Drug Combinations of Atovaquone-Proguanil (AP) With ACT

NCT ID: NCT03726593

Last Updated: 2021-03-02

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 252 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-10-04
• Study Completion Date: 2022-12-30

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.

Detailed Description

Efficacy to drugs that are currently available and new antimalarial candidates that are in development are threatened by multidrug resistant (MDR) malaria parasites, widely prevalent in Cambodia. Without effective interventions, MDR malaria can pose a substantial public health threat in the years to come. Therefore, accurate, timely and relevant data on antimalarial drug resistance is of critical importance. Prompt, effective and well-tolerated treatment remains one of the cornerstones in the malaria case management. Recent malaria outbreak in Thailand and rise of malaria cases observed in Cambodia in 2017 has brought to the forefront the urgency with which new drug candidates and new combination drug treatments must be identified; otherwise, patients may be left with ineffective treatments. Lack of available alternatives has a potential to result in significant setback to the recent gains in malaria control and malaria elimination efforts. Innovative approaches to treatment proposed here, using current ACTs in combination with non-ACT drugs, such as atovaquone-proguanil, need to be investigated to assess drug tolerability and overall efficacy when used under combination treatment. By early investment in the studies of drugs such as pyronaridine-artesunate (ASPY), in combination with other antimalarials, and drug combinations proposed under this protocol, this study will try to provide the latest evidence on the interventions that are most likely to work, even in areas of MDR, such as Cambodia, and along the Cambodia-Thai border. It is hoped that our approach for using combination treatments will not only provide more effective treatments, but it might prolong the lifespan of the remaining antimalarials and delay the spread of MDR malaria to neighboring countries.

Conditions

Plasmodium Falciparum Malaria (Drug Resistant)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

ASPY

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.

Group Type: EXPERIMENTAL

Artesunate and Pyronaridine

Intervention Type: DRUG

Standard weight based dosing

AP+ASPY

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

Group Type: EXPERIMENTAL

Atovaquone Proguanil and Artesunate Pyronaridine

Intervention Type: DRUG

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

AP+ASMQ

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.

Group Type: EXPERIMENTAL

Atovaquone Proguanil and Artesunate Mefloquine

Intervention Type: 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)

Interventions

Artesunate and Pyronaridine

Standard weight based dosing

Intervention Type: DRUG

Atovaquone Proguanil and Artesunate Pyronaridine

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

Intervention Type: DRUG

Atovaquone Proguanil and Artesunate Mefloquine

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

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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

Exclusion Criteria

• 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)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Center for Parasitology, Entomology, and Malaria Control (CNM)

UNKNOWN

Sponsor Role: collaborator

Naval Medical Research Unit-2 (NAMRU-2)

UNKNOWN

Sponsor Role: collaborator

Armed Forces Research Institute of Medical Sciences, Thailand

OTHER_GOV

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mariusz Wojnarski, MD

Role: PRINCIPAL_INVESTIGATOR

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

Locations

Anlong Veng Referral Hospital

Anlong Veaeng, , Cambodia

Site Status: RECRUITING

Kratie Referral Hospital

Kratié, , Cambodia

Site Status: RECRUITING

Stung Treng Referral Hospital

Stung Treng, , Cambodia

Site Status: NOT_YET_RECRUITING

Countries

Cambodia

Central Contacts

Mariusz Wojnarski, MD

Role: CONTACT

MARIUSZ.WOJNARSKI.MIL@AFRIMS.ORG

+66-84-527-4646

Norman Waters, PhD

Role: CONTACT

Norman.Waters.mil@afrims.org

+66 (0)2 696 2798

Facility Contacts

Phan Kong, M.A

Role: primary

016 51 09 09

Somaly Kieng, M.D

Role: primary

+855 72 971 755

Chanthap Lon, M.D

Role: backup

chanthapl@afrims.org

855 23 881 845

Dysoley Lek, MD

Role: primary

Other Identifiers

WR2530

Identifier Type: -

Identifier Source: org_study_id