Clinical trial NCT02020330: Optimising Operational Use of Artemether-lumefantrine Comparing 3 Day Versus 5 Day
Official title: An Open-label Randomized Controlled Trial to Evaluate the Effectiveness and Safety of a 3 Day Versus 5 Day Course of Artemether-lumefantrine for the Treatment of Uncomplicated Falciparum Malaria in Myanmar
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Plasmodium Falciparum Infection
Keywords: falciparum, malaria
Lead sponsor: University of Oxford
Sponsor class: OTHER
First posted: 2013-12-24
Enrollment: 150
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a randomised two arm study, comparing artemether-lumefantrine 3 days and 5 days treatment. Patients will be randomised in blocks of ten to one of the two treatment arms. The standard regimen is twice daily for three days with a delay of at least eight hours between the first and second doses. A single of primaquine will be given to all patients on the first day of treatment for gametocytocidal activity. The initial treatment will be given under supervision, all other subsequent doses will be given to the patient to the taken at home. Patients will be followed up for nine visits over forty two days.

Detailed description: * The study will be conducted in 6 village health centres in the Mon and Kayin states
* The patient or parent/guardian (in case of minor or under aged) must personally sign and date the latest approved version of the informed consent form before any study specific procedures are performed
* A case record form will be completed for each patient documenting symptoms prior to clinic attendance, concomitant illness, drug history. Height, weight, vital signs and physical examination findings will be recorded.
* At enrolment (D0) all patients will have the following samples taken:

  * Repeat parasite count (thick and thin films). Treatment should be started without waiting for the result.
  * Filter paper blood blots (3 dots on Whatman 3MM filter paper approx 180-300 µL blood) for parasite genotyping (MSP1, MSP2, GLURP in case of recurrence during follow-up)
  * Haemoglobin
* Laboratory procedures

  * Slide microscopy: Thick and thin blood films stained with Giemsa will be read and counts expressed as the number of parasites per 500 white blood cells
  * Molecular studies: The samples will be used to detect asexual parasites (blood smear, sensitive PCR), parasite population structure (Sequenom genotyping and sequencing), gametocytes (microscopy). The samples will be stored in a cool box and kept maximum 5 days in the field and will be transported to the local laboratory for processing. Plasma and buffy coat will be separated, frozen and stored. The frozen packed red cells will be transported to the molecular laboratory at MORU, Bangkok, Thailand, for sample processing (DNA extraction, quantitative PCRs).

Eligibility criteria: Inclusion Criteria:

1. Age ≥ 6 year
2. Symptomatic malaria infection, i.e. history of fever or presence of fever \>37.5°C
3. Microscopic confirmation of asexual stages of P. falciparum (may be mixed with non-falciparum species) with parasitaemia PFT≥5/500 WBC
4. Written informed consent given to participate in the trial

Exclusion Criteria:

1. Pregnancy or lactation (urine test for β HCG to be performed on any woman of child bearing age unless menstruating).
2. Female of 12 to 18 years of age
3. P. falciparum asexual stage parasitaemia greater than or equal to 4% red blood cells (175,000/µL).
4. Signs or symptoms indicative of severe malaria including:

   * Impaired consciousness (Blantyre Coma Score \<5 or Glasgow Coma Scale \<15)
   * Severe anaemia (Hb% \<5 mg/dl)
   * Bleeding disorder -evidenced by epistaxis, bleeding gums, frank haematuria, bleeding from venepuncture sites
   * Respiratory distress
   * Severe jaundice
   * Haemodynamic shock
5. A full course of artemether-lumefantrine treatment in the previous 28 days
6. Known hypersensitivity to artemisinins - defined as history of erythroderma/other severe cutaneous reaction, angioedema or anaphylaxis
7. History of splenectomy

Primary outcomes:
measure: proportion of patients with detectable parasitaemia
timeFrame: On day 5 and day 7
Secondary outcomes:
measure: Parasitaemia clearance time
timeFrame: On day 3 and Day 5
measure: Gametocyte carriage rates
timeFrame: Day 7
measure: artemether-lumefantrine tolerability
timeFrame: 5 days
measure: Comparison of effectiveness
timeFrame: Day 42
measure: concentrations of lumefantrine
timeFrame: Day 7
measure: Haematological recovery rate
timeFrame: Day 28
measure: Incidence of vivax malaria relapses
timeFrame: 42 days
measure: Comparison of addition of food supplement (fish oil)
timeFrame: day 3 to day 21
Other outcomes:
Locations:
city: Yangon
country: Myanmar
facility: Medical Action Myanmar
Study officials:
affiliation: Myanmar Oxford Clinical Research Unit
name: Frank Smithuis, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Tun KM, Jeeyapant A, Myint AH, Kyaw ZT, Dhorda M, Mukaka M, Cheah PY, Imwong M, Hlaing T, Kyaw TH, Ashley EA, Dondorp A, White NJ, Day NPJ, Smithuis F. Effectiveness and safety of 3 and 5 day courses of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in an area of emerging artemisinin resistance in Myanmar. Malar J. 2018 Jul 11;17(1):258. doi: 10.1186/s12936-018-2404-4.