Randomised Trial of 3 Artemisinin Combination Therapy for Malaria in Pregnancy

Study Overview
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Brief Summary
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This is a randomised, open label trial, comparing standard dose of dihydroartemisinin-piperaquine (DP) with standard fixed artesunate-mefloquine regimen (MAS3) and with a longer regimen of artemether-lumefantrine (ALN+) in the treatment of uncomplicated malaria in pregnant women. The sample size is 335 women in each arm which would be 1005 women in total. Pregnant patients in 2nd and 3rd trimester with acute uncomplicated malaria who meet eligibility criteria will be asked to participate in the study. The primary objective is to determine if the efficacy of DP and MAS3 are superior to ALN+ in the treatment of uncomplicated malaria in pregnancy. The study will also incorporate a dense pharmacokinetic study of mefloquine and artesunate (15 women in the MAS3 arm) and a population pharmacokinetic study for mefloquine, piperaquine and lumefantrine.

Detailed Description
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The 3 treatment regimens are 3 days of DHA-piperaquine (DP), 3 days of artesunate-mefloquine (MAS3) with mefloquine given as 8,8,8 mg/kg per day and an augmented dose of 4 days (5 tabs BID) of artemether- lumefantrine (ALN+). This will focus on efficacy and safety. Patients will be randomized equally to one of three treatment groups. Within the trial there are two nested pharmacokinetic studies comprising dense data on 15 women for mefloquine and artesunate and sparse data for mefloquine, lumefantrine and piperaquine. Pregnant women will be followed up until delivery or day 63 if later than delivery and their infants will be followed until the end of the first year of life The follow up of babies will be monthly until 1 year (summarized in the table). Visits will include body weight, length, head circumference, arm circumference, physical examination, motor milestones by observation and caregiver interview, developmental examination and monthly haematocrit and stool testing. The mother is free to bring her infant at any time to the clinic and investigations appropriate to the presenting complaint and symptoms will be carried out as necessary to provide care for the infant. Infants born to mothers who have a positive peripheral smear at delivery are at risk of congenital malaria and will be actively screened weekly for 2 months. In the last study one congenital malaria P.falciparum occurred at day 21 and the infant was very sick and was cured with artesunate. Infants who are positive for malaria would have a PCR spot to verify if the malaria was congenital.

Official Title
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A Randomised Open Label Trial Comparing Standard Dose of Dihydroartemisinin-piperaquine, Standard Fixed Artesunate-mefloquine Regimen and a Longer Regimen of Artemether-lumefantrine in the Treatment of Uncomplicated Malaria in Pregnancy

Conditions
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Malaria

Intervention / Treatment
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* Drug: dihydroartemisinin-piperaquine
* Drug: Artesunate-mefloquine
* Drug: arthemeter-lumefantrin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-45 years Viable pregnancy of any gestation as assessed by ultrasound scanning Microscopically confirmed uncomplicated malaria (parasitaemia ≥ 5/500 WBC) with Plasmodium falciparum or Mixed infection (i.e. P.falciparum & P.vivax/ovale/malariae) or Plasmodium vivax/ovale/malariae Willingness and ability to comply with the study protocol for the duration of the trial Written informed consent provided No signs of labour Additional criteria for patients in the detailed pharmacokinetic study group (N=24 in the MAS3 arm): HCT>25% (based on field reading i.e. capillary sample) P.falciparum monoinfection Agree to stay in the clinic for 7 days Written consent to participate the detailed PK subgroup Exclusion Criteria: Known hypersensitivity to the study drugs P.falciparum asexual stage parasitaemia ≥ 4% RBCs Clinical or laboratory features of severe malaria based on WHO criteria-Appendix 1 Gastrointestinal dysfunction that could alter absorption or motility History or known liver diseases or other chronic diseases (excluding thalassemia & G6PD deficiency) Presence of intercurrent illness or any condition which in the judgement of the investigator would place the patient at undue risk or interfere with the results of the study Splenectomy Hematocrit (HCT) <20% (based on field reading i.e. capillary sample) [ *NB: Dense mefloquine pharmacokinetic exclusion if HCT < 25%] Taking contraindicated medications History of narcotic or alcohol abuse

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MAS3<br>Standard three day regimen of artesunate-mefloquine (12/24 mg/kg) given as artesunate 4mg/kg/day and mefloquine 8mg/kg/day on Days 0, 1 and 2. | Drug: Artesunate-mefloquine<br>* Standard three day regimen of artesunate-mefloquine (12/24 mg/kg) given as artesunate 4mg/kg/day and mefloquine 8mg/kg/day on Days 0, 1 and 2.<br>|
| Active Comparator: ALN+<br>Augmented 4 day regimen of artemether lumefantrine 2 doses per day for 4 days. Each dose consists of 5 tablets (20/120 mg of artemether/lumefantrine per tablet) | Drug: arthemeter-lumefantrin<br>* Augmented 4 day regimen of artemether lumefantrine 2 doses per day for 4 days. Each dose consists of 5 tablets (20/120 mg of artemether/lumefantrine per tablet).<br>* Other names: Coartem;|
| Experimental: DP<br>Standard 3 days regimen DHA-piperaquine: (DHA/PPQ 40 mg/320 mg) 2.4 mg/kg DHA and 20 mg/kg PPQ once daily for 3 days | Drug: dihydroartemisinin-piperaquine<br>* Standard 3 days regimen DHA-piperaquine: (DHA/PPQ 40 mg/320 mg) 2.4 mg/kg DHA and 20 mg/kg PPQ once daily for 3 days<br>* Other names: Artekin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cure rate defined as clearance of asexual parasites without recurrence within the period between treatment and delivery or a 63 day period |  | Day 63 or until delivery, whichever occurs later | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of adverse events |  | Day 63 | 
| Biochemical and haematological changes |  | Day 28 | 
| Kinetic parameters of artesunate, mefloquine, piperaquine and lumefantrine |  | Day 42 | 
| Anaemia |  | Day 63 | 
| Gametocyte carriage |  | Day 63 | 
| Changes in the Reticulocyte counts |  | Day 63 | 
| Malaria infection rate at delivery and placental parasitaemia |  | Delivery | 
| Pregnancy outcomes (abortions, low birth weight, premature birth, congenital abnormality, stillbirths, neonatal and infant mortality) |  | Delivery | 
| Infant growth and development at 1 year of life |  | 1 year after delivery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pregnancy, malaria, artemisinin, vivax, falciparum