Study on the Treatment of Vivax Malaria (VHX)

• ClinicalTrials.gov Identifier: NCT01074905
• Recruitment Status: Completed
• First Posted: February 24, 2010
• Last Update Posted: August 28, 2013
• Sponsor: University of Oxford
• Collaborator: Mahidol University
• Information provided by (Responsible Party): University of Oxford

Tracking Information

• First Submitted Date: February 23, 2010
• First Posted Date: February 24, 2010
• Last Update Posted Date: August 28, 2013
• Study Start Date: May 2010
• Actual Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 23, 2010)

The first recurrence of Plasmodium vivax malaria [ Time Frame: Day 28 ]

The first recurrence of Plasmodium vivax malaria within 28 days

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 23, 2010)

• Any recurrence of Plasmodium vivax parasitemia [ Time Frame: 1 year ]
  Any recurrence of Plasmodium vivax parasitemia within the follow up period
• Time to first recurrence, median time between episodes of vivax infections and total number of episodes [ Time Frame: 1 year ]
  Time to first recurrence, median time between episodes of vivax infections and total number of episodes in the follow up period
• Overall number of days of illness and haematocrit below 30% [ Time Frame: 1 year ]
  Overall number of days of illness and haematocrit below 30% within the follow up period
• Chloroquine level [ Time Frame: Day 7 ]
  Whole blood chloroquine level at day 7 and any day of recurrence of Plasmodium vivax malaria
• Adverse events [ Time Frame: 1 year ]
  Adverse event profiles of artesunate, chloroquine and primaquine

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study on the Treatment of Vivax Malaria
• Official Title: A Randomised Open Label Study Comparing the Efficacy of Chloroquine/Primaquine, Chloroquine and Artesunate in the Treatment of Vivax Malaria Along the Thai-Burmese Border
• Brief Summary: This is a randomised open label trial with follow up for 1 year. 660 adults and children above 6 months diagnosed with acute Plasmodium vivax will be randomised into 3 groups, either chloroquine, artesunate, or chloroquine/primaquine therapy. Participants will be screened on the day of inclusion then followed weekly for 8 visits and every 4 weeks until week 52. The primary objective of the study is to compare the efficacy of the WHO and Thai Ministry of Public Health recommended radical curative regimen of chloroquine and primaquine with the currently used monotherapy regimens of chloroquine and artesunate along the Thai-Burmese border.

Detailed Description

Considerably less attention has been paid to Plasmodium vivax epidemiology than Plasmodium falciparum. In areas of relatively low unstable transmission, which comprise the majority of P.vivax affected areas, vivax malaria is predominantly a disease of children (Luxemburger et al 1999). Chloroquine has long been the standard treatment for vivax malaria. Primaquine is recommended for radical cure of vivax malaria, but is difficult to administer due to dosing duration and side effects.

This study aims to characterize the epidemiologic history comparing the efficacy of 3 antimalarial regimens (chloroquine, artesunate, and chloroquine/primaquine) for plasmodium vivax in western Thailand. Chloroquine is currently the standard of treatment for Plasmodium vivax. Due to the long half-life or chloroquine, the first relapse of vivax malaria may be delayed. In contrast, artesunate has a very short half-life, thus, having no impact on first relapse. It is not known whether chloroquine reduces the overall number of relapses, or only delays the first relapse. There are many important questions about the biology of vivax malaria of relevance to treatment that remain unanswered. For example is the number of relapses per infection (i.e. per successful inoculation) predetermined or adaptive? If it is predetermined then suppression of the first relapse (as with chloroquine, mefloquine or piperaquine) will reduce the total number of relapses and this is a clear benefit. If it is adaptive then these drugs will simply delay the relapses and there is less clear benefit. These various uncertainties illustrate the importance of detailed comparative longitudinal evaluations. In order to characterize the biology of vivax malaria, it will be necessary to compare regimens with and without primaquine. Because of the challenges that face primaquine prescription (side effects, toxicity in G6PD deficient patients and duration of treatment), it is not commonly deployed along the Thai Burma border. In effect, we will be comparing usual practice (non primaquine regimens) with the recommended WHO and Thai MOPH practice (use of primaquine for 14 days). The information we will gather is crucial to the understanding of chloroquine and its effect on the vivax parasite. This will lead to future studies and invariably change the way we treat vivax malaria.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Vivax Malaria

Intervention

• Drug: Artesunate
  2 mg/kg/day as single daily dose given for 5 days; maximum dose range is 1.6 to 2.4 mg/kg/day or a total of 8 to 12 mg/kg.
• Drug: Chloroquine
  25 mg base/kg given in divided doses (10,10,5) over 3 days; Absolute range 20-30 mg/kg.
• Drug: Chloroquine/Primaquine
  Chloroquine 3 days and Primaquine 14 days

Study Arms

• Active Comparator: Artesunate
  2 mg/kg/day as single daily dose given for 5 days; maximum dose range is 1.6 to 2.4 mg/kg/day or a total of 8 to 12 mg/kg.
  Intervention: Drug: Artesunate
• Active Comparator: Chloroquine
  25 mg base/kg given in divided doses (10,10,5) over 3 days; Absolute range 20-30 mg/kg.
  Intervention: Drug: Chloroquine
• Experimental: Chloroquine/Primaquine
  Chloroquine 3 days and Primaquine 14 days
  Intervention: Drug: Chloroquine/Primaquine

Publications *

• Chu CS, Phyo AP, Lwin KM, Win HH, San T, Aung AA, Raksapraidee R, Carrara VI, Bancone G, Watson J, Moore KA, Wiladphaingern J, Proux S, Sriprawat K, Winterberg M, Cheah PY, Chue AL, Tarning J, Imwong M, Nosten F, White NJ. Comparison of the Cumulative Efficacy and Safety of Chloroquine, Artesunate, and Chloroquine-Primaquine in Plasmodium vivax Malaria. Clin Infect Dis. 2018 Oct 30;67(10):1543-1549. doi: 10.1093/cid/ciy319.
• Pratt B, Zion D, Lwin KM, Cheah PY, Nosten F, Loff B. Closing the translation gap for justice requirements in international research. J Med Ethics. 2012 Sep;38(9):552-8. doi: 10.1136/medethics-2011-100301. Epub 2012 Mar 16.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 27, 2013): 655
• Original Estimated Enrollment (submitted: February 23, 2010): 660
• Actual Study Completion Date: October 2012
• Actual Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Adults and children > 6 months
• Weight > 7 kg for children
• Have not had primaquine since last Pv episode
• Participant (or parent/guardian if < 18 years old) is willing and able to give written informed consent
• Microscopic diagnosis of Plasmodium vivax mono-infection
• Ability (in the investigators opinion) and willingness of patient or parent/guardian to comply with all study requirements

Exclusion Criteria

• Allergy to artesunate, chloroquine or primaquine
• Severe malaria
• Patients with microscopic diagnosis of co-infection with Plasmodium falciparum
• Presence of any condition which in the judgement of the investigator would place the subject at undue risk or interfere with the results of the study
• Inability to tolerate oral medication
• Pregnancy
• Blood transfusion in the last 3 months
• Antimalarial in last 2 months

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 6 Months and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Thailand

Administrative Information

• NCT Number: NCT01074905
• Other Study ID Numbers: SMRU0908
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: University of Oxford
• Original Responsible Party: Francois Nosten, Shoklo Malaria Research Unit
• Current Study Sponsor: University of Oxford
• Original Study Sponsor: Same as current
• Collaborators: Mahidol University

Investigators

• Principal Investigator: Francois Nosten, MD; Shoklo Malaria Research Unit

• PRS Account: University of Oxford
• Verification Date: August 2013