Triple Artemisinin-based Combination Therapy for Delaying Drug Resistance Development - a Randomized Clinical Trial (3ACT)

December 6, 2024 updated by: Billy Ngasala, Muhimbili University of Health and Allied Sciences

Can Triple Artemisinin-based Combination Therapy for Treatment of Uncomplicated Plasmodium Falciparum Malaria, Delay Drug Resistance Development of Plasmodium Falciparum in Tanzania: a Randomized Three Arm Clinical Trial

Background: Artemisinin resistance has emerged in parts of Southeast Asia, and there are reports in Africa of reduced susceptibility of Plasmodium falciparum parasites against artemisinin-based combination therapy (ACT). No new drugs are available in the pipeline to replace ACTs in case they fail.

This study aims to assess whether a sequential administration of triple ACTs with different partner-drugs can improve the efficacy of ACT for treatment of uncomplicated malaria.

Methods: A health facility-based, three-arm partially blinded randomized clinical trial will be conducted to assess efficacy and safety of a sequential administration of artemether-lumefantrine followed immediately by artesunate-amodiaquine (AL+ASAQ) or artemether-lumefantrine with by amodiaquine (AL+AQ) compared to artemether-lumefantrine plus placebo (AL+PBO). Eligible children aged 6 - 120 months and with microscopy confirmed uncomplicated P. falciparum malaria will be enrolled, administered with trial medicines and followed-up at 0 (just prior to first drug intake) and 8 hours on day 0, 12 hourly on days 1, 2, 3, 4, 5, followed by once daily on days 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 28, 35, 42 and 56 for clinical and laboratory evaluations. Clinical evaluation will involve assessment of signs and symptoms related to the disease and or trial medicine during follow-up. Laboratory evaluation will include microscopic determination of presence of malaria parasites and species, hemoglobin level, molecular analysis for markers of drug resistance and to differentiate recrudescence from new infection. The primary outcome will be Polymerase Chain Reaction (PCR)-adjusted adequate clinical and parasitological cure rate on days 28 and 42.

Expected outcomes: The findings will give an insight on whether 3 ACTs are more efficacious than the use of first-line regimen alone, and are tolerable for treatment of uncomplicated falciparum malaria.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

384

Phase

  • Phase 2
  • Phase 3

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 Backup

Study Locations

  • Tanzania
    • Dar esSalaam
      • Bagamoyo, Dar esSalaam, Tanzania, 255
    • Yombo
      • Bagamoyo, Yombo, Tanzania, +255
        • Suspended
        • Yombo Dispensary

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

Ages Eligible for Study

6 months to 10 years (Child)

Accepts Healthy Volunteers

No

Description

Patients presenting at the health facility with suspected acute uncomplicated malaria will be screened for eligibility.

Inclusion Criteria:

  • Age from 6 - 120 months
  • Weight ≥ 5 kg
  • Body temperature ≥37.5°C or history of fever in the last 24 hours
  • Microscopy confirmed P. falciparum mono-infection
  • Parasitemia level of 1000-200000/μL
  • Ability to swallow oral medication
  • Ability and willingness to abide by the study protocol and the stipulated follow-up visits
  • A written proxy informed consent from a parent/guardian

Exclusion Criteria:

  • Children aged below 6 months will not be included in the study because ACTs are contraindicated in this group.
  • Evidence of severe malaria or danger signs
  • Known allergy to trial medicines
  • Reported antimalarial intake ≤2 weeks
  • Haemoglobin <5 g/dL
  • Blood transfusion within last 90 days
  • Febrile condition other than malaria
  • Known underlying chronic or severe disease (including severe malnutrition).

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: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Artemether-lumefantrine followed by artesunate amodiaquine
a standard 3-days dosage, twice a day course of Artemether-Lumefantrine (20/120mg) immediately followed by a standard 3-days, once a day course of Artesunate-Amodiaquine (40base)
Drug: Artemether-lumefantrine then Artesunate amodiaquine
AL will be given twice a day for three days then followed by artesunate amodiaquine once a day for three days
Other Names:
  • AL then ASAQ
Experimental: Artemether-lumefantrine with Amodiaquine
a standard 3-days dosage of Artemether-Lumefantrine (20/120mg) given together with Amodiaquine hydrocloride(40 base) followed by placebo for another 3 days;
Drug: Artemether-lumefantrine and Amodiaquine Drug Combination
AL and AQ will be given together for three days then followed by placebo for three days
Other Names:
  • AL+AQ
Active Comparator: Artemether-Lumefantrine alone
a standard 3-days dosage of Artemether-Lumefantrine (20/120mg) followed by placebo for another 3 days
Drug: Artemether-lumefantrine
This will be the comparator arm as standard treatment, where only AL will be given twice a day for three days then placebo for three days
Other Names:
  • AL + Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Crude recurrent parasitemia by day 56 in the respective arms
Time Frame: 56th day since enrolment
Laboratory assessment of parasitemia using light microscopy performed at last day of follow up will be the primary outcome assessing the differences in proportion of patients with recurrent parasitemia.
56th day since enrolment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
PCR adjusted cure rates by day 28, 42 and 56.
Time Frame: Through study completion, an average of 1 year
Assessment of cure rate as determined by parasitemia to distinguish recrudescence and reinfections
Through study completion, an average of 1 year

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Median time to recurrent parasitemia by microscopy
Time Frame: 56 days since enrolment
This outcome compares across the three arms how long it takes until patients return with parasitemia. It will provide information on the post treatment prophylaxis of each arm.
56 days since enrolment
PCR determined parasite clearance times
Time Frame: Baseline to day 3
PCR determined parasite clearance times are determined by using PCR to measure the amount of parasite DNA in the patient's blood at various time points after treatment. The parasite clearance time is then calculated as the time it takes for the amount of parasite DNA to fall below a certain threshold level, indicating that the parasite has been cleared from the patient's blood.
Baseline to day 3
Maximum plasma concentrations (Cmax) of the intervention drugs.
Time Frame: Baseline and Day 7
The Pharmacokinetics profiles of artesunate/dihydroartemisinin, lumefantrine/desbutyl-lumefantrine and amodiaquine/desethyl-amodiaquine will be assessed, focusing on Plasma concentrations to determine Cmax.
Baseline and Day 7
Change in hemoglobin level (g/dl)
Time Frame: Baseline and day 7
Haemoglobin concentration will be measured at baseline day 0 on day 7 to determine whether patients are anemic or not. . Anemia will be categorized as mild (Hb < 11 g/dL), moderate (< 7 g/dL) or severe (Hb < 5 g/dL).
Baseline and day 7
Proportion of Microscopy determined gametocyte carriage
Time Frame: Baseline and day 3
Assessment of how many patients in each treatment arm harbour gametocytes
Baseline and day 3
Prevalence of genetic markers of drug resistance.
Time Frame: Through study completion, an average of 1 year
Selection of genetic markers of drug resistance among recurrent parasitemia during follow-up and during the early treatment phase. The markers will include P. falciparum chloroquine resistance transporter gene (Pfcrt), and P. falciparum multidrug resistance gene 1 (Pfmdr1) for lumefantrine and amodiaquine; P. falciparum multidrug resistance proteins, the sarco/endoplasmic reticulum Ca2+-ATPase orthologue of P. falciparum (pfatp6), and P. falciparum kelch propeller gene 13 (PfKelch13) for artemisinin; and plasmepsin 2 and 3 for piperaquine.
Through study completion, an average of 1 year

Collaborators and Investigators

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

Sponsor

Muhimbili University of Health and Allied Sciences

Collaborators

Uppsala University
The Swedish Research Council

Investigators

  • Principal Investigator: Billy E Ngasala, PhD, Muhimbili University of Health and Allied Sciences
  • Principal Investigator: Andreas Mårtensson, PhD, Muhimbili University of Health and Allied Sciences

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

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)

May 1, 2023

Primary Completion (Estimated)

December 30, 2024

Study Completion (Estimated)

December 30, 2024

Study Registration Dates

First Submitted

February 1, 2023

First Submitted That Met QC Criteria

February 28, 2023

First Posted (Actual)

March 13, 2023

Study Record Updates

Last Update Posted (Estimated)

December 11, 2024

Last Update Submitted That Met QC Criteria

December 6, 2024

Last Verified

April 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 3ACT-2023

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

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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