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

Primary Purpose

Malaria

Status

Completed

Phase

Phase 3

Locations

Thailand

Study Type

Interventional

Intervention

dihydroartemisinin-piperaquine

Artesunate-mefloquine

arthemeter-lumefantrin

About this trial

This is an interventional treatment trial for Malaria focused on measuring pregnancy, malaria, artemisinin, vivax, falciparum

Eligibility Criteria

18 Years - 45 Years (Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Shoklo Malaria Research Unit

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Experimental

Arm Label

MAS3

ALN+

Arm Description

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.

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)

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

Outcomes

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

Secondary Outcome Measures

Number of adverse events

Biochemical and haematological changes

Kinetic parameters of artesunate, mefloquine, piperaquine and lumefantrine

Anaemia

Gametocyte carriage

Changes in the Reticulocyte counts

Malaria infection rate at delivery and placental parasitaemia

Pregnancy outcomes (abortions, low birth weight, premature birth, congenital abnormality, stillbirths, neonatal and infant mortality)

Infant growth and development at 1 year of life

Full Information

NCT ID

NCT01054248

First Posted

January 21, 2010

Last Updated

March 24, 2022

Sponsor

University of Oxford

1. Study Identification

Unique Protocol Identification Number

NCT01054248

Brief Title

Randomised Trial of 3 Artemisinin Combination Therapy for Malaria in Pregnancy

Acronym

DMA

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 Type

Interventional

2. Study Status

Record Verification Date

March 2022

Overall Recruitment Status

Completed

Study Start Date

February 16, 2010 (Actual)

Primary Completion Date

September 2016 (Actual)

Study Completion Date

September 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Oxford

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Malaria

Keywords

pregnancy, malaria, artemisinin, vivax, falciparum

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

Participant

Allocation

Randomized

Enrollment

511 (Actual)

8. Arms, Groups, and Interventions

Arm Title

MAS3

Arm Type

Experimental

Arm Description

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.

Arm Title

ALN+

Arm Type

Active Comparator

Arm Description

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)

Arm Title

Arm Type

Experimental

Arm Description

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

Intervention Name(s)

dihydroartemisinin-piperaquine

Other Intervention Name(s)

Artekin

Intervention Description

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

Intervention Name(s)

Artesunate-mefloquine

Intervention Description

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

Intervention Name(s)

arthemeter-lumefantrin

Other Intervention Name(s)

Coartem

Intervention Description

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).

Primary Outcome Measure Information:

Title

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 Measure Information:

Title

Number of adverse events

Time Frame

Day 63

Title

Biochemical and haematological changes

Time Frame

Day 28

Title

Kinetic parameters of artesunate, mefloquine, piperaquine and lumefantrine

Time Frame

Day 42

Title

Anaemia

Time Frame

Day 63

Title

Gametocyte carriage

Time Frame

Day 63

Title

Changes in the Reticulocyte counts

Time Frame

Day 63

Title

Malaria infection rate at delivery and placental parasitaemia

Time Frame

Delivery

Title

Pregnancy outcomes (abortions, low birth weight, premature birth, congenital abnormality, stillbirths, neonatal and infant mortality)

Time Frame

Delivery

Title

Infant growth and development at 1 year of life

Time Frame

1 year after delivery

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

45 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Rose McGready, MBBS

Organizational Affiliation

Shoklo Malaria Research Unit

Official's Role

Principal Investigator

Facility Information:

Facility Name

Shoklo Malaria Research Unit

City

Mae Sot

State/Province

Tak

Country

Thailand

12. IPD Sharing Statement

Citations:

PubMed Identifier

34107963

Citation

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.

Results Reference

derived

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Randomised Trial of 3 Artemisinin Combination Therapy for Malaria in Pregnancy

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