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

March 1, 2021 updated by: Armed Forces Research Institute of Medical Sciences, Thailand

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

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
252

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • Cambodia
      • Kratie, Cambodia
        • Recruiting
        • Kratie Referral Hospital
        • Contact:
          • Somaly Kieng, M.D
          • Phone Number: +855 72 971 755
        • Contact:
        • 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

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
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).
Time Frame: 6 weeks
6 weeks

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Prevalence of molecular markers of drug resistance
Time Frame: Day of enrollment and day of malaria recurrence up to 8 weeks
Day of enrollment and day of malaria recurrence up to 8 weeks
Drug susceptibility testing of parasite isolates against standard antimalarial drugs
Time Frame: Day of enrollment and day of malaria recurrence up to 8 weeks
Ex vivo drug susceptibility testing
Day of enrollment and day of malaria recurrence up to 8 weeks
Pharmakokinetics of each study drug - (Cmax)
Time Frame: multiple time points up to 8 weeks
Peak plasma concentration (Cmax) for study drugs
multiple time points up to 8 weeks
Pharmakokinetics of each study drug - (AUC)
Time Frame: multiple time points up to 8 weeks
Area under the plasma concentration versus time curve (AUC)
multiple time points up to 8 weeks
Pharmakokinetics of each study drug - volume of distribution
Time Frame: multiple time points throughout 6 weeks of follow up
volume of distribution for study drugs
multiple time points throughout 6 weeks of follow up
Pharmakokinetics of each study drug - (T1/2)
Time Frame: multiple time points up to 8 weeks
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
Time Frame: 6 weeks
6 weeks
Gametocyte carriage rates on days 0, 1, 2, 3, and weeks 1 through 6 for each treatment arm
Time Frame: Days 0, 1, 2, 3, and weekly, up to week 8
Days 0, 1, 2, 3, and weekly, up to week 8
The incidence of hepatotoxicity events for each treatment arm
Time Frame: Day 3 and week 6
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
Time Frame: 6 weeks
6 weeks
Severity of treatment-related adverse events
Time Frame: 6 weeks
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
Time Frame: day 2 and week 6
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)
Time Frame: 4 weeks, 6 weeks, and 8 weeks
4 weeks, 6 weeks, and 8 weeks
Incidence of Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency
Time Frame: Enrollment
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
Time Frame: Day 0, Day 3, Day 7, and on day of malaria recurrence up to 8 weeks
Day 0, Day 3, Day 7, and on day of malaria recurrence up to 8 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Armed Forces Research Institute of Medical Sciences, Thailand

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Center for Parasitology, Entomology, and Malaria Control (CNM)
Naval Medical Research Unit-2 (NAMRU-2)

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Mariusz Wojnarski, MD, Armed Forces Research Institute of Medical Sciences (AFRIMS) Bangkok, Thailand

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
October 4, 2018

Primary Completion (Anticipated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
August 30, 2022

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 30, 2022

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
October 16, 2018

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 30, 2018

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
October 31, 2018

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 2, 2021

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 1, 2021

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
March 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant 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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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