Events | up to 14 days | Determine the safety (defined as severity of AE's using the Common Toxicity Criteria) |
| Percentage of Parasite Clearance | 24 and 48 hours post dose | The target variable is detection (percentage) of asexual stage parasites of Plasmodium falciparum malaria in bloodstream by Giemsa - stained microscopy of thick and thin blood smears |
| Safety - Severity of Serious Adverse Events (SAE's) | up to 14 days | Determine the safety (defined as severity of SAE's using the Common Toxicity Criteria) |
| Safety - Serious Adverse Event (SAE) Relationship to Study Drug | Up to 14 days | Determine the safety (defined as relationship to study drug of SAE's) |
| Safety - Adverse Events Relationship to Study Drug | up to 14 days | Determine the safety (defined as relationship to study drug of AE's and SAE's) |
Countries
Kenya
Participant flow
Recruitment details
Thirty adult subjects with uncomplicated malaria were recruited from the endemic malarious region of Nyanza province in Kenya came to the New Nyanza Medical Center or sub-location recruitment sites.
Participants by arm
| Arm | Count |
|---|---|
| Artesunate and Malarone Subject are given intravenous Artesunate once a day for 3 days. Following completion of Artesunate treatment, all subjects received Malarone follow-on therapy to ensure parasitologic cure.
Artesunate and Malarone: Intravenous Artesunate (2.4 mg/kg) once a day for three days and Malarone (proguanil/atovaquone) follow-on therapy (4 tablets once daily for three days) | 30 |
| Total | 30 |
Baseline characteristics
| Characteristic | Artesunate and Malarone |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 30 Participants |
| Age, Continuous | 28 years STANDARD_DEVIATION 9.4 |
| Race/Ethnicity, Customized Tribe = Luo | 27 Participants |
| Race/Ethnicity, Customized Tribe = Luyha | 2 Participants |
| Race/Ethnicity, Customized Tribe = Other | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 30 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Region of Enrollment Kenya | 30 participants |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 30 / 30 |
| serious Total, serious adverse events | 1 / 30 |
Outcome results
Primary
Change in Percentage of Parasites Detected at 48 Hours
Change in Percentage of Parasites Detected at 48 Hours. With positive numbers to represent increases and negative numbers to represent decreases
Time frame: 48 hours
Population: Percentage of parasite change at 48 hours post dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Artesunate and Malarone | Change in Percentage of Parasites Detected at 48 Hours | 99.998 percentage of parasite change | Standard Deviation 0.0006 |
Secondary
Number of Subjects With Fever Clearance
Temperature is measured by oral digital thermometers, and fever clearance time is defined as the first time with resolution of fever (\<37.5C) sustained for 24 hours
Time frame: Within 48 hours post dose
Population: Summary of subject with fever clearance, defined as first sustained absence of fever (\<37.5C for least 24 hours)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Artesunate and Malarone | Number of Subjects With Fever Clearance | 29 Participants |
Secondary
Percentage of Parasite Clearance
The target variable is detection (percentage) of asexual stage parasites of Plasmodium falciparum malaria in bloodstream by Giemsa - stained microscopy of thick and thin blood smears
Time frame: 24 and 48 hours post dose
Population: Percentage of parasite clearance within the first 24 and 48 hours post dose of intravenous artesunate
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Artesunate and Malarone | Percentage of Parasite Clearance | 24 hours post dose | 99.421 percentage of parasite clearance | Standard Deviation 1.365 |
| Artesunate and Malarone | Percentage of Parasite Clearance | 48 hours post dose | 99.998 percentage of parasite clearance | Standard Deviation 0.0006 |
Secondary
Safety - Adverse Events Relationship to Study Drug
Determine the safety (defined as relationship to study drug of AE's and SAE's)
Time frame: up to 14 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Artesunate and Malarone | Safety - Adverse Events Relationship to Study Drug | None or remote | 89 Number of adverse events |
| Artesunate and Malarone | Safety - Adverse Events Relationship to Study Drug | Possible, probable, definate | 57 Number of adverse events |
Secondary
Safety - Serious Adverse Event (SAE) Relationship to Study Drug
Determine the safety (defined as relationship to study drug of SAE's)
Time frame: Up to 14 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Artesunate and Malarone | Safety - Serious Adverse Event (SAE) Relationship to Study Drug | None or Remote | 0 Number of events |
| Artesunate and Malarone | Safety - Serious Adverse Event (SAE) Relationship to Study Drug | Possible, Probable, Definate | 1 Number of events |
Secondary
Safety - Severity of Adverse Events
Determine the safety (defined as severity of AE's using the Common Toxicity Criteria)
Time frame: up to 14 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Artesunate and Malarone | Safety - Severity of Adverse Events | Mild | 123 Number of adverse events |
| Artesunate and Malarone | Safety - Severity of Adverse Events | Moderate | 17 Number of adverse events |
| Artesunate and Malarone | Safety - Severity of Adverse Events | Severe | 6 Number of adverse events |
Secondary
Safety - Severity of Serious Adverse Events (SAE's)
Determine the safety (defined as severity of SAE's using the Common Toxicity Criteria)
Time frame: up to 14 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Artesunate and Malarone | Safety - Severity of Serious Adverse Events (SAE's) | Mild | 0 Number of events |
| Artesunate and Malarone | Safety - Severity of Serious Adverse Events (SAE's) | Moderate | 0 Number of events |
| Artesunate and Malarone | Safety - Severity of Serious Adverse Events (SAE's) | Severe | 1 Number of events |