Randomised Trial of 3 Artemisinin Combination Therapy for Malaria in Pregnancy (DMA)

Study Description

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Malaria	Drug: dihydroartemisinin-piperaquine; Drug: Artesunate-mefloquine; Drug: arthemeter-lumefantrin	Phase 3

Detailed Description:

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.

Study Design

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	499 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Single (Participant)
Primary Purpose:	Treatment
Official Title:	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
Study Start Date :	February 2016
Actual Primary Completion Date :	September 2016
Actual Study Completion Date :	September 2016

Arms and Interventions

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Arm	Intervention/treatment
Experimental: MAS3; 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; 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.
Active Comparator: ALN+; 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; 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).; Other Name: Coartem
Experimental: DP; 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; 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; Other Name: Artekin

Outcome Measures

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Primary Outcome Measures :

1. Cure rate defined as clearance of asexual parasites without recurrence within the period between treatment and delivery or a 63 day period [ Time Frame: Day 63 or until delivery, whichever occurs later ]

Secondary Outcome Measures :

1. Number of adverse events [ Time Frame: Day 63 ]
2. Biochemical and haematological changes [ Time Frame: Day 28 ]
3. Kinetic parameters of artesunate, mefloquine, piperaquine and lumefantrine [ Time Frame: Day 42 ]
4. Anaemia [ Time Frame: Day 63 ]
5. Gametocyte carriage [ Time Frame: Day 63 ]
6. Changes in the Reticulocyte counts [ Time Frame: Day 63 ]
7. Malaria infection rate at delivery and placental parasitaemia [ Time Frame: Delivery ]
8. Pregnancy outcomes (abortions, low birth weight, premature birth, congenital abnormality, stillbirths, neonatal and infant mortality) [ Time Frame: Delivery ]
9. Infant growth and development at 1 year of life [ Time Frame: 1 year after delivery ]

Eligibility Criteria

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Ages Eligible for Study:	18 Years to 45 Years (Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

Thailand
Shoklo Malaria Research Unit
Mae Sot, Tak, Thailand

Sponsors and Collaborators

University of Oxford

Investigators

Principal Investigator:	Rose McGready, MBBS	Shoklo Malaria Research Unit

More Information

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	University of Oxford
ClinicalTrials.gov Identifier:	NCT01054248 History of Changes
Other Study ID Numbers:	SMRU0905
First Posted:	January 22, 2010
Last Update Posted:	September 14, 2016
Last Verified:	September 2016

Keywords provided by University of Oxford:

pregnancy, malaria, artemisinin, vivax, falciparum

Additional relevant MeSH terms:

Malaria; Protozoan Infections; Parasitic Diseases; Artesunate; Artemisinins; Lumefantrine; Artemether; Piperaquine; Artemether-lumefantrine combination; Dihydroartemisinin; Mefloquine	Artemisinine; Amebicides; Antiprotozoal Agents; Antiparasitic Agents; Anti-Infective Agents; Antimalarials; Antifungal Agents; Coccidiostats; Schistosomicides; Antiplatyhelmintic Agents; Anthelmintics