Clinical trial NCT03355664: Study to Compare the Triple ACT AL+AQ With the ACT AL in Cambodia and Vietnam
Official title: A Multi-centre, Open-label Randomised Trial to Assess the Efficacy, Safety and Tolerability of the Triple ACT Artemether-lumefantrine+Amodiaquine (AL+AQ) Compared to the ACT Artemether-lumefantrine (AL) in Uncomplicated Falciparum Malaria in Cambodia and Vietnam
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Malaria, Falciparum
Keywords: Malaria, Falciparum
Malaria
Protozoan Infections
Lumefantrine
Artemether
Amodiaquine
Piperaquine
Artemether-lumefantrine combination
Artemisinins
Dihydroartemisinin
Mefloquine
Artemisinin
Antimalarials
Antiparasitic Agents
Anti-Infective Agents
ACT
TACT
Triple ACT(s)
Resistance
Antimalarial resistance
Cardiotoxicity
Safety
Tolerability
Efficacy
Lead sponsor: University of Oxford
Sponsor class: OTHER
First posted: 2017-11-28
Enrollment: 310
Sex: ALL
Minimum age (years): 2
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: open-label randomised trial
Primary purpose: TREATMENT

Brief summary: This study is a multi-centre, open-label randomised trial to assess the efficacy, safety and tolerability of the Triple ACT artemether-lumefantrine+amodiaquine (AL+AQ) compared to the ACT artemether-lumefantrine (AL) in uncomplicated falciparum malaria in Cambodia and Vietnam. The estimated total sample size is 600 patients from 2 sites in Cambodia and 2 sites in Vietnam. There are 2 treatment arms Arm 1: Artemether-lumefantrine for 3 days Arm 2: Artemether-lumefantrine for 3 days plus Amodiaquine for 3 days. According to the World Health Organization guideline, all patients except children under 10 kilograms will also be treated with a single dose of primaquine as a gametocytocidal treatment.

Funder :Bill \& Melinda Gates Foundation (BMGF) Grant reference number: OPP1132628

Detailed description: "The study of artemether-lumefantrine or artemether-lumefantrine combined with amodiaquine will be a two-arm randomized open label comparative study.

The main activity proposed is a series of detailed in vivo clinical, parasitological and pharmacological assessments in 600 subjects across 2 sites in Cambodian (400 subjects) and 2 sites in Vietnam (200 subjects). The subjects will be randomized between the ACT artemether-lumefantrine and the TACT artemether-lumefantrine+amodiaquine.

Parasite clearance rates will be assessed by repeated assessments of the parasite counts after the start of the antimalarial treatments. Efficacy, safety and tolerability of ACTs and TACTs will be assessed through weekly follow up visits where vital signs, symptom questionnaires, physical examinations, blood smears, biochemistry assays and full blood counts will be performed.

Ex vivo assessments of parasite susceptibility to artemisinins and partner drugs will be measured and compared to historical data, clinical phenotype and other sites in an effort to identify artemisinin and partner drug resistance.

This study will obtain data on the effect of antimalarials on the corrected QT intervals. In addition, the effects of antimalarials on factors such as post-treatment haematocrit and haemoglobin levels will be assessed. Extensive pharmacokinetic analysis will allow for an assessment of drug-drug interactions.

Plasma histidine-rich protein 2 (HRP2) levels (a marker of parasite biomass) that could potentially serve for the estimation of parasitaemia dynamics before and after treatment will be measured and subsequently modelled."

Eligibility criteria: Inclusion Criteria:

* Male or female, aged from 2 years to 65 years old
* Acute uncomplicated P. falciparum malaria, confirmed by positive blood smear with asexual forms of P. falciparum (or mixed with non-falciparum species)
* Asexual P. falciparum parasitaemia: 16 to 200,000/microlitre, determined on a thin or thick blood film
* Fever defined as \> 37.5°C tympanic temperature or a history of fever within the last 24 hours
* Written informed consent (by parent/guardian in case of children)
* Willingness and ability of the patients or parents/guardians to comply with the study protocol for the duration of the study

Exclusion Criteria:

* Signs of severe/complicated malaria
* Haematocrit \< 25% or Hb \< 8 g/dL at screening
* Acute illness other than malaria requiring treatment
* For females: pregnancy, breast feeding
* Patients who have received artemisinin or a derivative or an artemisinin-containing combination therapy (ACT) within the previous 7 days
* History of allergy or known contraindication to artemisinins, lumefantrine or amodiaquine
* Previous splenectomy
* corrected QT interval \> 450 milliseconds at moment of presentation
* Documented or claimed history of cardiac conduction problems
* Previous participation in the current study or another study in the previous 3 months

Primary outcomes:
measure: Polymerase Chain Reaction Corrected Efficacy Defined as Adequate Clinical and Parasitological Response (ACPR) by Study Arm
timeFrame: 42 days
Secondary outcomes:
measure: 42-day Polymerase Chain Reaction Corrected Efficacy According to Site/Geographic Region
timeFrame: 42 day
measure: Parasite Clearance Half-life
timeFrame: 42 day
measure: Fever Clearance Time
timeFrame: 42 day
measure: Number of Severe Adverse Events by Study Arm
timeFrame: 42 days
measure: Incidence of Adverse Events Concerning Markers of Hepatic or Renal Toxicity
timeFrame: 42 day
measure: Incidence of Prolongation of the Corrected QT Interval
timeFrame: 28 day
measure: Prolongation of the Corrected QT Interval
timeFrame: Hour 4, Hour 24, Hour 28, Hour 48, Hour 52, Hour 60, Hour 64, Day 7 and Day 28 and between these time points
measure: Parasite Reduction Rates
timeFrame: 24 and 48 hours
measure: Parasite Count to Fall 50%
timeFrame: 42 days
measure: Parasite Count to Fall 90%
timeFrame: 42 days
measure: Parasite Count to Fall 99%
timeFrame: 42 days
measure: Change in Haematocrit
timeFrame: Day 1 to 7, 14, 21, 28, 35, 42
measure: Correlation Between the Host Genotype and the Pharmacokinetics and Pharmacodynamics of Antimalarials
timeFrame: 42 day
measure: Proportion of Patients That Reports Completing a Full Course of Observed TACT or ACT
timeFrame: 42 day
measure: Prevalence of Kelch13 Mutations of Known Significance
timeFrame: 42 day
measure: Prevalence/Incidence of Other Genetic Markers of Antimalarial Drug Resistance Such as Multidrug Resistance Gene 1 Copy Number and Multidrug Resistance Gene 1 Mutations
timeFrame: 48 hours
measure: Genome Wide Association With in Vivo/in Vitro Sensitivity Parasite Phenotype
timeFrame: 42 day
measure: Correlation Between Single Nucleotide Polymorphisms and Whole Genome Sequencing
timeFrame: 42 day
measure: A Comparison of Transcriptomic Patterns Between Sensitive and Resistant Parasites
timeFrame: baseline and t = 6 hours
measure: Correlation Between Quantitative Polymerase Chain Reaction Based Versus Microscopy Based Assessments of Parasite Clearance Dynamics
timeFrame: 14 days
measure: Proportion of Patients With Gametocytaemia Before, During and After Treatment With TACT or ACT
timeFrame: At admission and up to day 14
measure: Levels of RNA Transcription Coding for Male or Female Specific Gametocytes
timeFrame: 14 days
measure: In Vitro Sensitivity of P. Falciparum to Artemisinins and Partner Drugs
timeFrame: At admission & subjects with recurrent parasitaemia, up to 42 days
measure: Pharmacokinetic Profiles and Interactions (Cmax) of Artemisinin-derivatives and Partner Drugs
timeFrame: 42 days
measure: Pharmacokinetic Profiles and Interactions (AUC) of Artemisinin-derivatives and Partner Drugs
timeFrame: 42 days
measure: Day 7 Drug Levels of Partner Drugs in Association With Treatment Efficacy and Treatment Arm
timeFrame: 7 days
measure: Correlation Between Histidine-rich Protein 2 (HRP2) Based Versus Microscopy Based Assessments of Parasite Clearance Dynamics
timeFrame: 42 days
Other outcomes:
Locations:
city: Siem Pang
country: Cambodia
facility: Siem Pang Health Center
state: Stung Treng
city: Pailin
country: Cambodia
facility: Pailin Referral Hospital
city: Van Ninh
country: Vietnam
facility: Hospital for Tropical Diseases of Khanh Hoa,
state: Khanh Hoa
city: Phuoc Long
country: Vietnam
facility: Phuoc Long Hospital
state: Phuoc
Study officials:
References:
citation: Peto TJ, Tripura R, Callery JJ, Lek D, Nghia HDT, Nguon C, Thuong NTH, van der Pluijm RW, Dung NTP, Sokha M, Van Luong V, Long LT, Sovann Y, Duanguppama J, Waithira N, Hoglund RM, Chotsiri P, Chau NH, Ruecker A, Amaratunga C, Dhorda M, Miotto O, Maude RJ, Rekol H, Chotivanich K, Tarning J, von Seidlein L, Imwong M, Mukaka M, Day NPJ, Hien TT, White NJ, Dondorp AM. Triple therapy with artemether-lumefantrine plus amodiaquine versus artemether-lumefantrine alone for artemisinin-resistant, uncomplicated falciparum malaria: an open-label, randomised, multicentre trial. Lancet Infect Dis. 2022 Jun;22(6):867-878. doi: 10.1016/S1473-3099(21)00692-7. Epub 2022 Mar 8.