Drug Combinations of Atovaquone-Proguanil (AP) With ACT (APACT)

Multicenter Therapeutic Efficacy Assessment of Pyronaridine-Artesunate (Pyramax®) and New Drug Combinations With Atovaquone-Proguanil for the Treatment of Uncomplicated P. Falciparum Malaria in Cambodia

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.

Study Overview

• Status: Recruiting
• Conditions: Plasmodium Falciparum Malaria (Drug Resistant)
• Intervention / Treatment: Drug: Artesunate and Pyronaridine; Drug: Atovaquone Proguanil and Artesunate Pyronaridine; Drug: Atovaquone Proguanil and Artesunate Mefloquine

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.

• Study Type: Interventional
• Enrollment (Anticipated): 252
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Mariusz Wojnarski, MD; Phone Number: +66-84-527-4646; Email: MARIUSZ.WOJNARSKI.MIL@AFRIMS.ORG
• Study Contact Backup: Name: Norman Waters, PhD; Phone Number: +66 (0)2 696 2798; Email: Norman.Waters.mil@afrims.org

Study Locations

• Cambodia
  • Kratie, Cambodia
    • Recruiting
    • Kratie Referral Hospital
    • Contact: Somaly Kieng, M.D; Phone Number: +855 72 971 755
    • Contact: Chanthap Lon, M.D; Phone Number: 855 23 881 845; Email: chanthapl@afrims.org
    • Sub-Investigator: Darapiseth Sea, MD
    • Sub-Investigator: Dysoley Lek, MD
  • Stung Treng, Cambodia
    • Not yet recruiting
    • Stung Treng Referral Hospital
    • Contact: Dysoley Lek, MD
  • Ânlóng Vêng, Cambodia
    • Recruiting
    • Anlong Veng Referral Hospital
    • Sub-Investigator: Darapiseth Sea, MD
    • Sub-Investigator: Dysoley Lek, MD
    • Contact: Phan Kong, M.A; Phone Number: 016 51 09 09
    • Principal Investigator: Chanthap Lon, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Artesunate and Pyronaridine; Standard weight based dosing
Experimental: 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	Drug: Atovaquone Proguanil and Artesunate Pyronaridine; Both drugs (AP) and (ASPY) are administered once a day, on days 0, 1, and 2.
Experimental: 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.	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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Ex vivo drug susceptibility testing	Day of enrollment and day of malaria recurrence up to 8 weeks
Pharmakokinetics of each study drug - (Cmax)	Peak plasma concentration (Cmax) for study drugs	multiple time points up to 8 weeks
Pharmakokinetics of each study drug - (AUC)	Area under the plasma concentration versus time curve (AUC)	multiple time points up to 8 weeks
Pharmakokinetics of each study drug - volume of distribution	volume of distribution for study drugs	multiple time points throughout 6 weeks of follow up
Pharmakokinetics of each study drug - (T1/2)	elimination half-life (T1/2) for study drugs	multiple time points up to 8 weeks
Kaplan Meier survival analysis of asexual blood stage parasitemia and sexual stage gametocytes		6 weeks
Gametocyte carriage rates on days 0, 1, 2, 3, and weeks 1 through 6 for each treatment arm		Days 0, 1, 2, 3, and weekly, up to week 8
The incidence of hepatotoxicity events for each treatment arm	Alanine aminotransferase (ALT)>5 times the upper limit of normal (ULN) or percent of volunteers meeting the Hy's law definition (ALT or aspartate aminotransferase [AST] >3 x ULN and total bilirubin >2 x ULN) at any post-dose time point within 6 weeks of follow up	Day 3 and week 6
Rates of treatment-related adverse events		6 weeks
Severity of treatment-related adverse events	Grade 1 - mild, Grade 2 - moderate, Grade 3 - severe, Grade 4- life threatening	6 weeks
Number of participants who say they are willing to take the same drug combination in the future		day 2 and week 6
Point efficacy with 95% Confidence Interval against blood stage malaria infection classified according to the WHO malaria treatment outcome classifications (ETF, LTF, LCTF, LPTF)		4 weeks, 6 weeks, and 8 weeks
Incidence of Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency	Comparative incidence of G6PD deficiency in the study population as determined by G6PD rapid-diagnostic tests (RDTs) and quantitative tests, to include sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) for each of the point-of-care tests against 10%, 30%, and 60% thresholds of normal G6PD activity	Enrollment
Number of infected mosquitos following membrane feeding		Day 0, Day 3, Day 7, and on day of malaria recurrence up to 8 weeks

Collaborators and Investigators

• Sponsor: Armed Forces Research Institute of Medical Sciences, Thailand
• Collaborators: National Center for Parasitology, Entomology, and Malaria Control (CNM); Naval Medical Research Unit-2 (NAMRU-2)
• Investigators: Principal Investigator: Mariusz Wojnarski, MD, Armed Forces Research Institute of Medical Sciences (AFRIMS) Bangkok, Thailand

Study record dates

Study Major Dates

• Study Start (Actual): October 4, 2018
• Primary Completion (Anticipated): August 30, 2022
• Study Completion (Anticipated): December 30, 2022

Study Registration Dates

• First Submitted: October 16, 2018
• First Submitted That Met QC Criteria: October 30, 2018
• First Posted (Actual): October 31, 2018

Study Record Updates

• Last Update Posted (Actual): March 2, 2021
• Last Update Submitted That Met QC Criteria: March 1, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: malaria; triple therapy; mefloquine; atovaquone; combination treatment; plasmodium falciparum; malarone; pyramax; pyronaridine; multidrug resistant malaria
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Malaria, Falciparum; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites; Antineoplastic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Anthelmintics; Schistosomicides; Antiplatyhelmintic Agents; Atovaquone; Proguanil; Artesunate; Pyronaridine; Atovaquone, proguanil drug combination; Mefloquine
• Other Study ID Numbers: WR2530

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: The study site will maintain appropriate medical and research records for this trial until completion of the study, in compliance with Section 4.9 of International Conference on Harmonization E6 Good Clinical Practices, and institutional requirements. The investigators and other study personnel assigned from National Center for Parasitology, Entomology and Malaria Control (CNM), Armed Forces Research Institute of Medical Sciences (AFRIMS) and Naval Medical Research Center NMRC-Asia and their respective representatives are authorized access to the study data as part of their duties. The database may be shared with other collaborators, on a mutually agreed basis. Sharing and publication of the data with other parties can be done only after inter-institutional agreements are in place. The research findings may be disseminated to policy makers and other researchers for an informed decision on drug policy for the treatment of malaria.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No