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Study to Compare the Triple ACT AL+AQ With the ACT AL in Cambodia and Vietnam (TACT-CV)

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ClinicalTrials.gov Identifier: NCT03355664
Recruitment Status : Recruiting
First Posted : November 28, 2017
Last Update Posted : April 5, 2018
Sponsor:
Information provided by (Responsible Party):
University of Oxford

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.

Condition or disease Intervention/treatment Phase
Malaria, Falciparum Drug: ACT Drug: TACT Phase 3

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."


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 600 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: open-label randomised trial
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : March 19, 2018
Estimated Primary Completion Date : November 15, 2019
Estimated Study Completion Date : March 31, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Malaria

Arm Intervention/treatment
Active Comparator: ACT
Artemether-lumefantrine for 3 days plus primaquine at hour 24
Drug: ACT
Artemether-lumefantrine (20/120 mg) as a fixed dose combination twice daily for 3 days according to weight plus low dose primaquine at hour 24

Experimental: TACT
Artemether-lumefantrine for 3 days plus Amodiaquine for 3 days plus primaquine at hour 24
Drug: TACT
Artemether-lumefantrine (20/120 mg) as a fixed dose combination twice daily for 3 days according to weight plus Amodiaquine (150mg) twice daily for 3 days according to weight plus low dose primaquine at hour 24




Primary Outcome Measures :
  1. polymerase chain reaction corrected efficacy defined as adequate clinical and parasitological response (ACPR) by study arm [ Time Frame: 42 days ]
    polymerase chain reaction corrected efficacy defined as adequate clinical and parasitological response (ACPR) by study arm


Secondary Outcome Measures :
  1. 42-day polymerase chain reaction corrected efficacy according to site/geographic region [ Time Frame: 42 day ]
    42-day polymerase chain reaction corrected efficacy defined as adequate clinical and parasitological response (ACPR) according to site/geographic region.

  2. Parasite clearance half-life [ Time Frame: 42 day ]
    Parasite clearance half-life assessed by microscopy as primary parameter to determine parasite clearance

  3. Parasite reduction rates [ Time Frame: 24 and 48 hours ]
    Parasite reduction rates and ratios at 24 and 48 hours assessed by microscopy

  4. Parasite count to fall 50% [ Time Frame: 42 days ]
    Time for parasite count to fall 50% of initial parasite density

  5. Parasite count to fall 90% [ Time Frame: 42 days ]
    Time for parasite count to fall 90% of initial parasite density

  6. Parasite count to fall 99% [ Time Frame: 42 days ]
    Time for parasite count to fall 99% of initial parasite density

  7. Fever clearance time [ Time Frame: 42 day ]
    The time taken for the tympanic temperature to fall below 37.5˚C and remain there for at least 24 hours

  8. Incidence of adverse events and serious adverse events by study arm [ Time Frame: 42 day ]
    Incidence of adverse events and serious adverse events by study arm

  9. Incidence of adverse events concerning markers of hepatic or renal toxicity [ Time Frame: 42 day ]
    Total bilirubin, Alanine transaminase, Aspartate transaminase, Alkaline phosphatase and creatinine will be measured

  10. Incidence of prolongation of the corrected QT interval [ Time Frame: 28 day ]
    Incidence of the prolongation of the corrected QT interval above 500 ms or > 60 ms above baseline values

  11. Prolongation of the corrected QT interval [ Time Frame: Hour 4, Hour 24, Hour 28, Hour 48, Hour 52, Hour 60, Hour 64, Day 7 and Day 28 and between these time points ]
    Prolongation of the corrected QT interval compared to baseline at specific timepoints

  12. Change in haematocrit [ Time Frame: Day 1 to 7, 14, 21, 28, 35, 42 ]
    Change in haematocrit at specified time points according to geographical location and study arm, stratified for G6PD status

  13. Correlation between the host genotype and the pharmacokinetics and pharmacodynamics of antimalarials [ Time Frame: 42 day ]
    Correlation between the host genotype and the pharmacokinetics and pharmacodynamics of antimalarials

  14. Proportion of patients that reports completing a full course of observed TACT or ACT [ Time Frame: 42 day ]
    Proportion of patients 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

  15. Prevalence of Kelch13 mutations of known significance [ Time Frame: 42 day ]
    Prevalence of Kelch13 mutations of known significance

  16. Prevalence/incidence of other genetic markers of antimalarial drug resistance such as multidrug resistance gene 1 copy number and multidrug resistance gene 1 mutations [ Time Frame: 48 hours ]
    Prevalence/incidence of other genetic markers of antimalarial drug resistance such as multidrug resistance gene 1 copy number and multidrug resistance gene 1 mutations

  17. Genome wide association with in vivo/in vitro sensitivity parasite phenotype [ Time Frame: 42 day ]
    Genome wide association with in vivo/in vitro sensitivity parasite phenotype

  18. Correlation between single nucleotide polymorphisms and whole genome sequencing [ Time Frame: 42 day ]
    Correlation between single nucleotide polymorphisms measured in dry blood spots and whole genome sequencing in leukocyte depleted blood samples

  19. A comparison of transcriptomic patterns between sensitive and resistant parasites [ Time Frame: baseline and t = 6 hours ]
    Transcriptomic patterns measure at baseline and at specified time points after the start of treatment comparing sensitive and resistant parasites.

  20. Correlation between quantitative polymerase chain reaction based versus microscopy based assessments of parasite clearance dynamics [ Time Frame: 14 days ]
    Correlation between qPCR based versus microscopy based assessments of parasite clearance dynamics

  21. Proportion of patients with gametocytaemia before, during and after treatment with TACT or ACT [ Time Frame: At admission and up to day 14 ]
    Proportion of patients with gametocytaemia before, during and after treatment with TACT or ACT stratified by the presence of gametocytes at enrolment

  22. Levels of RNA transcription coding for male or female specific gametocytes [ Time Frame: 14 days ]
    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

  23. In vitro sensitivity of P. falciparum to artemisinins and partner drugs [ Time Frame: At admission & subjects with recurrent parasitaemia, up to 42 days ]
    In vitro sensitivity of P. falciparum to artemisinins and partner drugs according to study sites and genotype

  24. Pharmacokinetic profiles and interactions (Cmax) of artemisinin-derivatives and partner drugs [ Time Frame: 42 days ]
    Pharmacokinetic profiles and interactions (Cmax) of artemisinin-derivatives and partner drugs in 20 ACT treated and 20 TACT treated patients of both study arms in Vietnam

  25. Pharmacokinetic profiles and interactions (AUC) of artemisinin-derivatives and partner drugs [ Time Frame: 42 days ]
    Pharmacokinetic profiles and interactions (AUC) of artemisinin-derivatives and partner drugs in 20 ACT treated and 20 TACT treated patients of both study arms in Vietnam

  26. Day 7 drug levels of partner drugs in association with treatment efficacy and treatment arm [ Time Frame: 7 days ]
    Day 7 drug levels of partner drugs in association with treatment efficacy and treatment arm

  27. Correlation between histidine-rich protein 2 (HRP2) based versus microscopy based assessments of parasite clearance dynamics [ Time Frame: 42 days ]
    Correlation between histidine-rich protein 2 (HRP2) based versus microscopy based assessments of parasite clearance dynamics



Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03355664


Contacts
Contact: Arjen M Dondorp, M.D. (66) 2 203 6333 arjen@tropmedres.ac
Contact: Thomas J Peto, Ph.D. (66) 2 203 6333| Tom@tropmedres.ac

Locations
Cambodia
Siem Pang Health Center Recruiting
Siem Pang, Stung Treng, Cambodia, 1803
Contact: Rupam Tripura, M.D.    (66) 2 203 6333    Rupam@tropmedres.ac,   
Contact: James Callery    (66) 2 203 6333    James.C@tropmedres.ac   
Pailin Referral Hospital Not yet recruiting
Pailin, Cambodia, 2401
Contact: Rupam. , Tripura, M.D.    (66) 2 203 6333    Rupam@tropmedres.ac   
Contact: Thomas J Peto, PhD.    (66) 2 203 6333    Tom@tropmedres.ac   
Vietnam
Hospital for Tropical Diseases of Khanh Hoa, Not yet recruiting
Van Ninh, Khanh Hoa, Vietnam
Phuoc Long Hospital Not yet recruiting
Phuoc Long, Phuoc, Vietnam
Contact: Rob van der Pluijm, M.D.    (66) 2 203 6333    Rob@tropmedres.ac   
Sponsors and Collaborators
University of Oxford

Responsible Party: University of Oxford
ClinicalTrials.gov Identifier: NCT03355664     History of Changes
Other Study ID Numbers: MAL17008
First Posted: November 28, 2017    Key Record Dates
Last Update Posted: April 5, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Oxford:
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

Additional relevant MeSH terms:
Parasitic Diseases
Malaria
Malaria, Falciparum
Protozoan Infections
Lumefantrine
Artemether
Artemisinins
Primaquine
Artemether-lumefantrine combination
Amodiaquine
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Antifungal Agents
Coccidiostats
Schistosomicides
Antiplatyhelmintic Agents
Anthelmintics