Clinical trial NCT02453308: A Study by the Tracking Resistance to Artemisinin Collaboration (TRAC)
Official title: A Multi-centre, Open-label Randomised Trial to Assess the Efficacy, Safety and Tolerability of Triple Artemisinin-based Combination Therapies (TACTs) Com-pared to Artemisinin-based Combination Therapies (ACTs) in Uncomplicated Falciparum Malaria and to Map the Geographical Spread of Artemisinin and Partner Drug Resistance
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Malaria, Falciparum
Keywords: Artemisinin combination Therapies
Lead sponsor: University of Oxford
Sponsor class: OTHER
First posted: 2015-05-25
Enrollment: 1110
Sex: ALL
Minimum age (years): 6
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is an open-label randomised trial comparing standard ACT treatment with matching triple artemisinin-based combination therapies (TACTs), evaluating efficacy in safety and tolerability. The estimated total sample size is 2040 patients from 16 sites in Asia and 1 site in Africa. There are 2 arm study groups that have 2 treatment arms each.

Study group A:

A.1: Artemether-lumefantrine for 3 days. versus: A.2: Artemether-lumefantrine for 3 days plus Amodiaquine for 3 days.

Study group B:

B.1: Dihydroartemisinin-piperaquine for 3 days. versus: B.2: Dihydroartemisinin-piperaquine for 3 days plus Mefloquine hydrochloride for 3 days.

Study group C:

C.1: Artesunate-mefloquine for 3 days versus: C.2: Dihydroartemisinin-piperaquine for 3 days plus Mefloquine hydrochloride for 3 days.

According to the WHO guideline, all patients except for children under the age of 1 year or a weight below 10 kilograms will also be treated with a single dose of low dose primaquine.

Detailed description: In Laos, Myanmar, Bangladesh, India and DRC, the following two combinations will be used:

1. Artemether-lumefantrine combined with amodiaquine (TACT arm) or
2. Artemether-lumefantrine (ACT arm)

In Myanmar and Vietnam the following two combinations will be used:

1. Dihydroartemisinin-piperaquine combined with mefloquine (TACT arm) or
2. Dihydroartemisinin-piperaquine (ACT arm)

In Cambodia and Thailand the following two combinations will be used:

1. Dihydroartemisinin-piperaquine plus Mefloquine hydrochloride (TACT arm) or
2. Artesunate-mefloquine (ACT arm)

Eligibility criteria: Inclusion Criteria:

* Male or female, aged from 6 months 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: 5,000 to 200,000/uL, de-termined on a thin or thick blood film (In Cambodia patients with a parasitaemia of 16 to 200,000/uL are eligible. In DRC patients with a parasitaemia of 10,000 to 250,000/ul are eligi-ble)
* 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 \< 5 g/dL at screening (DRC: Hct\<15% and Hb \<5 g/dL due to high prevalence of anemia).
* 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
* Treatment with mefloquine in the 2 months prior to presentation will be an exclusion criteria in the DHA-P+MQ sites
* History of allergy or known contraindication to artemisinins, or to the ACT or TACT to be used at the site e.g. neuropsychiatric disorders will be a contraindication for the use of mefloquine.
* Previous splenectomy
* QTc-interval \> 450 milliseconds at moment of presentation
* Documented or claimed history of cardiac conduction problems
* Earlier participation within the TRACII trial or another trial in the previous 3 months.

Primary outcomes:
measure: PCR corrected efficacy defined as adequate clinical and parasitological response (ACPR)
timeFrame: 42 days
Secondary outcomes:
measure: Parasite clearance half-life
timeFrame: 42 days
measure: Parasite reduction rates and ratios at 24 and 48 hours assessed by microscopy
timeFrame: at 24 and 48 hours
measure: Time for parasite count to fall to 50% of initial parasite density
timeFrame: 42 days
measure: Time for parasite count to fall to 90% of initial parasite density
timeFrame: 42 days
measure: Time for parasite count to fall to 99% of initial parasite density
timeFrame: 42 days
measure: Fever clearance time
timeFrame: 42 days
measure: Incidence of adverse events and serious adverse events
timeFrame: 42 days
measure: Incidence of adverse events concerning markers of hepatic toxicity
timeFrame: 42 days
measure: Incidence of adverse events concerning markersof renal toxicity
timeFrame: 42 days
measure: Incidence of prolongation of the QTc-interval
timeFrame: 3 days
measure: Change in hemoglobin/hematocrit
timeFrame: 42 days
measure: Proportion of patients that reports completing a full course of observed TACT or ACT without withdrawal of consent or exclusion from study
timeFrame: 42 days
measure: Prevalence of Kelch13 mutations of known functional significance
timeFrame: 42 days
measure: Prevalence/incidence of other genetic markers of antimalarial drug resistance
timeFrame: 42 days
measure: Genome wide association with in vivo/in vitro sensitivity parasite phenotype
timeFrame: 42 days
measure: Correlation between SNPs measured in dry blood spots and whole genome sequencing in leukocyte depleted blood samples
timeFrame: 42 days
measure: Transcriptomic patterns at t=0 and t=6h comparing sensitive and resistant parasites
timeFrame: 6hrs after start of treatment
measure: Correlation between qPCR based versus microscopy based assessments of parasite clearance dynamics
timeFrame: 14 days
measure: Proportion of patients with gametocytemia before,after treatment with Primaquine
timeFrame: assessed at admission, up to day 14
measure: Levels of RNA transcription coding for male or female specific gametocytes
timeFrame: at admission up to day 14
measure: In vitro sensitivity (expressed in IC50 values among others) of P. falciparum to artemisinins and partner drugs
timeFrame: 42 days
measure: • Pharmacokinetic profiles and interactions of artemisinin-derivatives and partner drugs (half-life, Cmax, AUC, Tmax) in 20 ACT treated and 20 TACT treated patients of both study arms
timeFrame: 42 days
measure: Day 7 drug levels of partner drugs in association with treatment efficacy and treatment arm
timeFrame: Day 7
Other outcomes:
Locations:
city: Ramu
country: Bangladesh
facility: College of Medicine Chittagong
city: Pailin
country: Cambodia
facility: Pailin
city: Preah Vihear
country: Cambodia
facility: Preah Vihear
city: Pursat
country: Cambodia
facility: Pursat
city: Ratankiri
country: Cambodia
facility: Ratanakiri
city: Kinshasa
country: Congo, The Democratic Republic of the
facility: Kinshasa
city: Agartala
country: India
facility: Mohanpur Community health center
city: Midnapore
country: India
facility: Midnapore
city: Rourkela
country: India
facility: Ispat General hospital
city: Sekong
country: Lao People's Democratic Republic
facility: Sekong
city: Ann
country: Myanmar
facility: Ann Hospital
city: Pyay
country: Myanmar
facility: Pyay hospital
city: Pyin oo Lwin
country: Myanmar
facility: Pyin oo Lwin hospital
city: Thabeikkyin
country: Myanmar
facility: Thabeikkyin hospital
city: Phusing
country: Thailand
facility: Phusing hospital
state: Srisaket
city: Tha Song Yang
country: Thailand
facility: Tha Song Yang hospital
state: Tak
city: Chumphon
country: Thailand
facility: Chumphon hospital
city: Si Sa Ket
country: Thailand
facility: Kunhan Hospital
city: Yala
country: Thailand
facility: Thanto Hospital
city: Binh Phuoc
country: Vietnam
facility: Binh Phuoc hospital
Study officials:
affiliation: Mahidol Oxford Tropical Medicine Research Unit
name: Arjen Dondorp, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: van der Pluijm RW, Tripura R, Hoglund RM, Pyae Phyo A, Lek D, Ul Islam A, Anvikar AR, Satpathi P, Satpathi S, Behera PK, Tripura A, Baidya S, Onyamboko M, Chau NH, Sovann Y, Suon S, Sreng S, Mao S, Oun S, Yen S, Amaratunga C, Chutasmit K, Saelow C, Runcharern R, Kaewmok W, Hoa NT, Thanh NV, Hanboonkunupakarn B, Callery JJ, Mohanty AK, Heaton J, Thant M, Gantait K, Ghosh T, Amato R, Pearson RD, Jacob CG, Goncalves S, Mukaka M, Waithira N, Woodrow CJ, Grobusch MP, van Vugt M, Fairhurst RM, Cheah PY, Peto TJ, von Seidlein L, Dhorda M, Maude RJ, Winterberg M, Thuy-Nhien NT, Kwiatkowski DP, Imwong M, Jittamala P, Lin K, Hlaing TM, Chotivanich K, Huy R, Fanello C, Ashley E, Mayxay M, Newton PN, Hien TT, Valecha N, Smithuis F, Pukrittayakamee S, Faiz A, Miotto O, Tarning J, Day NPJ, White NJ, Dondorp AM; Tracking Resistance to Artemisinin Collaboration. Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trial. Lancet. 2020 Apr 25;395(10233):1345-1360. doi: 10.1016/S0140-6736(20)30552-3. Epub 2020 Mar 11.
citation: van der Pluijm RW, Imwong M, Chau NH, Hoa NT, Thuy-Nhien NT, Thanh NV, Jittamala P, Hanboonkunupakarn B, Chutasmit K, Saelow C, Runjarern R, Kaewmok W, Tripura R, Peto TJ, Yok S, Suon S, Sreng S, Mao S, Oun S, Yen S, Amaratunga C, Lek D, Huy R, Dhorda M, Chotivanich K, Ashley EA, Mukaka M, Waithira N, Cheah PY, Maude RJ, Amato R, Pearson RD, Goncalves S, Jacob CG, Hamilton WL, Fairhurst RM, Tarning J, Winterberg M, Kwiatkowski DP, Pukrittayakamee S, Hien TT, Day NP, Miotto O, White NJ, Dondorp AM. Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study. Lancet Infect Dis. 2019 Sep;19(9):952-961. doi: 10.1016/S1473-3099(19)30391-3. Epub 2019 Jul 22.