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Pilot Human Study of Tinidazole Efficacy For Radical Cure Of Plasmodium Vivax

Primary Purpose

Malaria, Vivax

Status
Completed
Phase
Phase 2
Locations
Thailand
Study Type
Interventional
Intervention
Tinidazole
chloroquine
Sponsored by
Walter Reed Army Institute of Research (WRAIR)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Malaria, Vivax focused on measuring Malaria, Vivax/*drug therapy, Tinidazole/pharmacology/*therapeutic use, Recurrence, Plasmodium vivax/*drug effects

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Adult male and non-pregnant female volunteers that can communicate in the Burmese or Karen language.
  • Age: Between 18 and 65 years (inclusive).
  • Acute, symptomatic, blood smear positive diagnosis of Plasmodium vivax mono-infection.
  • Ability to comprehend and comply with the requirements of the protocol.
  • Willing to provide written informed consent.
  • Willing to abstain from alcohol (EtOH) use during initial treatment and for 72 hours thereafter.
  • Sexually active females must test negative on urine pregnancy test and must be counseled on an effective method of avoiding pregnancy (e.g., intrauterine contraceptive device; oral contraceptives; diaphragm or condom in combination with contraceptive jelly, cream or foam; Norplant® or Depo-Provera®), be surgically sterile, be post-menopause for at least one year, or be monogamous with a sterile sexual partner for at least 15 days prior to dosing with study product and at least 72 hours after their last dose of test drug.

Exclusion Criteria:

  • Subjects positive for G6PD deficiency.
  • Pregnant women (clinically or by positive urine β-HCG) and nursing mothers.
  • Concomitant use of metronidazole, albendazole or mebendazole.
  • Any malaria treatment or use of azithromycin or other macrolides, tetracyclines, sulfonamides, doxycycline, tetracycline or other sulfa based or other drug with antimalarial activity for the previous 4 weeks prior to screening. Additionally, concomitant use of phenobarbitol, rifampin, phenytoin, fosphenytoin, cimetidine, ketoconazole, cholestryramine constitute exclusion criteria.
  • Significant health problems, including, but not limited to significant, cardiac, renal or liver disease or lab abnormalities and those subjects in whom it is suspected that they will not abstain from alcohol use during treatment and for the subsequent 3 days.
  • Mixed malaria infection on admission determined by malaria smear and/or any positive HRP2 antigen testing.
  • A previous history of significant intolerance or hypersensitivity to the study drug tinidazole or to chloroquine or primaquine. (nausea alone from previous primaquine use will not be an excluding factor unless subject was unable to complete a primaquine course due to this discomfort.)
  • Subjects that have received transfusions within the previous 30 days.
  • Presenting hematocrit <25%.

Sites / Locations

  • Malaria Research Unit, 68/30 Ban Toong Road, P.O. Box 46

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Treatment Arm

Comparator Arm

Arm Description

Comparator Arm

Outcomes

Primary Outcome Measures

Cure is defined as absence of malaria infection on thick/thin malaria smears up to and on day 63 after initial clearance of parasitemia. Subjects will be followed to day 90 to rule out delayed presentation of malaria (as opposed to cure).

Secondary Outcome Measures

Recurrence (relapse, recrudescence or re-infection) of Plasmodium vivax between blood stage clearance and 90 days.

Full Information

First Posted
December 17, 2008
Last Updated
November 30, 2012
Sponsor
Walter Reed Army Institute of Research (WRAIR)
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1. Study Identification

Unique Protocol Identification Number
NCT00811096
Brief Title
Pilot Human Study of Tinidazole Efficacy For Radical Cure Of Plasmodium Vivax
Official Title
Pilot Human Study of Tinidazole Efficacy For Radical Cure Of Plasmodium Vivax
Study Type
Interventional

2. Study Status

Record Verification Date
November 2012
Overall Recruitment Status
Completed
Study Start Date
November 2008 (undefined)
Primary Completion Date
January 2009 (Actual)
Study Completion Date
April 2009 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Walter Reed Army Institute of Research (WRAIR)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Assess the efficacy of 2 grams of tinidazole given for 5 days with standard dose chloroquine to achieve radical cure of Plasmodium vivax within a 90 day follow-up period sufficient to justify an IND and formal phase II evaluation.
Detailed Description
This is a randomized, open-label study that will treat adult subjects with Plasmodium vivax infection with chloroquine for 3 days and tinidazole for 5 days concomitantly to assess efficacy for radical cure (clearance of blood and liver stages of infection). There will be randomization to a positive comparator arm treated with chloroquine and primaquine (definitive radical cure) in order to obtain an estimate of the rate of re-infection during the monitoring period in the study population. A simple randomization procedure will assign subjects to one of the two arms (treatment arm or comparator arm). The ratio of assignment will be 2:1, treatment arm to the comparator arm. The exact number assigned to the treatment arm will vary depending on the initial outcome of early enrollees per the sequential analysis design of the trial. In the worse case scenario of no clear trend developing early, no more than 50 subjects will be required to complete the trial in the study drug arm in order to arrive at a conclusion regarding the study drug. Follow-up period will be for 90 days. This will allow us to capture essentially all early relapses that would occur under normal circumstances, as well as assess if tinidazole may delay but not fully eliminate recurrence. Subjects without a recurrence at 90 days will be considered to have achieved radical cure. This study will use a modified triangular test, a form of sequential analysis designed to enable repeated statistical analyses throughout the study recruitment period, while maintaining a pre-specified power and type I error. The trial can be stopped as soon as the information accumulated is considered sufficient to reach a conclusion and it will limit enrollment and exposure to a failing treatment regimen. Results of this study will be sufficient to determine whether tinidazole should be designated as an "early kill" (an ineffective drug for vivax malaria radical cure with no future evaluation) or whether it is sufficiently efficacious to warrant further investment with an IND and formal phase II study to seek an SNDA.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malaria, Vivax
Keywords
Malaria, Vivax/*drug therapy, Tinidazole/pharmacology/*therapeutic use, Recurrence, Plasmodium vivax/*drug effects

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
20 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment Arm
Arm Type
Experimental
Arm Title
Comparator Arm
Arm Type
Active Comparator
Arm Description
Comparator Arm
Intervention Type
Drug
Intervention Name(s)
Tinidazole
Intervention Description
2gms, p.o. q.d. for 5 days
Intervention Type
Drug
Intervention Name(s)
chloroquine
Primary Outcome Measure Information:
Title
Cure is defined as absence of malaria infection on thick/thin malaria smears up to and on day 63 after initial clearance of parasitemia. Subjects will be followed to day 90 to rule out delayed presentation of malaria (as opposed to cure).
Time Frame
63 days
Secondary Outcome Measure Information:
Title
Recurrence (relapse, recrudescence or re-infection) of Plasmodium vivax between blood stage clearance and 90 days.
Time Frame
90 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Adult male and non-pregnant female volunteers that can communicate in the Burmese or Karen language. Age: Between 18 and 65 years (inclusive). Acute, symptomatic, blood smear positive diagnosis of Plasmodium vivax mono-infection. Ability to comprehend and comply with the requirements of the protocol. Willing to provide written informed consent. Willing to abstain from alcohol (EtOH) use during initial treatment and for 72 hours thereafter. Sexually active females must test negative on urine pregnancy test and must be counseled on an effective method of avoiding pregnancy (e.g., intrauterine contraceptive device; oral contraceptives; diaphragm or condom in combination with contraceptive jelly, cream or foam; Norplant® or Depo-Provera®), be surgically sterile, be post-menopause for at least one year, or be monogamous with a sterile sexual partner for at least 15 days prior to dosing with study product and at least 72 hours after their last dose of test drug. Exclusion Criteria: Subjects positive for G6PD deficiency. Pregnant women (clinically or by positive urine β-HCG) and nursing mothers. Concomitant use of metronidazole, albendazole or mebendazole. Any malaria treatment or use of azithromycin or other macrolides, tetracyclines, sulfonamides, doxycycline, tetracycline or other sulfa based or other drug with antimalarial activity for the previous 4 weeks prior to screening. Additionally, concomitant use of phenobarbitol, rifampin, phenytoin, fosphenytoin, cimetidine, ketoconazole, cholestryramine constitute exclusion criteria. Significant health problems, including, but not limited to significant, cardiac, renal or liver disease or lab abnormalities and those subjects in whom it is suspected that they will not abstain from alcohol use during treatment and for the subsequent 3 days. Mixed malaria infection on admission determined by malaria smear and/or any positive HRP2 antigen testing. A previous history of significant intolerance or hypersensitivity to the study drug tinidazole or to chloroquine or primaquine. (nausea alone from previous primaquine use will not be an excluding factor unless subject was unable to complete a primaquine course due to this discomfort.) Subjects that have received transfusions within the previous 30 days. Presenting hematocrit <25%.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Francois Nosten, MD
Organizational Affiliation
Malaria Research Unit, Thailand
Official's Role
Principal Investigator
Facility Information:
Facility Name
Malaria Research Unit, 68/30 Ban Toong Road, P.O. Box 46
City
Mae Sot, 63110
State/Province
Tak
Country
Thailand

12. IPD Sharing Statement

Citations:
PubMed Identifier
23718705
Citation
Macareo L, Lwin KM, Cheah PY, Yuentrakul P, Miller RS, Nosten F. Triangular test design to evaluate tinidazole in the prevention of Plasmodium vivax relapse. Malar J. 2013 May 29;12:173. doi: 10.1186/1475-2875-12-173.
Results Reference
derived

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Pilot Human Study of Tinidazole Efficacy For Radical Cure Of Plasmodium Vivax

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