Artemisinin Resistance in Cambodia II (ARC II)

The purpose of this study is to determine the impact of varying doses of artesunate on treatment outcome and whether higher doses of artesunate can overcome the problem of compromised artemisinin sensitivity in the region.

To determine the safety and tolerability of this previously untested experimental high dose (6 mg/Kg/D X 7 day, total 42 mg/Kg) artesunate monotherapy regimen.

Study Overview

• Status: Completed
• Conditions: Falciparum Malaria
• Intervention / Treatment: Drug: Artesunate; Drug: Artesunate; Drug: Artesunate

Detailed Description

A total of 150 volunteers with acute uncomplicated falciparum malaria will be randomly assigned one of 3 arms to be treated with artesunate monotherapy for 7 days at a ratio of 2:1:2.

Arm 2 serves as a control and will serve as a bridge to the ARC 1 study performed in 2006/2007. Patients in Arm 1 will receive a relatively low "standard" dose, and patients in Arm 2 will receive the intermediate dose of 4 mg/kg that was used in the ARC1 study. Patients in Arm 3 will receive an experimental "high-dose" regimen. Currently available safety data extends to subjects who have received the 28 mg/Kg total dose over 7 days and to another study administering 8 mg/Kg/day for 3 days (total dose 24 mg/Kg). Subjects randomized into this study's 'high-dose' Arm 3 will, therefore, receive a total dose that is higher than has been previously studied in humans.

The study design will be based on the WHO recommendations for the 'Assessment and Monitoring of Antimalarial Drug Efficacy for the Treatment of Uncomplicated Falciparum Malaria' (WHO, 2003).

• Study Type: Interventional
• Enrollment (Actual): 143
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Cambodia
  • Battambang
    • Sam Lot District, Battambang, Cambodia
      • Tasanh Health Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Acute symptomatic falciparum malaria infection as determined by malaria smear with a parasite density of 1000 to 200,000 asexual parasites/Micro-liter as determined on the thick/thin screening smear with fever (defined as ≥ 37.5ºC), or reported history of fever within the last 48 hours.
2. Age: 18-65 years old
3. All females between the age of 18 and 50 are required to have a negative human chorionic gonadotropin (hCG) pregnancy test (urine). All females of childbearing potential (not surgically sterile, or less than two years menopausal) are required to use an acceptable method of contraception, such as implant, injectable, or oral contraceptive(s), if possible with additional barrier contraception, intrauterine device, sexual abstinence, or vasectomized partner, throughout the study.
4. Written informed consent obtained
5. Willing to stay under close medical supervision for the study duration of 42 days
6. Otherwise healthy Out-patients

Exclusion Criteria:

1. Pregnant women, nursing mothers, or women of childbearing potential who do not use an acceptable method of contraception (as described in Inclusion Criteria, # 3)
2. Mixed malaria infection on admission by malaria smear
3. A previous history of intolerance or hypersensitivity to the study drug artesunate or to drugs with similar chemical structures, such as artemether, artemisinin or dihydroartemisinin
4. History of malaria drug therapy administered in the past 30 days
5. Previous participation in this trial, or participation in any other studies involving investigational or marketed products, concomitantly or within 30 days prior to entry in the study
6. History of significant cardiovascular, liver or renal functional abnormality or any other clinically significant illness, which in the opinion of the investigator would place them at increased risk.
7. Symptoms of severe vomiting (no food or inability to take food during the previous 8 hours).
8. Signs or symptoms of severe malaria (adapted from WHO recommendations (2003): prostration, impaired consciousness, respiratory distress, convulsions, systolic blood pressure < 70 mm Hg, abnormal bleeding, severe anemia with hemoglobin < 8 g/dL or HCT < 24%, hyperparasitemia at > 4% parasitized red blood cells).
9. Unable and/or unlikely to comprehend and/or follow the protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Arm 1; Oral Artesunate ("standard" dose)	Drug: Artesunate; 2 mg/kg/day x 7 days; Drug: Artesunate; 4 mg/kg/day x 7 days; Drug: Artesunate; 6 mg/kg/day x 7 days
ACTIVE_COMPARATOR: Arm 2; Oral Artesunate ("ARC1" dose)	Drug: Artesunate; 2 mg/kg/day x 7 days; Drug: Artesunate; 4 mg/kg/day x 7 days; Drug: Artesunate; 6 mg/kg/day x 7 days
EXPERIMENTAL: Arm 3; Oral Artesunate (experimental "high" dose)	Drug: Artesunate; 2 mg/kg/day x 7 days; Drug: Artesunate; 4 mg/kg/day x 7 days; Drug: Artesunate; 6 mg/kg/day x 7 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Primary clinical outcome is cure (Adequate Clinical and Parasitological Response - ACPR as defined by WHO criteria) on Day 28 and 42	Day 28 and 42
Safety and tolerability of oral artesunate	Up to 42 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Secondary outcome measures are time until parasite, fever, and gametocyte clearance (PCT, FCT, and GCT).	Day 3

Collaborators and Investigators

• Sponsor: Armed Forces Research Institute of Medical Sciences, Thailand
• Collaborators: Bill and Melinda Gates Foundation; World Health Organization
• Investigators: Principal Investigator: Delia Bethell, BM BCh, Armed Forces Research Institute of Medical Sciences (AFRIMS); Principal Investigator: Socheat Duong, M.D., National Center for Parasitology, Entomology and Malaria Control; Principal Investigator: Se Youry, M.D., M.P.H.M., Armed Forces Research Institute of Medical Sciences (AFRIMS)

Publications and helpful links

General Publications

• Bethell D, Se Y, Lon C, Tyner S, Saunders D, Sriwichai S, Darapiseth S, Teja-Isavadharm P, Khemawoot P, Schaecher K, Ruttvisutinunt W, Lin J, Kuntawungin W, Gosi P, Timmermans A, Smith B, Socheat D, Fukuda MM. Artesunate dose escalation for the treatment of uncomplicated malaria in a region of reported artemisinin resistance: a randomized clinical trial. PLoS One. 2011;6(5):e19283. doi: 10.1371/journal.pone.0019283. Epub 2011 May 13.
• Bethell D, Se Y, Lon C, Socheat D, Saunders D, Teja-Isavadharm P, Khemawoot P, Darapiseth S, Lin J, Sriwichai S, Kuntawungin W, Surasri S, Lee SJ, Sarim S, Tyner S, Smith B, Fukuda MM. Dose-dependent risk of neutropenia after 7-day courses of artesunate monotherapy in Cambodian patients with acute Plasmodium falciparum malaria. Clin Infect Dis. 2010 Dec 15;51(12):e105-14. doi: 10.1086/657402. Epub 2010 Nov 11.

Study record dates

Study Major Dates

• Study Start: July 1, 2008
• Primary Completion (ACTUAL): August 1, 2009
• Study Completion (ACTUAL): August 1, 2009

Study Registration Dates

• First Submitted: July 23, 2008
• First Submitted That Met QC Criteria: July 23, 2008
• First Posted (ESTIMATE): July 25, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): January 25, 2011
• Last Update Submitted That Met QC Criteria: January 24, 2011
• Last Verified: January 1, 2011

More Information

Terms related to this study

• Keywords: Plasmodium Falciparum; Artesunate; Cambodia
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Malaria, Falciparum; Anti-Infective Agents; Antiviral Agents; Antineoplastic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Anthelmintics; Schistosomicides; Antiplatyhelmintic Agents; Artesunate
• Other Study ID Numbers: WRAIR 1396; HSRRB number A-14479; WHO RPC252