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 Overview

• Status: Completed
• Conditions: Malaria
• Intervention / Treatment: Drug: Artesunate; Drug: quinine-doxycycline

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 126
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Bangladesh
  • Bandarban
    • Bandarban Sadar, Bandarban, Bangladesh
      • Bandarban Sadar Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 65 years (Child, 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 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AS 2mg/kg; Artesunate monotherapy 2mg/kg/day for 7 days	Drug: Artesunate; 2 or 4 mg/kg/day for 7 days
Experimental: AS 4mg/kg; Artesunate monotherapy 4mg/kg/day for 7 days	Drug: Artesunate; 2 or 4 mg/kg/day for 7 days
Active Comparator: QD Control; Quinine-doxycycline for 7 days	Drug: quinine-doxycycline; quinine-doxycycline for 7 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cure	Cure is defined as adequate clinical and parasitological response (ACPR) as opposed to early treatment failure / late treatment failure	42 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment response	Treatment response parameters: parasite, fever, and gametocyte clearance	42 Days

Collaborators and Investigators

• Sponsor: Medical University of Vienna
• Collaborators: International Centre for Diarrhoeal Disease Research, Bangladesh; World Health Organization
• Investigators: Principal Investigator: Harald Noedl, MD, PhD, Medical University of Vienna

Publications and helpful links

General Publications

• Starzengruber P, Swoboda P, Fuehrer HP, Khan WA, Hofecker V, Siedl A, Fally M, Graf O, Teja-Isavadharm P, Haque R, Ringwald P, Noedl H. Current status of artemisinin-resistant falciparum malaria in South Asia: a randomized controlled artesunate monotherapy trial in Bangladesh. PLoS One. 2012;7(12):e52236. doi: 10.1371/journal.pone.0052236. Epub 2012 Dec 18.

Helpful Links

• Medical University of Vienna
• MARIB - Malaria Research Initiative Bandarban
• ICDDR,B

Study record dates

Study Major Dates

• Study Start: June 1, 2008
• Primary Completion (Actual): November 1, 2009
• Study Completion (Actual): November 1, 2009

Study Registration Dates

• First Submitted: March 14, 2008
• First Submitted That Met QC Criteria: March 14, 2008
• First Posted (Estimate): March 20, 2008

Study Record Updates

• Last Update Posted (Estimate): August 23, 2013
• Last Update Submitted That Met QC Criteria: August 22, 2013
• Last Verified: August 1, 2013

More Information

Terms related to this study

• Keywords: Uncomplicated P. falciparum malaria
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Physiological Effects of Drugs; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antineoplastic Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Neuromuscular Agents; Antimalarials; Anthelmintics; Muscle Relaxants, Central; Schistosomicides; Antiplatyhelmintic Agents; Doxycycline; Artesunate; Quinine
• Other Study ID Numbers: MUW # 83/2008