Randomised Trial of 3 Artemisinin Combination Therapy for Malaria in Pregnancy - Full Text View

Purpose

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	Intervention	Phase
Malaria	Drug: dihydroartemisinin-piperaquine Drug: Artesunate-mefloquine Drug: arthemeter-lumefantrin	Phase 3


Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Single Blind (Subject) 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

Resource links provided by NLM:

MedlinePlus related topics: Malaria

Drug Information available for: Mefloquine hydrochloride Artemether Lumefantrine

Genetic and Rare Diseases Information Center resources: Malaria

U.S. FDA Resources

Further study details as provided by University of Oxford:

Primary Outcome Measures:

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 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Number of adverse events [ Time Frame: Day 63 ] [ Designated as safety issue: Yes ]
Biochemical and haematological changes [ Time Frame: Day 28 ] [ Designated as safety issue: Yes ]
Kinetic parameters of artesunate, mefloquine, piperaquine and lumefantrine [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
Anaemia [ Time Frame: Day 63 ] [ Designated as safety issue: No ]
Gametocyte carriage [ Time Frame: Day 63 ] [ Designated as safety issue: No ]
Changes in the Reticulocyte counts [ Time Frame: Day 63 ] [ Designated as safety issue: No ]
Malaria infection rate at delivery and placental parasitaemia [ Time Frame: Delivery ] [ Designated as safety issue: No ]
Pregnancy outcomes (abortions, low birth weight, premature birth, congenital abnormality, stillbirths, neonatal and infant mortality) [ Time Frame: Delivery ] [ Designated as safety issue: No ]
Infant growth and development at 1 year of life [ Time Frame: 1 year after delivery ] [ Designated as safety issue: No ]


Enrollment:	499
Study Start Date:	February 2016
Study Completion Date:	September 2016
Primary Completion Date:	September 2016 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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

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.

Eligibility


Ages Eligible for Study:	18 Years to 45 Years (Adult)
Genders Eligible for Study:	Both
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

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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01054248

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


Responsible Party:	University of Oxford
ClinicalTrials.gov Identifier:	NCT01054248 History of Changes
Other Study ID Numbers:	SMRU0905
Study First Received:	January 21, 2010
Last Updated:	September 13, 2016
Health Authority:	Thailand: Ethical Committee

Keywords provided by University of Oxford:


pregnancy, malaria, artemisinin, vivax, falciparum

Additional relevant MeSH terms:


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

ClinicalTrials.gov processed this record on September 23, 2016

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