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

Uncomplicated Plasmodium Falciparum Malaria Clinical Trial

— 3ACT  

Official 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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05764746
• Other study ID #: 3ACT-2023
• Status: Not yet recruiting
• Phase: Phase 2/Phase 3
• Start date: April 1, 2023
• Est. completion date: January 30, 2024

Study information

• Verified date: February 2023
• Source: Muhimbili University of Health and Allied Sciences
• Contact: Lwidiko E Mhamilawa, PhD
• Phone: +255712865206
• Email: lwidikoedward[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 384
• Est. completion date: January 30, 2024
• Est. primary completion date: September 30, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Months to 120 Months

Eligibility

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 2000-200000/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).

Related Conditions & MeSH terms

• Malaria
• Malaria, Falciparum
• Uncomplicated Plasmodium Falciparum Malaria

Intervention

Drug:
• Artemether-lumefantrine and Amodiaquine Drug Combination
AL and AQ will be given together for three days then followed by placebo for three days
• 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
• 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

Locations

Country	Name	City	State
Tanzania	Kibindu	Bagamoyo	Dar esSalaam
Tanzania	Yombo Dispensary	Bagamoyo	Yombo

Sponsors (3)

Lead Sponsor	Collaborator
Muhimbili University of Health and Allied Sciences	The Swedish Research Council, Uppsala University

Country where clinical trial is conducted

Tanzania, 

References & Publications (6)

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. Erratum In: N Engl J Med. 2009 Oct 22;361(17):1714. — View Citation

Holmstrom O, Linder N, Ngasala B, Martensson A, Linder E, Lundin M, Moilanen H, Suutala A, Diwan V, Lundin J. Point-of-care mobile digital microscopy and deep learning for the detection of soil-transmitted helminths and Schistosoma haematobium. Glob Health Action. 2017 Jun;10(sup3):1337325. doi: 10.1080/16549716.2017.1337325. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Median time to recurrent parasitemia by microscopy	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
Other	PCR determined parasite clearance times	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
Other	Maximum plasma concentrations (Cmax) of the intervention drugs.	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
Other	Change in hemoglobin level (g/dl)	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
Other	Proportion of Microscopy determined gametocyte carriage	Assessment of how many patients in each treatment arm harbour gametocytes	Baseline and day 3
Other	Prevalence of genetic markers of drug resistance.	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
Primary	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	PCR adjusted cure rates by day 28, 42 and 56.	Assessment of cure rate as determined by parasitemia to distinguish recrudescence and reinfections	Through study completion, an average of 1 year