A Study by the Tracking Resistance to Artemisinin Collaboration (TRAC)

Malaria, Falciparum Clinical Trial

— TRACII  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02453308
• Other study ID #: BAKMAL1502
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: August 2015
• Est. completion date: March 2018

Study information

• Verified date: May 2018
• Source: University of Oxford
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1110
• Est. completion date: March 2018
• Est. primary completion date: March 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Months to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Malaria
• Malaria, Falciparum

Intervention

Drug:
• ACT
Artemether-lumefantrine for 3 days Dihydroartemisinin-piperaquine for 3 days. Artesunate-mefloquine for 3 days
• TACT
Artemether-lumefantrine for 3 days plus Amodiaquine for 3 days. Dihydroartemisinin-piperaquine for 3 days plus Mefloquine hydrochloride for 3 days. Dihydroartemisinin-piperaquine for 3 days plus Mefloquine hydrochloride for 3 days.

Locations

Country	Name	City	State
Bangladesh	College of Medicine Chittagong	Ramu
Cambodia	Pailin	Pailin
Cambodia	Preah Vihear	Preah Vihear
Cambodia	Pursat	Pursat
Cambodia	Ratanakiri	Ratankiri
Congo, The Democratic Republic of the	Kinshasa	Kinshasa
India	Mohanpur Community health center	Agartala
India	Midnapore	Midnapore
India	Ispat General hospital	Rourkela
Lao People's Democratic Republic	Sekong	Sekong
Myanmar	Ann Hospital	Ann
Myanmar	Pyay hospital	Pyay
Myanmar	Pyin oo Lwin hospital	Pyin oo Lwin
Myanmar	Thabeikkyin hospital	Thabeikkyin
Thailand	Chumphon hospital	Chumphon
Thailand	Phusing hospital	Phusing	Srisaket
Thailand	Kunhan Hospital	Si Sa Ket
Thailand	Tha Song Yang hospital	Tha Song Yang	Tak
Thailand	Thanto Hospital	Yala
Vietnam	Binh Phuoc hospital	Binh Phuoc

Sponsors (1)

Lead Sponsor	Collaborator
University of Oxford

Countries where clinical trial is conducted

Bangladesh,  Cambodia,  Congo, The Democratic Republic of the,  India,  Lao People's Democratic Republic,  Myanmar,  Thailand,  Vietnam, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	PCR corrected efficacy defined as adequate clinical and parasitological response (ACPR)		42 days
Secondary	Parasite clearance half-life	Parasite clearance half-life assessed by microscopy as primary parameter to de-termine parasite clearance	42 days
Secondary	Parasite reduction rates and ratios at 24 and 48 hours assessed by microscopy		at 24 and 48 hours
Secondary	Time for parasite count to fall to 50% of initial parasite density		42 days
Secondary	Time for parasite count to fall to 90% of initial parasite density		42 days
Secondary	Time for parasite count to fall to 99% of initial parasite density		42 days
Secondary	Fever clearance time		42 days
Secondary	Incidence of adverse events and serious adverse events		42 days
Secondary	Incidence of adverse events concerning markers of hepatic toxicity	Total billirubin, ALT, AST and Alkaline Phosphatase will be measured	42 days
Secondary	Incidence of adverse events concerning markersof renal toxicity	Creatinine will be measured	42 days
Secondary	Incidence of prolongation of the QTc-interval	Incidence of prolongation of the Qtc-interval above 500 ms or > 60ms above baseline values	3 days
Secondary	Change in hemoglobin/hematocrit	Change in hemoglobin/hematocrit on day 1 to 7, 14, 21, 28, 35 and 42 according to geographical location and study arm, stratified for G6PD status	42 days
Secondary	Proportion of patients that reports completing a full course of observed TACT or ACT without withdrawal of consent or exclusion from study		42 days
Secondary	Prevalence of Kelch13 mutations of known functional significance		42 days
Secondary	Prevalence/incidence of other genetic markers of antimalarial drug resistance		42 days
Secondary	Genome wide association with in vivo/in vitro sensitivity parasite phenotype		42 days
Secondary	Correlation between SNPs measured in dry blood spots and whole genome sequencing in leukocyte depleted blood samples		42 days
Secondary	Transcriptomic patterns at t=0 and t=6h comparing sensitive and resistant parasites		6hrs after start of treatment
Secondary	Correlation between qPCR based versus microscopy based assessments of parasite clearance dynamics		14 days
Secondary	Proportion of patients with gametocytemia before,after treatment with Primaquine		assessed at admission, up to day 14
Secondary	Levels of RNA transcription coding for male or female specific gametocytes		at admission up to day 14
Secondary	In vitro sensitivity (expressed in IC50 values among others) of P. falciparum to artemisinins and partner drugs		42 days
Secondary	• 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		42 days
Secondary	Day 7 drug levels of partner drugs in association with treatment efficacy and treatment arm		Day 7