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Antimalarial Drug Resistance With Assessment of Transmission Blocking Activity

Primary Purpose

Uncomplicated Plasmodium Falciparum Malaria

Status

Suspended

Phase

Not Applicable

Locations

Cambodia

Study Type

Interventional

Intervention

DHA-piperaquine and Primaquine

About this trial

This is an interventional treatment trial for Uncomplicated Plasmodium Falciparum Malaria focused on measuring Malaria, Drug resistance, DHA-piperaquine, Cambodia, Transmission Blocking

Eligibility Criteria

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

Inclusion Criteria:

Volunteer with uncomplicated P. falciparum malaria (volunteers with mixed P. falciparum and P. vivax infections may be enrolled), 18-65 years of age
Baseline asexual parasite density between 1,000-200,000 parasites/uL
Able to provide informed consent
Available and agree to follow-up for anticipated study duration including 3 day treatment course at the MTF and weekly follow-up for the 42-day period
Authorized by local commander to participate if active duty military

Exclusion Criteria:

Allergic reaction or contraindication to DHA, piperaquine or primaquine
Significant acute comorbidity requiring urgent medical intervention
Signs/symptoms and parasitological confirmation of severe malaria
Use of any anti-malarial within the past 14 days.
Class I or II G6PD deficiency (defined as severe) as determined at screening
Pregnant or lactating female, or female of childbearing age, up to 50 years of age, who does not agree to use an acceptable form of contraception during the study
Clinically significant abnormal EKG, including a QTcF interval > 500 ms at enrollment.
Known or suspected concomitant use of QTc prolonging medications.
Judged by the investigator to be otherwise unsuitable for study participation

Sites / Locations

Anlong Veng Referral Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Arm Label

DHA-piperaquine with Primaquine

DHA-piperaquine without Primaquine

Arm Description

3-day treatment course of DHA-piperaquine with 45mg single dose primaquine

3-day treatment course of DHA-piperaquine

Outcomes

Primary Outcome Measures

Clinical efficacy of DP

Efficacy rates at 42 days (with 95% confidence intervals) for DP with and without single dose primaquine for uncomplicated P. falciparum diagnosed by positive PCR-corrected malaria microscopy.

Secondary Outcome Measures

Efficacy of Primaquine to treat sexual stage gametocyte infection and prevent transmission of P. falciparum gametocytes to mosquitoes.

To detect efficacy of a onetime dose of primaquine after completion of therapy for blood stage infection on gametocytemia that may persist after DP treatment by using comparative rates of sexual stage infections between patients dosed with and without primaquine based on a composite endpoint of light microscopy and PCR detection and staging of gamteocytes with mosquito membrane feeding assay to detect oocysts in sterile lab-reared mosquitoes.

Full Information

NCT ID

NCT01849640

First Posted

February 27, 2013

Last Updated

July 13, 2015

Sponsor

David Saunders

Collaborators

National Centre for Parasitology, Entomology and Malaria Control, Cambodia, Royal Cambodian Armed Forces, US Department of Defense Armed Forces Health Surveillance Center

1. Study Identification

Unique Protocol Identification Number

NCT01849640

Brief Title

Antimalarial Drug Resistance With Assessment of Transmission Blocking Activity

Official Title

Active Surveillance for P. Falciparum Drug Resistance With Assessment of Transmission Blocking Activity of Single Dose Primaquine in Cambodia

Study Type

Interventional

2. Study Status

Record Verification Date

July 2015

Overall Recruitment Status

Suspended

Why Stopped

Poor efficacy of DHA-piperaquine due to likely drug resistance.

Study Start Date

December 2012 (undefined)

Primary Completion Date

December 2014 (Actual)

Study Completion Date

June 2016 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

David Saunders

Collaborators

National Centre for Parasitology, Entomology and Malaria Control, Cambodia, Royal Cambodian Armed Forces, US Department of Defense Armed Forces Health Surveillance Center

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This is a two-arm, open label Treatment Study comparing the efficacy, safety, tolerability and pharmacokinetics of a three-day course of Dihydroartemisinin-Piperaquine (DP) with or without single-dose primaquine in patients with uncomplicated Plasmodium falciparum malaria. On the last day of DP therapy, volunteers will be randomized to receive either a single 45 mg dose of primaquine (PQ) or DP treatment only (no primaquine).

Detailed Description

Volunteers with uncomplicated malaria in Cambodia will be enrolled to current standard of care therapy with DHA-piperaquine to monitor therapeutic efficacy and measure resistance. The cardiac safety of piperaquine will be monitored with electrocardiograms during the treatment period. Resistance to DP and DP-PQ will be assessed by a combination of clinical, pharmacologic, and parasitologic parameters including genomic signatures of selection during careful weekly follow-up visits for 42 days. Volunteers will be randomized on day 3 to either a single 45mg dose of primaquine or no sexual stage therapy to evaluate effects of primaquine on the sexual stages of malaria (gametocytes) and potential transmissibility of infection to Anopheles mosquitoes as compared to those not treated with primaquine.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Uncomplicated Plasmodium Falciparum Malaria

Keywords

Malaria, Drug resistance, DHA-piperaquine, Cambodia, Transmission Blocking

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

150 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

DHA-piperaquine with Primaquine

Arm Type

Active Comparator

Arm Description

3-day treatment course of DHA-piperaquine with 45mg single dose primaquine

Arm Title

DHA-piperaquine without Primaquine

Arm Type

Active Comparator

Arm Description

3-day treatment course of DHA-piperaquine

Intervention Type

Drug

Intervention Name(s)

DHA-piperaquine and Primaquine

Intervention Description

Subject will be enrolled in open label fashion to a 3-day treatment course of DHA-piperaquine (DP) by directly observed therapy (DOT, all patients will receive a total of 9 tablets containing 40mg DHA and 320mg of piperaquine in divided doses at 0, 24 and 48 hours (3 tablets once per day) for the 3 day course. At completion of DP treatment volunteers will be randomized in an open label fashion to receive a single 45 mg dose of primaquine or no therapy.

Primary Outcome Measure Information:

Title

Clinical efficacy of DP

Description

Efficacy rates at 42 days (with 95% confidence intervals) for DP with and without single dose primaquine for uncomplicated P. falciparum diagnosed by positive PCR-corrected malaria microscopy.

Time Frame

3 years

Secondary Outcome Measure Information:

Title

Efficacy of Primaquine to treat sexual stage gametocyte infection and prevent transmission of P. falciparum gametocytes to mosquitoes.

Description

Time Frame

3 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Volunteer with uncomplicated P. falciparum malaria (volunteers with mixed P. falciparum and P. vivax infections may be enrolled), 18-65 years of age Baseline asexual parasite density between 1,000-200,000 parasites/uL Able to provide informed consent Available and agree to follow-up for anticipated study duration including 3 day treatment course at the MTF and weekly follow-up for the 42-day period Authorized by local commander to participate if active duty military Exclusion Criteria: Allergic reaction or contraindication to DHA, piperaquine or primaquine Significant acute comorbidity requiring urgent medical intervention Signs/symptoms and parasitological confirmation of severe malaria Use of any anti-malarial within the past 14 days. Class I or II G6PD deficiency (defined as severe) as determined at screening Pregnant or lactating female, or female of childbearing age, up to 50 years of age, who does not agree to use an acceptable form of contraception during the study Clinically significant abnormal EKG, including a QTcF interval > 500 ms at enrollment. Known or suspected concomitant use of QTc prolonging medications. Judged by the investigator to be otherwise unsuitable for study participation

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

David Saunders, MD, MPH

Organizational Affiliation

Dept. of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences (AFRIMS)

Official's Role

Principal Investigator

Facility Information:

Facility Name

Anlong Veng Referral Hospital

City

Anlong Veng

State/Province

Oddormean Chey

Country

Cambodia

12. IPD Sharing Statement

Citations:

PubMed Identifier

25075853

Citation

Saunders DL, Vanachayangkul P, Lon C; U.S. Army Military Malaria Research Program; National Center for Parasitology, Entomology, and Malaria Control (CNM); Royal Cambodian Armed Forces. Dihydroartemisinin-piperaquine failure in Cambodia. N Engl J Med. 2014 Jul 31;371(5):484-5. doi: 10.1056/NEJMc1403007. No abstract available.

Results Reference

background

PubMed Identifier

25877962

Citation

Spring MD, Lin JT, Manning JE, Vanachayangkul P, Somethy S, Bun R, Se Y, Chann S, Ittiverakul M, Sia-ngam P, Kuntawunginn W, Arsanok M, Buathong N, Chaorattanakawee S, Gosi P, Ta-aksorn W, Chanarat N, Sundrakes S, Kong N, Heng TK, Nou S, Teja-isavadharm P, Pichyangkul S, Phann ST, Balasubramanian S, Juliano JJ, Meshnick SR, Chour CM, Prom S, Lanteri CA, Lon C, Saunders DL. Dihydroartemisinin-piperaquine failure associated with a triple mutant including kelch13 C580Y in Cambodia: an observational cohort study. Lancet Infect Dis. 2015 Jun;15(6):683-91. doi: 10.1016/S1473-3099(15)70049-6. Epub 2015 Apr 12.

Results Reference

result

PubMed Identifier

28193647

Citation

Vanachayangkul P, Lon C, Spring M, Sok S, Ta-Aksorn W, Kodchakorn C, Pann ST, Chann S, Ittiverakul M, Sriwichai S, Buathong N, Kuntawunginn W, So M, Youdaline T, Milner E, Wojnarski M, Lanteri C, Manning J, Prom S, Haigney M, Cantilena L, Saunders D. Piperaquine Population Pharmacokinetics and Cardiac Safety in Cambodia. Antimicrob Agents Chemother. 2017 Apr 24;61(5):e02000-16. doi: 10.1128/AAC.02000-16. Print 2017 May.

Results Reference

derived

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Antimalarial Drug Resistance With Assessment of Transmission Blocking Activity

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