A Trial to Compare the Efficacy, Safety and Tolerability of Combinations of 3 Anti-malarial Drugs Against Combina-tions of 2 Anti-malarial Drugs.

Plasmodium Falciparum Malaria (Uncomplicated) Clinical Trial

— DeTACT-Africa  

Official title:

A Multi-centre Randomised Controlled Non-inferiority Trial to Compare the Efficacy, Safety and Tolerability of Triple Artemisinin-based Combination Therapies Versus First-line ACTs + Placebo for the Treatment of Uncomplicated Plasmodium Falciparum Malaria in Africa

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03923725
• Other study ID #: MAL18004
• Status: Recruiting
• Phase: Phase 3
• Start date: September 1, 2020
• Est. completion date: September 2024

Study information

• Verified date: April 2023
• Source: University of Oxford
• Contact: Mehul Dhorda, Ph.D
• Phone: +66 2 203-6333
• Email: Mehul[@]tropmedres.ac
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A partially blinded randomised controlled non-inferiority trial comparing the efficacy, tolerability and safety of Triple ACTs artemether-lumefantrine+amodiaquine (AL+AQ) and artesunate-mefloquine+piperaquine (ASMQ+PPQ) and the ACTs artemether-lumefantrine+placebo (AL+PBO), artesunate-mefloquine+placebo (ASMQ+PBO) (with single-low dose primaquine in some sites) for the treatment of uncomplicated Plasmodium falciparum malaria to assess and compare their efficacy, safety, tolerability.

Description:

Subjects will be randomized to up to four arms: artemether-lumefantrine + amodiaquine, artemether-lumefantrine + placebo, artesunate-mefloquine + piperaquine and artesunate-mefloquine + placebo. As a contingency measure in case of significant differences in the efficacy or safety of one of the combinations being tested and/or study drug expiry or unavailability, subjects may be randomised to 2 arms with a matching ACT-TACT pair, i.e., with artemether-lumefantrine + placebo or artemether-lumefantrine + amodiaquine OR artesunate-mefloquine + placebo or artesunate-mefloquine + piperaquine.

Some sites may randomize between 2 arms only with matching ACT-TACT pairs, i.e., artemether-lumefantrine + placebo or artemether-lumefantrine + amodiaquine OR artesunate-mefloquine + placebo or artesunate-mefloquine + piperaquine. In Rwanda, subjects will be randomized between 2 arms consisting of artemether-lumefantrine + placebo or artemether-lumefantrine + amodiaquine.

In the control arms, the ACT will be co-packed with a matched (appearance) placebo.

In lower transmission settings (Annual Parasite Incidence <50 per 1000 population per year) the treatment will include a single 0.25 mg/kg gametocytocidal dose of primaquine as recommended by the WHO for children ≥10 kg. All drug administrations will be observed.

Subjects will be treated in an in-patient unit for 3 days and followed up weekly up to D63. Microscopy to detect and quantify malaria parasitaemia will be performed daily (more frequently in patients with parasite density of >5000/µL at inclusion) during hospitalization, at all weekly and unscheduled visits. A physical examination and measurements of vital signs along with a symptom questionnaire for tolerability will be performed and recorded through a standardized method at baseline, daily during admission and weekly during follow up through D42 and at all unscheduled visits. Physical exam, vital sign measurements and assessments of symptoms will be performed on D49, D56, and D63 only for patients who are parasitaemic or those who report fever or other symptoms. Electrocardiographs will be performed during admission (H0, H4, H52 or H64) and day 42 of follow up to assess and compare the effect of ACTs and TACTs antimalarials on QT or QTc intervals.

The DeTACT-Africa Trial is funded by UK Aid from the UK government's Foreign, Commonwealth and Development Office.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 3240
• Est. completion date: September 2024
• Est. primary completion date: March 15, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Months to 12 Years

Eligibility

Inclusion Criteria:

• Male or female, aged =6 months to <12 years (For Gambia, Rwanda sites only: =6 months)

• Ability to take oral medication

• Acute uncomplicated P. falciparum monoinfection

• Asexual P. falciparum parasitaemia: 1,000/µL to =10% parasitaemia, determined on a peripheral blood film (At Gambia, Rwanda sites only: For subjects =12 years - 1000/µL to 200,000/µL)

• Fever defined as = 37.5°C tympanic temperature or a history of fever within the last 24 hours

• Written informed consent by the subject or by parent/guardian in case of children lower than the age of consent and assent if required (per local regulations)

• Willingness and ability of the subjects or parents/guardians to comply with the study protocol for the duration of the study

Exclusion Criteria:

• Signs of severe malaria (adapted from WHO criteria)

• Patients not fulfilling criteria for severe malaria but with another indication for parenteral antimalarial treatment at the discretion of the treating physician

• Haematocrit <15% at screening (For Gambia, Rwanda sites only: For subjects =12 years - Haematocrit <20% at screening)

• Subjects who have received artemisinin or a derivative within the previous 7 days OR lumefantrine or amodiaquine within the previous 14 days OR mefloquine or piperaquine within the previous 30 days

• In applicable countries: use of seasonal malaria chemoprophylaxis (SMC) within the last 14 days.

• Acute illness other than malaria requiring systemic treatment

• Severe acute malnutrition (in Niger only - only those patients with Severe Acute Malnutrition and complications requiring inpatient nutritional treatment will be excluded)

• Known HIV infection

• Known tuberculosis infection

• For females: post-menarche (For Gambia, Rwanda sites only: females who are pregnant, trying to get pregnant or are lactating)

• History of allergy or known contraindication to any of the study drugs, including neuropsychiatric disorders and epilepsy

• Previous splenectomy

• Enrolment in DeTACT in the previous 3 months

• Participation in another interventional study in the previous 3 months

Related Conditions & MeSH terms

• Malaria
• Malaria, Falciparum
• Plasmodium Falciparum Malaria (Uncomplicated)

Intervention

Drug:
• Artemether-lumefantrine+ Amodiaquine (AL+AQ)
AL: Currently available as dispersible tablets containing 20 mg of artemether and 120 mg of lumefantrine, in a fixed-dose combination formulation. The flavoured dispersible tablet paediatric formulation facilitates use in young children. The dose of artemether-lumefantrine is administered approaching the WHO-recommended target ranges of artemether 5-24 mg/kg and lumefantrine 29-144 mg/kg over 3 days. AQ: is available as dispersible tablets of 40 mg. The weight-based treatment schedule aims for a dosage of approximately 10mg (4.5-15mg)/kg/day amodiaquine for three days.
• Artemether-lumefantrine + placebo (AL+PBO)
AL: Currently available as dispersible tablets containing 20 mg of artemether and 120 mg of lumefantrine, in a fixed-dose combination formulation. The flavoured dispersible tablet paediatric formulation facilitates use in young children. The dose of artemether-lumefantrine is administered approaching the WHO-recommended target ranges of artemether 5-24 mg/kg and lumefantrine 29-144 mg/kg over 3 days. PBO: Placebo tablets for amodiaquine are identical in size, shape and color to the amodiaquine tablets.
• Artesunate-mefloquine+piperaquine (AS-MQ+PPQ)
AS: Artesunate will be administered according to an optimised dosing schedule using tablets of 32 or 100 mg artesunate with a dosing target of 4 mg/kg/day. MQ: Mefloquine will be administered according to an optimised dosing schedule using tablets of 70 or 220 mg mefloquine hydrochloride with a dosing target of 8.3 mg/kg/day. PPQ: Piperaquine will be administered according to an optimised dosing schedule using tablets of 160 or 500 mg of piperaquine tetraphosphate. The weight-based treatment aims for a dosage of approximately. 24 mg/kg/day in patients <25 kg (range 16.0 - 32.0 mg/kg) piperaquine for three days, thereby approaching the WHO-recommended target range of 20 - 32 mg/kg per day. 18 mg/kg/day in patients =25 kg (range 15.0 - 29.4 mg/kg) piperaquine for three days, thereby approaching the WHO-recommended target range of 16 - 27 mg/kg per day.
• Artesunate-mefloquine+placebo (AS-MQ+PBO)
AS: Artesunate will be administered according to an optimised dosing schedule using tablets of 32 or 100 mg artesunate with a dosing target of 4 mg/kg/day. MQ: Mefloquine will be administered according to an optimised dosing schedule using tablets of 70 or 220 mg mefloquine hydrochloride with a dosing target of 8.3 mg/kg/day. PBO: Placebo tablets for piperaquine are identical in size, shape and colour to the piperaquine tablets.

Locations

Country	Name	City	State
Burkina Faso	Institut des Sciences et Techniques (INSTech)	Bobo-Dioulasso 01
Congo, The Democratic Republic of the	Kinshasa School of Public Health	Kinshasa
Gambia	MRC Unit The Gambia at LSHTM	Fajara	Banjul
Guinea	Centre National de Formation et de Recherche en Santé Rurale de Mafèrinyah	Conakry
Niger	Epicentre Niger	Niamey
Nigeria	Centre for Malaria and Other Tropical Diseases (CEMTROD)	Ilorin	Kwara State
Rwanda	College of Medicine and Health Sciences, University of Rwanda	Kigali
Tanzania	National Institute For Medical Research (NIMR), Tanga Medical Research Centre	Tanga

Sponsors (2)

Lead Sponsor	Collaborator
University of Oxford	Mahidol Oxford Tropical Medicine Research Unit

Countries where clinical trial is conducted

Burkina Faso,  Congo, The Democratic Republic of the,  Gambia,  Guinea,  Niger,  Nigeria,  Rwanda,  Tanzania, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Comparison of 63-day vs 42-day PCR corrected and uncorrected efficacy	Comparison of 63-day vs 42-day PCR corrected and uncorrected efficacy of ACTs vs TACTs	63 days
Other	Proportions of recurrent infections	Proportions of recurrent infections with parasites carrying mutations of known functional significance	63 days
Other	Proportions of specimens collected at baseline with parasites carrying mutations	Proportions of specimens collected at baseline with parasites carrying mutations of known functional or operational significance (pfkelch13, pfcrt, pfmdr1, pfdhfr, pfdhps, pfplasmepsin2 , partial or complete deletions of pfhrp2 and other current parasite genetic markers associated with resistance or identified over the course of the study)	baseline
Other	Candidate markers of resistance	Candidate markers of resistance identified through genome wide association studies with in vivo or in vitro parasite drug sensitivity phenotypes	63 days
Other	In vitro sensitivity of P. falciparum to artemisinins and partner drugs	In vitro sensitivity of P. falciparum to artemisinins and partner drugs according to study sites and genotype	63 days.
Other	Accuracy of SNPs assessment	Accuracy of SNPs assessment from dry blood spots versus from whole genome sequencing in leukocyte depleted blood samples	63 days.
Other	Correlation between qPCR based versus microscopy based assessments of parasite clearance dynamics		14 days
Other	Correlation of parasite clearance metrics as assessed by microscopy versus digital microscopy		3 days
Other	Comparison of transcriptomic patterns of drug sensitive and resistant parasites	Comparison of transcriptomic patterns of drug sensitive and resistant parasites before treatment and 6, 12 and 24 hours after start of treatment	63 days
Other	Levels of RNA transcription coding for male or female specific gametocytes	Levels of RNA transcription coding for male or female specific gametocytes at admission up to day 14, stratified by the presence of gametocytes at enrolment	14 days
Other	Correlation between the host genotype and the pharmacokinetics and pharmacodynamics of antimalarials.	Host genotype (e.g., CYP2D6, CYP3A4, KCNQ1/LQT1, KCNH2/LQT2, SCN5A/LQT3)	42 days
Other	Correlations between the place of residence, work, recent travel history	Correlations between the place of residence, work, recent travel history assessed by interview and mobile phone records to identify behaviours and risk factors associated with malaria infection.	63 days
Other	Correlation between titres of antibodies against malaria parasite antigens and - efficacy defined as PCR corrected adequate clinical and parasitological response (ACPR) - efficacy defined as adequate clinical and parasitological response (ACPR)		63 days
Primary	42 days Efficacy defined as PCR corrected adequate clinical and parasitological response (ACPR).	42 days Efficacy defined as PCR corrected adequate clinical and parasitological response (ACPR).	42 days
Secondary	63-day PCR corrected and uncorrected efficacy		63 days
Secondary	42-day PCR uncorrected efficacy		42 days
Secondary	Parasite clearance half-life	Assessed by microscopy as primary parameter to determine parasite clearance	3 Days
Secondary	Proportion of subjects with microscopically detectable P. falciparum parasitaemia		Day 3
Secondary	Fever clearance time	fever clearance time (i.e. the time taken for the tympanic temperature to fall below 37.5 ºC)	63 Days
Secondary	Proportion of subjects with gametocytaemia	proportion of subjects with gametocytaemia during and after treatment stratified by presence of gametocytes at enrolment	63 Days
Secondary	Incidence of adverse events	including markers of hepatic, renal or bone marrow toxicity; cardiotoxicity	42 days
Secondary	Incidence of serious adverse events	including markers of hepatic, renal or bone marrow toxicity; cardiotoxicity	42 days
Secondary	Number of cardiotoxicity events	In particular QT or QTc-interval above 500 ms at timepoint H4 and H52/H64 and between these time points	52 or 64 hours depends on treatment arm
Secondary	Change in haemoglobin stratified for G6PD status/genotype		28 days
Secondary	Proportion of subjects requiring retreatment due to vomiting	Proportion of subjects requiring retreatment due to vomiting within 1 hour after administration of the study drugs	1 hour
Secondary	Proportion of subjects that reports completing a full course of observed TACT		3 days
Secondary	Proportion of subjects that reports completing a full course of observed ACT		3 days
Secondary	proportion of subjects that reports completing a full course of observed TACT or ACT without withdrawal of consent or exclusion from study because of drug related serious adverse event.		42 days
Secondary	Pharmacokinetic profiles	including Cmax and AUC) of artemisinin-derivatives and partner drugs in ACT and TACT treated subjects in correlation with pharmacodynamics measures of drug efficacy	42 days
Secondary	Pharmacokinetic interactions	including Cmax and AUC) of artemisinin-derivatives and partner drugs in ACT and TACT treated subjects in correlation with pharmacodynamics measures of drug efficacy	42 days
Secondary	Plasma levels of partner drugs	Plasma levels of partner drugs in correlation with treatment efficacy and treatment arm	7 days