- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00522132
Phase II Artesunate Study in Severe Malaria
Phase II Randomized, Double-Blind Study of the Efficacy, Safety, Tolerability, and Pharmacokinetics of Intravenous Artesunate in Children With Severe Malaria
The primary objective of the study is to evaluate the effectiveness of 2 intravenous artesunate dosing regimens (2.4 mg/kg initially and at 12, 24, 48, and 72 hours or 4.0 mg/kg initially and at 24 and 48 hours) in clearing P. falciparum parasites in children with severe malaria.
Secondary objectives include:
- To compare the tolerability and safety of the 2 intravenous artesunate dosing regimens.
- To evaluate differences in the pharmacokinetic profile of intravenous artesunate by patient age and clinical presentation.
Study Overview
Detailed Description
This is a Phase II, double-blind, multicenter, randomized, parallel-group study of the antimalarial activity and safety of 2 intravenous artesunate regimens in children with severe P. falciparum malaria (Appendix B). It will compare the efficacy, safety and tolerability of the SEAQUAMAT regimen, the recommended dosing regimen for adults,8 which requires twice daily artesunate dosing on the first day, to a simpler once daily regimen. The study will also evaluate the pharmacokinetic profile of artesunate in pediatric patients.
Prior to study initiation, the protocol will be approved by the Independent Ethics Committee/Institutional Review Board(s) (IEC/IRB) of each site and the national regulatory authority of each study site.
Approximately 200 patients will be randomized at 3 study sites in Africa, which are part of the Severe Malaria in African Children (SMAC) network. Patients will be randomized to 1 of 2 treatment cohorts:
- Cohort 1: artesunate 2.4 mg/kg initially, and at 12, 24, 48, and 72 hours (12 mg/kg total dose); or
- Cohort 2: artesunate 4 mg/kg initially, and at 24 and 48 hours (12 mg/kg total dose), normal saline will be administered as a placebo at 12 and 72 hours in order to maintain the study blind.
The study is divided into 3 main periods including the Pre-Treatment Period (Screening/Day 0), the Treatment Period (Days 0 through 3; Day 0 is the first day of study drug dosing), and the Post-Treatment Period (including evaluations on Days 7, 14, and 28). Children presenting to the study hospitals with signs/symptoms of severe malaria will be screened for study enrollment. Those with presumed severe malaria will be identified and informed consent for participation from parents/guardians will be obtained while confirmation of malaria is determined by microscopic analysis of a Giemsa-stained thick smear. Patients who meet study inclusion criteria and none of the exclusion criteria will be randomized and promptly treated with 1 of the artesunate regimens, while hospitalized for at least 4 days (Days 0, 1, 2, and 3). Adjunctive therapy, including fluids, glucose, and blood, will follow SMAC standards, based on WHO guidelines for the treatment of severe malaria (Appendix C). As soon as the patient is able to receive oral medication and no signs and symptoms of severe malaria are present, but not before the last pharmacokinetic sample is taken (approximately 50 hours after the start of therapy), a single dose of sulfadoxine/pyrimethamine will be administered to ensure parasitological cure. Patients who received sulfadoxine/pyrimethamine within 14 days prior Study Day 0 will receive mefloquine instead of SP,, to ensure effective parasitological cure.
If the parasitemia is controlled and the safety laboratory tests from Day 3 indicate no clinical concern warranting prolonged hospitalization, the patient may be discharged at the discretion of the investigator. If a patient is discharged from the hospital on Day 3, he/she will return to the study site on Day 7 for evaluation. If the patient is unable to tolerate oral liquids or food within 6-24 hours after the last dose of artesunate, the patient will continue to be hospitalized and treated with parenteral antimalarial therapy until he/she is able to resume oral intake or a total of 7 days of therapy have been completed. All patients will return to the study site for evaluation on Days 14 and 28 to assess resolution of clinical complications and monitor for safety of therapy.
Efficacy will be assessed by various parasite clearance parameters. Safety evaluations including physical examinations, vital signs, hematology and chemistry laboratory parameters and monitoring of adverse events will be performed throughout the study. Pharmacokinetic assessments will be performed at 3 different timepoints during the study.
If adverse events reported during the study are unresolved by Day 28, patients will be followed for an additional 30 days or until resolution of the event or determination that no further medical management is deemed necessary. Similarly, the investigator will instruct the parents/guardians to return the patient to the study site if any untoward event occurs within 30 days of completing study drug.
Study Type
Enrollment (Anticipated)
Phase
- Phase 2
Contacts and Locations
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Male or female children aged 6 months and ≥ 5kg to 10 years, inclusive.
- Clinical diagnosis of severe P. falciparum malaria (see Appendix B) requiring hospitalization.
- Parasitemia (more than 5,000 parasites/microL on initial blood smear).
- Availability of child's parent/guardian and their willingness to provide written informed consent in accordance to local practice.
- Willingness and ability to comply with the study protocol for the duration of the study.
- Willingness to remain in the hospital for 4 days
Exclusion Criteria:
- Known serious adverse reaction or hypersensitivity to artemisinins, including artesunate, artemether, dihydroartemisinins or Co-Artem (artemether/lumefantrine).
- Any underlying disease that may compromise the diagnosis and the evaluation of the response to the study medication (including concomitant infection, concomitant neurological disease and malnutrition)
- Participation in any investigational drug study during the 30 days prior to Screening.
- Adequate anti-malarial treatment within 24 hours prior to admission.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: RANDOMIZED
- Interventional Model: PARALLEL
- Masking: QUADRUPLE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
ACTIVE_COMPARATOR: cohort 1
2.4 mg/kg iv artesunate at 0, 12, 24, 48and 72 hours
|
intravenous application
|
EXPERIMENTAL: cohort 2
4.0 mg/kg iv Artesunate at 0, 24 and 48 h
|
intravenous application
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
The proportion of patients with parasite clearance (more than 99% reduction from the baseline asexual parasite count) at 24 hours after initiation of study drug.
Time Frame: 24 hours after initiation of study
|
24 hours after initiation of study
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Time to total clearance of asexual parasites (PC100)
Time Frame: after study drug administration
|
after study drug administration
|
Time to 99% reduction of asexual parasites (PC99)
Time Frame: after study drug administration
|
after study drug administration
|
Time to 90% reduction of asexual parasites (PC90)
Time Frame: after study drug administration
|
after study drug administration
|
PCR corrected Adequate Clinical and Parasitological Response on day 28
Time Frame: on day 28
|
on day 28
|
plasma concentrations of artesunate following intravenous administration
Time Frame: after study drug administration
|
after study drug administration
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Peter Kremsner, MD, Universitat Tubingen
Publications and helpful links
Study record dates
Study Major Dates
Study Start
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ESTIMATE)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- EDCTP/MMV07-01
- EDCTP Grant #2004.01.M.d2
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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