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

Primary Purpose

Plasmodium Falciparum Malaria (Drug Resistant)

Status

Unknown status

Phase

Phase 4

Locations

Cambodia

Study Type

Interventional

Intervention

Artesunate and Pyronaridine

Atovaquone Proguanil and Artesunate Pyronaridine

Atovaquone Proguanil and Artesunate Mefloquine

About this trial

This is an interventional treatment trial for Plasmodium Falciparum Malaria (Drug Resistant) focused on measuring malaria, plasmodium falciparum, malarone, atovaquone, mefloquine, pyramax, pyronaridine, combination treatment, triple therapy, multidrug resistant malaria

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

Kratie Referral HospitalRecruiting
Stung Treng Referral Hospital
Anlong Veng Referral HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

ASPY

AP+ASPY

AP+ASMQ

Arm Description

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.

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

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Prevalence of molecular markers of drug resistance

Drug susceptibility testing of parasite isolates against standard antimalarial drugs

Ex vivo drug susceptibility testing

Pharmakokinetics of each study drug - (Cmax)

Peak plasma concentration (Cmax) for study drugs

Pharmakokinetics of each study drug - (AUC)

Area under the plasma concentration versus time curve (AUC)

Pharmakokinetics of each study drug - volume of distribution

volume of distribution for study drugs

Pharmakokinetics of each study drug - (T1/2)

elimination half-life (T1/2) for study drugs

Kaplan Meier survival analysis of asexual blood stage parasitemia and sexual stage gametocytes

Gametocyte carriage rates on days 0, 1, 2, 3, and weeks 1 through 6 for each treatment arm

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

Rates of treatment-related adverse events

Severity of treatment-related adverse events

Grade 1 - mild, Grade 2 - moderate, Grade 3 - severe, Grade 4- life threatening

Number of participants who say they are willing to take the same drug combination in the future

Point efficacy with 95% Confidence Interval against blood stage malaria infection classified according to the WHO malaria treatment outcome classifications (ETF, LTF, LCTF, LPTF)

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

Number of infected mosquitos following membrane feeding

Full Information

NCT ID

NCT03726593

First Posted

October 16, 2018

Last Updated

March 1, 2021

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)

1. Study Identification

Unique Protocol Identification Number

NCT03726593

Brief Title

Drug Combinations of Atovaquone-Proguanil (AP) With ACT

Acronym

APACT

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

2. Study Status

Record Verification Date

March 2021

Overall Recruitment Status

Unknown status

Study Start Date

October 4, 2018 (Actual)

Primary Completion Date

August 30, 2022 (Anticipated)

Study Completion Date

December 30, 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the 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)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Plasmodium Falciparum Malaria (Drug Resistant)

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

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).

Masking

None (Open Label)

Allocation

Randomized

Enrollment

252 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

ASPY

Arm Type

Experimental

Arm Description

Arm Title

AP+ASPY

Arm Type

Experimental

Arm Description

Arm Title

AP+ASMQ

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Artesunate and Pyronaridine

Intervention Description

Standard weight based dosing

Intervention Type

Drug

Intervention Name(s)

Atovaquone Proguanil and Artesunate Pyronaridine

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Atovaquone Proguanil and Artesunate Mefloquine

Intervention Description

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

Primary Outcome Measure Information:

Title

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

Secondary Outcome Measure Information:

Title

Prevalence of molecular markers of drug resistance

Time Frame

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

Title

Drug susceptibility testing of parasite isolates against standard antimalarial drugs

Description

Ex vivo drug susceptibility testing

Time Frame

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

Title

Pharmakokinetics of each study drug - (Cmax)

Description

Peak plasma concentration (Cmax) for study drugs

Time Frame

multiple time points up to 8 weeks

Title

Pharmakokinetics of each study drug - (AUC)

Description

Area under the plasma concentration versus time curve (AUC)

Time Frame

multiple time points up to 8 weeks

Title

Pharmakokinetics of each study drug - volume of distribution

Description

volume of distribution for study drugs

Time Frame

multiple time points throughout 6 weeks of follow up

Title

Pharmakokinetics of each study drug - (T1/2)

Description

elimination half-life (T1/2) for study drugs

Time Frame

multiple time points up to 8 weeks

Title

Kaplan Meier survival analysis of asexual blood stage parasitemia and sexual stage gametocytes

Time Frame

6 weeks

Title

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

Title

The incidence of hepatotoxicity events for each treatment arm

Description

Time Frame

Day 3 and week 6

Title

Rates of treatment-related adverse events

Time Frame

6 weeks

Title

Severity of treatment-related adverse events

Description

Grade 1 - mild, Grade 2 - moderate, Grade 3 - severe, Grade 4- life threatening

Time Frame

6 weeks

Title

Number of participants who say they are willing to take the same drug combination in the future

Time Frame

day 2 and week 6

Title

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

Title

Incidence of Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency

Description

Time Frame

Enrollment

Title

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

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)

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Mariusz Wojnarski, MD

Phone

+66-84-527-4646

MARIUSZ.WOJNARSKI.MIL@AFRIMS.ORG

First Name & Middle Initial & Last Name or Official Title & Degree

Norman Waters, PhD

Phone

+66 (0)2 696 2798

Norman.Waters.mil@afrims.org

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Mariusz Wojnarski, MD

Organizational Affiliation

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

Official's Role

Principal Investigator

Facility Information:

Facility Name

Kratie Referral Hospital

City

Kratie

Country

Cambodia

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Somaly Kieng, M.D

Phone

+855 72 971 755

First Name & Middle Initial & Last Name & Degree

Chanthap Lon, M.D

Phone

855 23 881 845

chanthapl@afrims.org

First Name & Middle Initial & Last Name & Degree

Darapiseth Sea, MD

First Name & Middle Initial & Last Name & Degree

Dysoley Lek, MD

Facility Name

Stung Treng Referral Hospital

City

Stung Treng

Country

Cambodia

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Dysoley Lek, MD

Facility Name

Anlong Veng Referral Hospital

City

Ânlóng Vêng

Country

Cambodia

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Phan Kong, M.A

Phone

016 51 09 09

First Name & Middle Initial & Last Name & Degree

Chanthap Lon, MD

First Name & Middle Initial & Last Name & Degree

Darapiseth Sea, MD

First Name & Middle Initial & Last Name & Degree

Dysoley Lek, MD

12. IPD Sharing Statement

Plan to Share IPD

IPD Sharing 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.

Learn more about this trial

Drug Combinations of Atovaquone-Proguanil (AP) With ACT

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