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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03241901
Recruitment Status : Completed
First Posted : August 8, 2017
Last Update Posted : March 27, 2018
Sponsor:
Collaborators:
Uppsala University
Karolinska Institutet
The University of Western Australia
Information provided by (Responsible Party):
Dr. Lwidiko Edward, Muhimbili University of Health and Allied Sciences

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
Malaria,Falciparum 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.

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Study Type : Interventional  (Clinical Trial)
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.

  1. Access to the randomization code will be strictly controlled.
  2. A taste-matching agent for the placebo.
  3. 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 : July 27, 2017
Actual Primary Completion Date : December 28, 2017
Actual Study Completion Date : February 17, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Malaria

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 Name: ALU

Other: Placebo
Aqueous solution prepared to mimic the taste of the intervention drug.
Other Name: 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 Name: ALU

Drug: Primaquine Phosphate 0.25 mg/kg
Primaquine Phosphate 0.25 mg/kg
Other Name: PQ




Primary Outcome Measures :
  1. Parasite Clearance Times [ Time Frame: 5 Days ]
    Proportion of PCR detectable parasitemia on Day 5

  2. Parasite Clearance Times [ Time Frame: 7 Days ]
    Proportion of PCR detectable parasitemia on Day 7


Secondary Outcome Measures :
  1. Gametocyte Clearance [ Time Frame: 42 Days ]
    PCR determined gametocyte carriage/clearance times

  2. Cure Rate [ Time Frame: 28 Days ]
    Crude and PCR corrected cure rates by day 28

  3. Genetic Markers of Drug Resistance [ Time Frame: 6 Days ]
    Selection of genetic drug resistance markers during the early treatment phase

  4. Pharmacokinetics [ Time Frame: 7 Days ]
    Area under the plasma concentration versus time curve (AUC) of Artemether-lumefantrine

  5. 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

  6. Day 7 plasma lumefantrine [ Time Frame: 7 Days ]
    Day 7 plasma lumefantrine concentrations in the respective arms


Other Outcome Measures:
  1. Fever Clearance Time [ Time Frame: 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) [ Time Frame: Baseline and day 7 ]
    Incidence of prolonged Corrected QT interval in ECG measures at day 7

  3. 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

  4. Incidence of Biochemistry parameters derangements [ Time Frame: Baseline and day 7 ]
    Proportions of biochemistry parameters (ALAT, ASAT, Bilirubin and Creatinine) outside the normal range .



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   1 Year to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

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): NCT03241901


Locations
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Tanzania
Fukayosi Dispensary
Bagamoyo, Pwani, Tanzania, +255
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
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Principal Investigator: Lwidiko E Mhamilawa, MD Muhimbili University of Health and Allied Sciences
Study Chair: Andreas Martensson, PhD Uppsala University
  Study Documents (Full-Text)

Documents provided by Dr. Lwidiko Edward, Muhimbili University of Health and Allied Sciences:
Additional Information:
Publications:
R. Mwaiswelo, B. Ngasala, I. Jovel, W. Xu, and M. Malmberg, "Occurrence of day 3 submicroscopic Plasmodium falciparum parasitemia before and after implementation of artemether-lumefantrine treatment policy in Tanzania .," Dar Es Salaam, 2016

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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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: August 8, 2017    Key Record Dates
Last Update Posted: March 27, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Dr. Lwidiko Edward, Muhimbili University of Health and Allied Sciences:
Artemether-Lumefantrine, Primaquine
Additional relevant MeSH terms:
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Malaria, Falciparum
Malaria
Protozoan Infections
Parasitic Diseases
Lumefantrine
Artemether
Primaquine
Artemether, Lumefantrine Drug Combination
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents