Randomised Trial of 3 Artemisinin Combination Therapy for Malaria in Pregnancy

NCT ID: NCT01054248

Last Updated: 2022-03-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 511 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-02-16
• Study Completion Date: 2016-09-30

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.

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.

Conditions

Malaria

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

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.

Group Type: EXPERIMENTAL

Artesunate-mefloquine

Intervention Type: DRUG

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.

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)

Group Type: ACTIVE_COMPARATOR

arthemeter-lumefantrin

Intervention Type: DRUG

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).

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

Group Type: EXPERIMENTAL

dihydroartemisinin-piperaquine

Intervention Type: DRUG

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

Interventions

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

Intervention Type: 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.

Intervention Type: 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).

Intervention Type: DRUG

Other Intervention Names

Artekin; Coartem

Eligibility 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Oxford

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Rose McGready, MBBS

Role: PRINCIPAL_INVESTIGATOR

Shoklo Malaria Research Unit

Locations

Shoklo Malaria Research Unit

Mae Sot, Changwat Tak, Thailand

Countries

Thailand

References

Saito M, Wilaisrisak P, Pimanpanarak M, Viladpai-Nguen J, Paw MK, Koesukwiwat U, Tarning J, White NJ, Nosten F, McGready R. Comparison of lumefantrine, mefloquine, and piperaquine concentrations between capillary plasma and venous plasma samples in pregnant women with uncomplicated falciparum and vivax malaria. Antimicrob Agents Chemother. 2024 May 2;68(5):e0009324. doi: 10.1128/aac.00093-24. Epub 2024 Apr 10.

Reference Type: DERIVED

PMID: 38597636 (View on PubMed)

Saito M, Carrara VI, Gilder ME, Min AM, Tun NW, Pimanpanarak M, Viladpai-Nguen J, Paw MK, Haohankhunnatham W, Konghahong K, Phyo AP, Chu C, Turner C, Lee SJ, Duanguppama J, Imwong M, Bancone G, Proux S, Singhasivanon P, White NJ, Nosten F, McGready R. A randomized controlled trial of dihydroartemisinin-piperaquine, artesunate-mefloquine and extended artemether-lumefantrine treatments for malaria in pregnancy on the Thailand-Myanmar border. BMC Med. 2021 Jun 10;19(1):132. doi: 10.1186/s12916-021-02002-8.

Reference Type: DERIVED

PMID: 34107963 (View on PubMed)

Other Identifiers

SMRU0905

Identifier Type: -

Identifier Source: org_study_id