Official Title: “Artemisinin Resistance in Bangladesh”

A randomized, controlled clinical trial conducted in Southeastern Bangladesh using artesunate monotherapy to determine the baseline sensitivity of P.

falciparum to artemisinins.

Study Type: Interventional

Study Design: N/A

A total number of 100 volunteers with acute uncomplicated falciparum malaria will be randomly assigned one of 3 arms to be treated with artesunate monotherapy or quinine/doxycycline for 7 days at a ratio of 2:2:1. 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 participants will be otherwise healthy malaria patients aged 8 to 65 years with uncomplicated falciparum malaria recruited at the Bandarban Sadar Hospital, Bangladesh.

The artesunate will be administered orally (a single dose of 2 or 4 mg/kg/day) over a total duration of 7 days by directly observed therapy.

Patients will be admitted to the hospital for the duration of study drug administration or until all signs and symptoms of malaria have disappeared, whichever comes later. Thereafter they will be followed as outpatients until Day 42 with scheduled follow-up visits on Day 14, 28, 35, and 42.

In vitro drug sensitivity assays will be performed from samples on inclusion and in case of recrudescence. Drug levels will be measured on the first and last day of therapy. Primary clinical outcome is cure (Adequate Clinical and Parasitological Response - ACPR) on Day 28 and 42. Secondary outcome measures are time until parasite, fever, and gametocyte clearance (PCT, FCT, and GCT). Parasite genotyping will be used to distinguish recrudescences from reinfections by PCR for patients in whom recrudescences cannot be fully excluded. Subjects will be monitored for clinical adverse events throughout the study duration.

Blood will be drawn on the day of admission (before initiating therapy) for in vitro drug sensitivity testing and for PCR (markers of drug resistance and to distinguish recrudescence from reinfection by genotyping). Malaria smears will be prepared twice daily until parasite clearance and on Days 7, 14, 21, 28, 35, and 42 or whenever symptoms consistent with malaria appear. Plasma samples for determining drug levels will be obtained on the first and last day of therapy. Study participation for each individual will be 42 days.

Intervention(s) in this Clinical Trial

• Drug: Artesunate
  • 2 or 4 mg/kg/day for 7 days
• Drug: quinine-doxycycline
  • quinine-doxycycline for 7 days

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: 1
  • Artesunate monotherapy 2mg/kg/day for 7 days
• Experimental: 2
  • Artesunate monotherapy 4mg/kg/day for 7 days
• Active Comparator: 3
  • Quinine-doxycycline for 7 days

Primary Measures

• ACPR-ETF-LTF
  • Time Frame: 42 days
    Safety Issue?: No

Secondary Measures

• PCT-GCT-FCT
  • Time Frame: 42 Days
    Safety Issue?: No

Inclusion Criteria:

• 1. Acute symptomatic falciparum malaria infection as determined by malaria smear with a parasite density of 1,000 to 100,000 asexual parasites/uL as determined on the screening smear with fever (defined as ≥37.5C), or reported history of fever within the last 48 hours.
• 2. Age: 8-65 years old
• 3. All females between the age of 12 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 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 outpatients

Exclusion Criteria:

• 1. Pregnant women, nursing mothers, or women of childbearing potential who do not use an acceptable method of contraception
• 2. Mixed malaria infection on admission by malaria smear
• 3. A previous history of intolerance or hypersensitivity to the study drugs or to drugs with similar chemical structures
• 4. Malaria drug therapy administered in the past 30 days by history
• 5. 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.
• 6. Symptoms of severe vomiting (no food or inability to take food during the previous 8 hours).
• 7. Signs or symptoms of severe malaria (as defined by WHO 2000)
• 8. Unable and/or unlikely to comprehend and/or follow the protocol

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 8 Years

Maximum Age for this Clinical Trial: 65 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Medical University of Vienna

Overall Clinical Trial Officials and Contacts

Overall Contact: Harald Noedl, MD, PhD +43-1-4277-64882 harald.noedl@meduniwien.ac.at

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00639873

Study ID Number: MUW # 83/2008

ClinicalTrials.gov Identifier: NCT00639873

Health Authority: Switzerland: Ethikkommission

MARIB - Malaria Research Initiative Bandarban

Medical University of Vienna

ICDDR,B