Drug Combinations of Atovaquone-Proguanil (AP) With ACT

NCT03726593 | Unknown Phase 4 DMC

• 1 other identifier: WR2530
• Study Type: interventional
• Target: 252
• Locations: 1 country
• Sites: 3

Brief Summary

Investigators are conducting this study due to recent reports of many of existing malaria drugs becoming less effective for treatment of malaria. The drugs may not always kill all the parasites, therefore not all patients with malaria are being cured. The main objective of the study is to find out which malaria drugs and what drug combinations are still effective in Cambodia, an area of multi-drug resistance where 4-5 artemisinin-based combination therapies have shown inadequate response, below that established by the World Health Organization (WHO). New drug combinations (taking more than one drug for malaria at the same time), as long as well tolerated, can provide cure in patients that harbor parasites not responsive to standard first-line medications. Human genetic testing will be done to identify patients who may have suboptimal response to treatments and to study the differences in human gene expression to explain why some persons are at higher risk of complications during treatment. Markers of drug resistance to commonly used antimalarial drugs will also be evaluated and shared with national malaria program (CNM) to better guide future malaria treatment decisions in Cambodia.

Conditions

Plasmodium Falciparum Malaria (Drug Resistant)

Keywords

malaria; plasmodium falciparum; malarone; atovaquone; mefloquine; pyramax; pyronaridine; combination treatment; triple therapy; multidrug resistant malaria

Outcome Measures

Primary Outcomes (1)

• 42-day polymerase chain reaction (PCR) corrected adequate clinical and parasitological response (ACPR), following treatment with ASPY and new drug combinations (AP+ACTs).

  6 weeks

Secondary Outcomes (15)

• Prevalence of molecular markers of drug resistance

  Day of enrollment and day of malaria recurrence up to 8 weeks

• Drug susceptibility testing of parasite isolates against standard antimalarial drugs

  Day of enrollment and day of malaria recurrence up to 8 weeks

• Pharmakokinetics of each study drug - (Cmax)

  multiple time points up to 8 weeks

• Pharmakokinetics of each study drug - (AUC)

  multiple time points up to 8 weeks

• Pharmakokinetics of each study drug - volume of distribution

  multiple time points throughout 6 weeks of follow up

Study Arms (3)

ASPY

EXPERIMENTAL

Artesunate-pyronaridine, once daily for three days, following standard weight-based dosing per drug label. All volunteers with P.f monoinfection will receive single dose of primaquine (PQ) (15 mg) for transmission blocking.

Drug: Artesunate and Pyronaridine

AP+ASPY

EXPERIMENTAL

Atovaquone-Proguanil (AP) + Artesunate-Pyronaridine (ASPY), once daily for three days, following standard weight-based dosing per drug label for each drug. All volunteers with P.f monoinfection receive single dose of PQ (15 mg) for transmission blocking

Drug: Atovaquone Proguanil and Artesunate Pyronaridine

AP+ASMQ

EXPERIMENTAL

Atovaquone-Proguanil (AP) + Artesunate-Mefloquine (ASMQ); ASMQ once daily for three days (D0, D1, D2), following standard weight-based dosing per drug label. Subsequently, volunteers continue their treatment with AP once daily starting on day 3, for three additional days (D3, 4, 5). All volunteers with P.f monoinfection receive single dose of PQ (15 mg) for transmission blocking.

Drug: Atovaquone Proguanil and Artesunate Mefloquine

Interventions

Artesunate and Pyronaridine DRUG

Standard weight based dosing

ASPY

Atovaquone Proguanil and Artesunate Pyronaridine DRUG

Both drugs (AP) and (ASPY) are administered once a day, on days 0, 1, and 2.

AP+ASPY

Atovaquone Proguanil and Artesunate Mefloquine DRUG

Sequential treatment with ASMQ (on days 0, 1, and 2) followed by the treatment with AP for 3 more days (total 6 days treatment)

AP+ASMQ

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Understands Khmer spoken language
• Male or female (18 to 70 years old)
• Microscopic confirmation of asexual stages of Pf or mixed infection with Pf, with baseline asexual parasite densities between 100/µL to 200,000/µL
• Able to take oral medications
• Hemoglobin on day of enrollment ≥9.0 g/dL
• Agree to follow-up for the anticipated study duration, including a minimum of 3 nights at the medical treatment facility (inpatient hospitalization) and weekly follow-up visits for at least 6 weeks
• If the volunteer is on active duty in the military, the volunteer has written permission from their supervisor or states to have been authorized by his/her supervisor or the local commander to participate; and allow study staff to contact their supervisor to confirm this information

You may not qualify if:

• Known allergic reaction to any of the study drugs or history of severe intolerance to any of the antimalarials used in this study.
• Pregnant or lactating females and females of childbearing potential who do not agree to use an acceptable form of contraception during the study period and for 6 weeks following the last dose of the study drug.
• Symptoms of severe vomiting (inability to tolerate oral fluids or oral medications during the previous 8 hours or vomiting \>3 times in the last 24 hrs).
• Diagnosis of severe malaria
• Abnormal liver function tests i.e AST or ALT or total bilirubin \> 1.5 upper limit of normal (ULN) with nausea AND right upper quadrant abdominal pain OR jaundice on exam
• Isolated AST or ALT or Total Bilirubin \>2x ULN
• Known significant cardiovascular, liver or renal abnormality or any other clinically significant illness, which in the opinion of the investigator would place the volunteer at significantly higher risk
• Treatment for malaria within the last 4 weeks
• Unable to provide informed consent
• Judged by the investigator to be otherwise unsuitable for study participation (to include, but not limited to, taking other medications that are known to cause serious drug-drug interactions with the study drugs, as determined by the study physician, or having suspected medical condition or taking other drugs that may affect test results interpretation or put the volunteer at much higher risk)

Sponsors & Collaborators

• Armed Forces Research Institute of Medical Sciences, Thailand: lead
• National Center for Parasitology, Entomology, and Malaria Control (CNM): collaborator
• Naval Medical Research Unit-2 (NAMRU-2): collaborator

Study Sites (3)

Anlong Veng Referral Hospital

Anlong Veaeng, Cambodia

RECRUITING

Kratie Referral Hospital

Kratié, Cambodia

RECRUITING

Stung Treng Referral Hospital

Stung Treng, Cambodia

NOT YET RECRUITING

MeSH Terms

Conditions

Malaria, Falciparum; Malaria

Interventions

pyronaridine tetraphosphate, artesunate drug combination; atovaquone, proguanil drug combination

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Study Officials

• Mariusz Wojnarski, MD

  Armed Forces Research Institute of Medical Sciences (AFRIMS) Bangkok, Thailand

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Mariusz Wojnarski, MD

CONTACT

+66-84-527-4646; MARIUSZ.WOJNARSKI.MIL@AFRIMS.ORG

Norman Waters, PhD

CONTACT

+66 (0)2 696 2798; Norman.Waters.mil@afrims.org

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Model Details: Randomized, open-label clinical trial to evaluate the tolerability and clinical and parasitological responses after treatment of Pf and/or mixed infections (Pf/Pv) in volunteers with uncomplicated malaria. The assignment of volunteers will be 1:1:1 for ASPY (Pyramax), AP+ASPY (AP+Pyramax), and AP+ASMQ. All study drug administration will be by directly observed therapy (DOT).

Study Record Dates

• First Submitted: October 16, 2018
• First Posted: October 31, 2018
• Study Start: October 4, 2018
• Primary Completion: August 30, 2022
• Study Completion: December 30, 2022
• Last Updated: March 2, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will not share

Locations

CA (3)