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

March 24, 2018 updated by: Dr. Lwidiko Edward, Muhimbili University of Health and Allied Sciences

"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"

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

280

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Tanzania
    • Pwani
      • Bagamoyo, Pwani, Tanzania, +255
        • Fukayosi Dispensary
    • Yombo
      • Bagamoyo, Yombo, Tanzania, +255
        • Yombo Dispensary

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year to 65 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

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

Oral tablets of artemether-lumefantrine (20-120mg):

  1. tablet for 5-14kg;
  2. tablets for 15-24 kg;
  3. tables for 25 - 34kg and
  4. 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Parasite Clearance Times
Time Frame: 5 Days
Proportion of PCR detectable parasitemia on Day 5
5 Days
Parasite Clearance Times
Time Frame: 7 Days
Proportion of PCR detectable parasitemia on Day 7
7 Days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Gametocyte Clearance
Time Frame: 42 Days
PCR determined gametocyte carriage/clearance times
42 Days
Cure Rate
Time Frame: 28 Days
Crude and PCR corrected cure rates by day 28
28 Days
Genetic Markers of Drug Resistance
Time Frame: 6 Days
Selection of genetic drug resistance markers during the early treatment phase
6 Days
Pharmacokinetics
Time Frame: 7 Days
Area under the plasma concentration versus time curve (AUC) of Artemether-lumefantrine
7 Days
Peak Plasma Concentration (Cmax)
Time Frame: 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
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
Day 7 plasma lumefantrine
Time Frame: 7 Days
Day 7 plasma lumefantrine concentrations in the respective arms
7 Days

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Fever Clearance Time
Time Frame: 7 Days
This will assess the rate of clearance of fever after initiation of treatment
7 Days
Incidence of Treatment-Emergent Adverse Events (Safety and tolerability)
Time Frame: Baseline and day 7
Incidence of prolonged Corrected QT interval in ECG measures at day 7
Baseline and day 7
Incidence of Severe anemia
Time Frame: baseline to day 7, 14, 28, 42
Proportion of Severe anemia as measured by hemoglobin baseline to day 7, 14, 28, 42
baseline to day 7, 14, 28, 42
Incidence of Biochemistry parameters derangements
Time Frame: Baseline and day 7
Proportions of biochemistry parameters (ALAT, ASAT, Bilirubin and Creatinine) outside the normal range .
Baseline and day 7

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Muhimbili University of Health and Allied Sciences

Collaborators

Karolinska Institutet
Uppsala University
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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 27, 2017

Primary Completion (Actual)

December 28, 2017

Study Completion (Actual)

February 17, 2018

Study Registration Dates

First Submitted

July 5, 2017

First Submitted That Met QC Criteria

August 6, 2017

First Posted (Actual)

August 8, 2017

Study Record Updates

Last Update Posted (Actual)

March 27, 2018

Last Update Submitted That Met QC Criteria

March 24, 2018

Last Verified

March 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • No. 01.05.2017

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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