Clincosm LogoSign in Get a demo

ALU-PQ: "Prolonging the Therapeutic Life Span of Artemisinin-based Combination Therapies (ACT) in Bagamoyo District, Tanzania"

Sponsor
Muhimbili University of Health and Allied Sciences (Other)
Overall Status
Completed
CT.gov ID
NCT03241901
Collaborator
Uppsala University (Other), Karolinska Institutet (Other), The University of Western Australia (Other)
280
Enrollment
2
Locations
2
Arms
6.7
Actual Duration (Months)
140
Patients Per Site
20.8
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This clinical trial evaluates the advantage of prolonging the therapeutic life span of Artemether-lumefantrine from 3 days to 6 days, and addition of single low dose of Primaquine 0.25mg/kg. The study will have two arms, one that will receive standard treatment of uncomplicated malaria with Artemether-lumefantrine, and the other arm will receive the prolonged dose of 6 days together with single low dose primaquine. This approach is expected to provide strategies for malaria control in an era of imminent Plasmodium falciparum resistance.

Condition or Disease Intervention/Treatment Phase
  • Drug: Artemether-Lumefantrine Tab 20-120mg
  • Drug: Primaquine Phosphate 0.25 mg/kg
  • Other: Placebo
 Phase 4

Detailed Description

Despite documented high cure rates of ACT in Tanzania, and Africa elsewhere, clinical trials conducted in Tanzania with Swedish International Development cooperation Agency (SIDA) and Swedish Research Council support, provide evidence for in vivo selection of lumefantrine tolerant/resistant parasites among recurrent infections. Similarly, molecular epidemiology studies from Bagamoyo District, Tanzania, have shown temporal selection of lumefantrine associated genetic tolerance/resistance markers in the parasite population following wide scale use of Artemether-lumefantrine, but without signs of compromised treatment efficacy.

During the last decade, and despite the documented rapid microscopy determined parasite clearance of artemether-lumefantrine in Bagamoyo District, interest has developed in understanding the observation of high residual polymerase chain reaction (PCR) determined positivity rate on day 3 after supervised artemether-lumefantrine treatment in the magnitude of almost 30% in previous assessments from 2015. Using deep sequencing approaches studies have recently detected PCR determined delayed parasite clearance curves in P. falciparum sub-populations in Bagamoyo District. The clearance times by PCR of these sub-populations were similar to artemisinin resistant parasites in Myanmar as assessed by microscopy, but the former did, importantly, not harbor any of the described mutations in Kelch13 propeller associated with artemisinin resistance. However, these Tanzanian parasite sub-populations need to be further studied and characterized since they may provide important clues to the understanding of artemisinin survival strategies among the East African P. falciparum parasite population.

Taken together, longitudinal clinical and molecular data described above from Tanzania, East Africa, extending from pre-ACT implementation, (before 2006), to a decade of wide scale artemether-lumefantrine use in Bagamoyo district, provide evidence for declining susceptibility to ACT, both to artemether and lumefantrine, among the P. falciparum population. These parasites ("last man standing") that survived 10 years of ACT exposure have indeed shown excellent survival instincts and may thus be particularly resistant prone. However, if P. falciparum resistance to ACT develops in Africa, this will have devastating effects on malaria morbidity and mortality and may swiftly ruin the improvements the global malaria community achieved during the past decade with ACT as a key component for success.

Based on the above the investigators suggest prolonged treatment with ACT and addition of transmission blocking treatment using a single low dose of primaquine administered on the last day of ACT treatment.

Study Design

Study Type:
Interventional
Actual Enrollment :
280 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Single (Participant)
Masking Description:
Due to the objectives of the study, the identity of test and control treatments will be known only to investigators, research staff, but NOT patients. The following study procedures will be in place to ensure single-blind administration of study treatments. Access to the randomization code will be strictly controlled. A taste-matching agent for the placebo. Packaging and labeling of test and control treatments will be identical to maintain the blind. During the study, the blind may be broken only in emergencies when knowledge of the patient's treatment group is necessary for further patient management. When possible, the Investigator should discuss the emergency with the Medical Monitor prior to un-blinding
Primary Purpose:
Treatment
Official Title:
"Aiming at Prolonging the Therapeutic Life Span of Artemisinin-based Combination Therapies (ACT) in an Era of Imminent Plasmodium Falciparum Resistance in Bagamoyo District, Tanzania - New Strategies With Old Tools"
Actual Study Start Date :
Jul 27, 2017
Actual Primary Completion Date :
Dec 28, 2017
Actual Study Completion Date :
Feb 17, 2018

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: 3 Days Artemether-Lumefantrine + Placebo

Oral tablets of artemether-lumefantrine (20-120mg): tablet for 5-14kg; tablets for 15-24 kg; tables for 25 - 34kg and tablets for above 35 Kg. The full course of treatment is 6-doses for 3 days given twice daily, at 0, 8, 24, 36, 48, 60 with the dose being given as directly observed therapy. Oral placebo after completion of the standard 3 days-six dose regimen. A fatty snack (biscuits) will be administered together with all artemether-lumefantrine doses to optimize absorption.

Drug: Artemether-Lumefantrine Tab 20-120mg
Artemether-Lumefantrine Tablet 20-120mg
Other Names:
  • ALU

    • Other: Placebo
    Aqueous solution prepared to mimic the taste of the intervention drug.
    Other Names:
  • Placebo for Artemether Lumefantrine + Primaquine Phosphate

    		•
    Experimental: 6Days Artemether/Lumefantrine+Primaquine

    Artemether-lumefantrine (20-120mg) twice daily for 6 days according to body weight as in the active comparator arm. And in addition to that, , a single 0.25 mg/kg primaquine dose (Primaquine phosphate) will be administered concomitantly with the last (i.e. twelfth) artemether-lumefantrine dose. Primaquine will be prepared and administered in an aqueous solution.

    Drug: Artemether-Lumefantrine Tab 20-120mg
    Artemether-Lumefantrine Tablet 20-120mg
    Other Names:
  • ALU

    • Drug: Primaquine Phosphate 0.25 mg/kg
    Primaquine Phosphate 0.25 mg/kg
    Other Names:
  • PQ

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Parasite Clearance Times [5 Days]

      Proportion of PCR detectable parasitemia on Day 5

    2. Parasite Clearance Times [7 Days]

      Proportion of PCR detectable parasitemia on Day 7

    Secondary Outcome Measures

    1. Gametocyte Clearance [42 Days]

      PCR determined gametocyte carriage/clearance times

    2. Cure Rate [28 Days]

      Crude and PCR corrected cure rates by day 28

    3. Genetic Markers of Drug Resistance [6 Days]

      Selection of genetic drug resistance markers during the early treatment phase

    4. Pharmacokinetics [7 Days]

      Area under the plasma concentration versus time curve (AUC) of Artemether-lumefantrine

    5. Peak Plasma Concentration (Cmax) [At hours, -1, 0 ,2 ,4 ,12, 24, 36, 40, 48, 52, 60, 72, 84, 88, 96, 100, 108,120, 132, 134, 136 ,144, 168, 192, 240, 336, 504 and 672]

      Peak Plasma Concentration (Cmax) of Lumefantrine measured for 28 days

    6. Day 7 plasma lumefantrine [7 Days]

      Day 7 plasma lumefantrine concentrations in the respective arms

    Other Outcome Measures

    1. Fever Clearance Time [7 Days]

      This will assess the rate of clearance of fever after initiation of treatment

    2. Incidence of Treatment-Emergent Adverse Events (Safety and tolerability) [Baseline and day 7]

      Incidence of prolonged Corrected QT interval in ECG measures at day 7

    3. Incidence of Severe anemia [baseline to day 7, 14, 28, 42]

      Proportion of Severe anemia as measured by hemoglobin baseline to day 7, 14, 28, 42

    4. Incidence of Biochemistry parameters derangements [Baseline and day 7]

      Proportions of biochemistry parameters (ALAT, ASAT, Bilirubin and Creatinine) outside the normal range .

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    1 Year to 65 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    1. Age more than 1 year and less than 65 years.

    2. Weight 10 kg and above;

    3. Body temperature ≥37.5°C or history of fever in the last 24 hours;

    4. Microscopy determined asexual P. falciparum mono-infection regardless of parasitemia

    5. Normal - corrected QT Interval in Baseline ECG of less than 440ms in male and 460ms in females

    Exclusion Criteria:

    1. Symptoms/signs of severe malaria or danger signs;

    2. Pregnancy, Breastfeeding or unwilling to practice birth control during participation in the study.

    3. Known allergy to study medications;

    4. Hb <8 g/dl;

    5. Reported antimalarial intake within last 2 weeks;

    6. On regular medication, which may interfere with antimalarial pharmacokinetics and

    7. Blood transfusion within last 90 days.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Fukayosi Dispensary Bagamoyo Pwani Tanzania +255
    2 Yombo Dispensary Bagamoyo Yombo Tanzania +255

    Sponsors and Collaborators

    • Muhimbili University of Health and Allied Sciences
    • Uppsala University
    • Karolinska Institutet
    • The University of Western Australia

    Investigators

    • Principal Investigator: Lwidiko E Mhamilawa, MD, Muhimbili University of Health and Allied Sciences
    • Study Chair: Andreas Martensson, PhD, Uppsala University

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    Responsible Party:
    Dr. Lwidiko Edward, Medical Doctor, Muhimbili University of Health and Allied Sciences
    ClinicalTrials.gov Identifier:
    NCT03241901
    Other Study ID Numbers:
    • No. 01.05.2017
    First Posted:
    Aug 8, 2017
    Last Update Posted:
    Mar 27, 2018
    Last Verified:
    Mar 1, 2018
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Dr. Lwidiko Edward, Medical Doctor, Muhimbili University of Health and Allied Sciences
    Artemether-Lumefantrine, Primaquine
    Additional relevant MeSH terms:
    Malaria, Falciparum
    Lumefantrine
    Artemether
    Primaquine
    Artemether, Lumefantrine Drug Combination

    Study Results

    No Results Posted as of Mar 27, 2018