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NCT Number: NCT05764746

Triple Artemisinin-based Combination Therapy for Delaying Drug Resistance Development - a Randomized 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.

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Key information

Conditions

Uncomplicated Plasmodium Falciparum Malaria Infections Malaria Malaria, Falciparum Mosquito-Borne Diseases Parasitic Diseases Protozoan Infections Vector Borne Diseases

Age range

6 month–120 month

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2 / Phase 3

Primary location

Kibindu, Bagamoyo, Dar esSalaam, Tanzania

Loading trial locations.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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).

Treatment and study plan

Artemether-lumefantrine and Amodiaquine Drug Combination

Drug

AL and AQ will be given together for three days then followed by placebo for three days

Other names: AL+AQ

Artemether-lumefantrine then Artesunate amodiaquine

Drug

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

Artemether-lumefantrine

Drug

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

Primary outcomes

  1. 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.

Secondary outcomes

  1. 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

Other outcomes

  1. 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.

  2. 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.

  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.

  4. 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).

  5. Proportion of Microscopy determined gametocyte carriage

    Time frame: Baseline and day 3

    Assessment of how many patients in each treatment arm harbour gametocytes

  6. 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.

Sponsors and collaborators

Lead sponsor

Muhimbili University of Health and Allied Sciences

Other

Collaborators

  • The Swedish Research Council
  • Uppsala University

Registry information

Official study title

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

Acronym: 3ACT

Important dates

Study start
2023
Primary completion
2024
Study completion
2025
First posted
Mar 13, 2023
Registry last updated
Jul 28, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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