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

NCT05764746 | Recruiting Phase 2 DMC

• 1 other identifier: 3ACT-2023
• Study Type: interventional
• Target: 384
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Uncomplicated Plasmodium Falciparum Malaria

Keywords

Artemisinin-based Combination Therapy; Plasmodium falciparum; Uncomplicated malaria

Outcome Measures

Primary Outcomes (1)

• Crude recurrent parasitemia by day 56 in the respective arms

  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 Outcomes (1)

• PCR adjusted cure rates by day 28, 42 and 56.

  Through study completion, an average of 1 year

Other Outcomes (6)

• Median time to recurrent parasitemia by microscopy

  56 days since enrolment

• PCR determined parasite clearance times

  Baseline to day 3

• Maximum plasma concentrations (Cmax) of the intervention drugs.

  Baseline and Day 7

Study Arms (3)

Artemether-lumefantrine followed by artesunate amodiaquine

EXPERIMENTAL

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

Artemether-lumefantrine with Amodiaquine

EXPERIMENTAL

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

Artemether-Lumefantrine alone

ACTIVE COMPARATOR

a standard 3-days dosage of Artemether-Lumefantrine (20/120mg) followed by placebo for another 3 days

Drug: Artemether-lumefantrine

Interventions

Artemether-lumefantrine and Amodiaquine Drug Combination DRUG

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

Also known as: AL+AQ

Artemether-lumefantrine with Amodiaquine

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

Also known as: AL then ASAQ

Artemether-lumefantrine followed by artesunate amodiaquine

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

Also known as: AL + Placebo

Artemether-Lumefantrine alone

Eligibility Criteria

• Age: 6 Months - 120 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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).

Sponsors & Collaborators

• Muhimbili University of Health and Allied Sciences: lead
• The Swedish Research Council: collaborator
• Uppsala University: collaborator

Study Sites (2)

Kibindu

Bagamoyo, Dar esSalaam, 255, Tanzania

RECRUITING

Yombo Dispensary

Bagamoyo, Yombo, +255, Tanzania

SUSPENDED

Related Publications (6)

• Coran AG, Tyler HB. Aortic dissection. A complication of translumbar aortography. Am J Surg. 1968 May;115(5):709-11. doi: 10.1016/0002-9610(68)90107-4. No abstract available.

  PMID: 5645671 BACKGROUND

• Smit MR, Ochomo EO, Aljayyoussi G, Kwambai TK, Abong'o BO, Chen T, Bousema T, Slater HC, Waterhouse D, Bayoh NM, Gimnig JE, Samuels AM, Desai MR, Phillips-Howard PA, Kariuki SK, Wang D, Ward SA, Ter Kuile FO. Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): a randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2018 Jun;18(6):615-626. doi: 10.1016/S1473-3099(18)30163-4. Epub 2018 Mar 27.

  PMID: 29602751 BACKGROUND

• Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, Lwin KM, Ariey F, Hanpithakpong W, Lee SJ, Ringwald P, Silamut K, Imwong M, Chotivanich K, Lim P, Herdman T, An SS, Yeung S, Singhasivanon P, Day NP, Lindegardh N, Socheat D, White NJ. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2009 Jul 30;361(5):455-67. doi: 10.1056/NEJMoa0808859.

  PMID: 19641202 BACKGROUND

• Leang R, Taylor WR, Bouth DM, Song L, Tarning J, Char MC, Kim S, Witkowski B, Duru V, Domergue A, Khim N, Ringwald P, Menard D. Evidence of Plasmodium falciparum Malaria Multidrug Resistance to Artemisinin and Piperaquine in Western Cambodia: Dihydroartemisinin-Piperaquine Open-Label Multicenter Clinical Assessment. Antimicrob Agents Chemother. 2015 Aug;59(8):4719-26. doi: 10.1128/AAC.00835-15. Epub 2015 May 26.

  PMID: 26014949 BACKGROUND

• Mwaiswelo R, Ngasala B, Gil JP, Malmberg M, Jovel I, Xu W, Premji Z, Mmbando BP, Bjorkman A, Martensson A. Sustained High Cure Rate of Artemether-Lumefantrine against Uncomplicated Plasmodium falciparum Malaria after 8 Years of Its Wide-Scale Use in Bagamoyo District, Tanzania. Am J Trop Med Hyg. 2017 Aug;97(2):526-532. doi: 10.4269/ajtmh.16-0780.

  PMID: 28829723 BACKGROUND

• Mwaiswelo R, Ngasala B, Jovel I, Xu W, Larsson E, Malmberg M, Gil JP, Premji Z, Mmbando BP, Martensson A. Prevalence of and Risk Factors Associated with Polymerase Chain Reaction-Determined Plasmodium falciparum Positivity on Day 3 after Initiation of Artemether-Lumefantrine Treatment for Uncomplicated Malaria in Bagamoyo District, Tanzania. Am J Trop Med Hyg. 2019 May;100(5):1179-1186. doi: 10.4269/ajtmh.18-0729.

  PMID: 30860013 BACKGROUND

MeSH Terms

Conditions

Malaria, Falciparum

Interventions

Artemether, Lumefantrine Drug Combination

Condition Hierarchy (Ancestors)

Malaria; Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Artemether; Artemisinins; Reactive Oxygen Species; Free Radicals; Inorganic Chemicals; Organic Chemicals; Lumefantrine; Fluorenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sesquiterpenes; Terpenes; Polycyclic Compounds; Drug Combinations; Pharmaceutical Preparations

Study Officials

• Billy E Ngasala, PhD

  Muhimbili University of Health and Allied Sciences

  PRINCIPAL INVESTIGATOR

• Andreas Mårtensson, PhD

  Muhimbili University of Health and Allied Sciences

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Lwidiko E Mhamilawa, PhD

CONTACT

+255712865206; lwidikoedward@gmail.com

Billy E Ngasala, PhD

CONTACT

+255 754 316 359; bngasala70@yahoo.co.uk

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Model Details: 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).

Study Record Dates

• First Submitted: February 1, 2023
• First Posted: March 13, 2023
• Study Start: May 1, 2023
• Primary Completion: December 30, 2024
• Study Completion: December 30, 2024
• Last Updated: December 11, 2024

Record last verified: 2024-04

Locations

TA (2)