Clinical trial NCT03726593: Drug Combinations of Atovaquone-Proguanil (AP) With ACT
Official title: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Plasmodium Falciparum Malaria (Drug Resistant)
Keywords: malaria
plasmodium falciparum
malarone
atovaquone
mefloquine
pyramax
pyronaridine
combination treatment
triple therapy
multidrug resistant malaria
Lead sponsor: Armed Forces Research Institute of Medical Sciences, Thailand
Sponsor class: OTHER_GOV
Collaborators: name: National Center for Parasitology, Entomology, and Malaria Control (CNM)
name: Naval Medical Research Unit-2 (NAMRU-2)
First posted: 2018-10-31
Enrollment: 252
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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).
Primary purpose: TREATMENT

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.

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)

Primary outcomes:
measure: 42-day polymerase chain reaction (PCR) corrected adequate clinical and parasitological response (ACPR), following treatment with ASPY and new drug combinations (AP+ACTs).
timeFrame: 6 weeks
Secondary outcomes:
measure: Prevalence of molecular markers of drug resistance
timeFrame: Day of enrollment and day of malaria recurrence up to 8 weeks
measure: Drug susceptibility testing of parasite isolates against standard antimalarial drugs
timeFrame: Day of enrollment and day of malaria recurrence up to 8 weeks
measure: Pharmakokinetics of each study drug - (Cmax)
timeFrame: multiple time points up to 8 weeks
measure: Pharmakokinetics of each study drug - (AUC)
timeFrame: multiple time points up to 8 weeks
measure: Pharmakokinetics of each study drug - volume of distribution
timeFrame: multiple time points throughout 6 weeks of follow up
measure: Pharmakokinetics of each study drug - (T1/2)
timeFrame: multiple time points up to 8 weeks
measure: Kaplan Meier survival analysis of asexual blood stage parasitemia and sexual stage gametocytes
timeFrame: 6 weeks
measure: Gametocyte carriage rates on days 0, 1, 2, 3, and weeks 1 through 6 for each treatment arm
timeFrame: Days 0, 1, 2, 3, and weekly, up to week 8
measure: The incidence of hepatotoxicity events for each treatment arm
timeFrame: Day 3 and week 6
measure: Rates of treatment-related adverse events
timeFrame: 6 weeks
measure: Severity of treatment-related adverse events
timeFrame: 6 weeks
measure: Number of participants who say they are willing to take the same drug combination in the future
timeFrame: day 2 and week 6
measure: Point efficacy with 95% Confidence Interval against blood stage malaria infection classified according to the WHO malaria treatment outcome classifications (ETF, LTF, LCTF, LPTF)
timeFrame: 4 weeks, 6 weeks, and 8 weeks
measure: Incidence of Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency
timeFrame: Enrollment
measure: Number of infected mosquitos following membrane feeding
timeFrame: Day 0, Day 3, Day 7, and on day of malaria recurrence up to 8 weeks
Other outcomes:
Locations:
city: Kratie
country: Cambodia
facility: Kratie Referral Hospital
city: Stung Treng
country: Cambodia
facility: Stung Treng Referral Hospital
city: Ânlóng Vêng
country: Cambodia
facility: Anlong Veng Referral Hospital
Study officials:
affiliation: Armed Forces Research Institute of Medical Sciences (AFRIMS) Bangkok, Thailand
name: Mariusz Wojnarski, MD
role: PRINCIPAL_INVESTIGATOR
References: