Safe and Efficacious Artemisinin-based Combination Treatments for African Pregnant Women With Malaria

NCT00852423 | Completed Phase 3 DMC

• 1 other identifier: ITMP0308
• Study Type: interventional
• Target: 3,428
• Locations: 4 countries
• Sites: 7

Brief Summary

Malaria is the most important human parasitic disease and is responsible of high morbidity and mortality in resource-poor countries. Pregnant women, who are a high-risk group, are almost always excluded from clinical trials; thus, the investigators lack sufficient information on the safety and efficacy of most antimalarials in pregnancy. The recommendation of the World Health Organization to use artemisinin combination therapy (ACT) in the 2nd and 3rd trimester is already implemented in several African countries, however documentation of their efficacy and safety in pregnancy is still limited. Thus, the investigators propose to evaluate the efficacy and safety of 4 ACT(artemether-lumefantrine, amodiaquine-artesunate, mefloquine-artesunate and dihydroartemisinin-piperaquine), when used to treat pregnant women with P. falciparum malaria; the results will help to recommend the optimal therapy for this high-risk group in Africa.

Conditions

Malaria in Pregnancy

Keywords

Malaria in pregnancy; Sub-saharan Africa; Treatment; Artemisinin containing Therapy; Efficacy; Safety

Outcome Measures

Primary Outcomes (2)

• Treatment Failure (PCR adjusted)

  Day 63

• Safety profiles including significant changes in relevant laboratory values

  Until delivery

Secondary Outcomes (10)

• Time to failure

  Case by case

• PCR unadjusted treatment failure

  Day 63

• Gametocyte carriage (gametocyte-weeks)

  Case by case

• Asexual parasite clearance time

  Days to 2 consecutive negative blood slides.

• Gametocytaemia (prevalence and density)

  Day 7, 14, 21, 28 and 63 after treatment

Study Arms (4)

DHAPQ

EXPERIMENTAL

Three-day treatment with dihydroartemisinin-piperaquine

Drug: Dihydroartemisinin-piperaquine

MQAS

EXPERIMENTAL

Three-day treatment with mefloquine artesunate

Drug: Artesunate-mefloquine

AQAS

ACTIVE COMPARATOR

Three-day treatment with artesunate-amodiaquine

Drug: Artesunate-amodiaquine

AL

ACTIVE COMPARATOR

Three day treatment with artemether-lumefantrine (Coartem(R)

Drug: Artemether-lumefantrine

Interventions

Dihydroartemisinin-piperaquine DRUG

DHA-PQ tablets are green film coated intended for oral use and contain 20/160mg or 40/320mg of dihydroartemisinin (DHA) and piperaquine phosphate (PQ) respectively. In this trial the 40/320mg for adults will be used. Developed by Sigma Tau in partnership with Medicines for Malaria Venture.

Also known as: DHAPQ, Eurartesim

DHAPQ

Artesunate-mefloquine DRUG

MQAS will be provided as a fixed-dose ACT. There are 2 strengths (AS25+MQ55mg and AS100+MQ220mg) and dosing regimen is calculated according to 12 mg/kg AS and 24mg/kgMQ total dose over three days. Pregnant women will receive 2 tablets/day for 3 days. It is developed by Farmanguinhos with the Drugs for Neglected Diseases Initiative. To be noted: if the FDCs will not get the WHO pre-qualification before the start of recruitment, the separate AS and MQ will be used

Also known as: MQAS

MQAS

Artesunate-amodiaquine DRUG

AQAS, developed by teh DNDi with Sanofi-Aventis and manufactured by Sanofi-Aventis, has been pre-qualified by the WHO in 2008 and is available in several African countries, including those involved in this trial. AQ-AS tablets are round, yellow on one side and white-slightly yellow on the other, with a breaking bar, AS engraved on one side and either 25, 50 or 100 on the other side. Tablets to be used in this trial are those 100mg/270mg AS/AQ, containing 100 mg of artesunate, 352.640 mg of amodiaquine hydrochloride corresponding to 270mg of amodiaquine base.

Also known as: AQAS, artesunate-amodiaquine Winthrop®

AQAS

Artemether-lumefantrine DRUG

AL (tablets containing a FDC of 20 mg of artemether and 120 mg of lumefantrine) is manufactured by Novartis and has been extensively used in Africa for the treatment of uncomplicated malaria. AL was registered in Switzerland in 1999, has since received marketing authorisation in several endemic and non-endemic countries and it is WHO pre-qualified.

Also known as: AL, Coartem, Riamet

AL

Eligibility Criteria

• Age: 15 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Gestation of at least 16 weeks and \<37 weeks;
• P. falciparum monoinfection of any density, with or without symptoms
• Hb equal or higher than 7 g/dL;
• At least 15 years old;
• Residence within the health facility catchment's area;
• Willing to deliver at the health facility;
• Willing to adhere to study requirements (including in Zambia and Malawi, HIV VCT)
• Ability to provide written informed consent; if the woman is minor of age/not emancipated, the consent must be given by a parent or legal guardian according to national law (however, in this case, the investigator is responsible to check that the woman herself is also freely willing to take part in the study, and the woman will be asked to sign for "assent").

You may not qualify if:

• History of allergic reactions to the study drugs;
• History of known pregnancy complications or bad obstetric history such as repeated stillbirths or eclampsia;
• History or presence of major illnesses likely to influence pregnancy outcome including diabetes mellitus, severe renal or heart disease, or active tuberculosis;
• Current cotrimoxazole prophylaxis or ARV treatment;
• Any significant illness at the time of screening that requires hospitalization, including severe malaria;
• Intent to move out of the study catchment area before delivery or deliver at relative's home out of the catchment area.
• Prior enrollment in the study or concurrent enrollment in another study.
• Unable to take oral medication
• Clear evidence of recent (1 week) treatment with antimalarials or antimicrobials with antimalarial activity (clindamycin; azythromycin; etc.)

Sponsors & Collaborators

• Institute of Tropical Medicine, Belgium: lead
• National Institute for Medical Research, Tanzania: collaborator
• Kwame Nkrumah University of Science and Technology: collaborator
• Centre Muraz: collaborator
• Kamuzu University of Health Sciences: collaborator
• Tropical Diseases Research Centre, Zambia: collaborator
• Institute of Tropical Medicine(KIT), Amsterdam: collaborator
• Liverpool School of Tropical Medicine: collaborator

Study Sites (7)

ISSR/Centre Muraz

Nanoro, Burkina Faso

Location

ISSR/Centre Muraz

Nazoanga, Burkina Faso

Location

Kwame Nkrumah University of Science & Technology, Kumasi

Ejisu Sekyere East, Ashanti Region, Ghana

Location

Kwame Nrumah University of Science and Technology, Kumasi

Juaben Government Hospital, Ashanti Region, Ghana

Location

Effiduase Government Hospital

Effiduase, Ghana

Location

College of Medicine, University of Malawi

Chikwawa District Hospital, Blantyre, Malawi

Location

St Paul Hospital

Nchelenge, Nchelenge District, Zambia

Location

Related Publications (6)

• PREGACT Study Group; Pekyi D, Ampromfi AA, Tinto H, Traore-Coulibaly M, Tahita MC, Valea I, Mwapasa V, Kalilani-Phiri L, Kalanda G, Madanitsa M, Ravinetto R, Mutabingwa T, Gbekor P, Tagbor H, Antwi G, Menten J, De Crop M, Claeys Y, Schurmans C, Van Overmeir C, Thriemer K, Van Geertruyden JP, D'Alessandro U, Nambozi M, Mulenga M, Hachizovu S, Kabuya JB, Mulenga J. Four Artemisinin-Based Treatments in African Pregnant Women with Malaria. N Engl J Med. 2016 Mar 10;374(10):913-27. doi: 10.1056/NEJMoa1508606.

  PMID: 26962727 RESULT

• Patson N, Mukaka M, D'Alessandro U, Chapotera G, Mwapasa V, Mathanga D, Kazembe L, Laufer MK, Chirwa T. Joint modelling of multivariate longitudinal clinical laboratory safety outcomes, concomitant medication and clinical adverse events: application to artemisinin-based treatment during pregnancy clinical trial. BMC Med Res Methodol. 2021 Oct 9;21(1):208. doi: 10.1186/s12874-021-01412-9.

  PMID: 34627141 DERIVED

• Nambozi M, Tinto H, Mwapasa V, Tagbor H, Kabuya JB, Hachizovu S, Traore M, Valea I, Tahita MC, Ampofo G, Buyze J, Ravinetto R, Arango D, Thriemer K, Mulenga M, van Geertruyden JP, D'Alessandro U. Artemisinin-based combination therapy during pregnancy: outcome of pregnancy and infant mortality: a cohort study. Malar J. 2019 Mar 28;18(1):105. doi: 10.1186/s12936-019-2737-7.

  PMID: 30922317 DERIVED

• PREGACT Study Group; Pekyi D, Ampromfi AA, Tinto H, Traore-Coulibaly M, Tahita MC, Valea I, Mwapasa V, Kalilani-Phiri L, Kalanda G, Madanitsa M, Ravinetto R, Mutabingwa T, Gbekor P, Tagbor H, Antwi G, Menten J, De Crop M, Claeys Y, Schurmans C, Van Overmeir C, Thriemer K, Van Geertruyden JP, D'Alessandro U, Nambozi M, Mulenga M, Hachizovu S, Kabuya JB, Mulenga J. Four artemisinin-based treatments in African pregnant women with malaria. Malawi Med J. 2016 Sep;28(3):139-149.

  PMID: 27895848 DERIVED

• Tahita MC, Tinto H, Yarga S, Kazienga A, Traore Coulibaly M, Valea I, Van Overmeir C, Rosanas-Urgell A, Ouedraogo JB, Guiguemde RT, van Geertruyden JP, Erhart A, D'Alessandro U. Ex vivo anti-malarial drug susceptibility of Plasmodium falciparum isolates from pregnant women in an area of highly seasonal transmission in Burkina Faso. Malar J. 2015 Jun 20;14:251. doi: 10.1186/s12936-015-0769-1.

  PMID: 26088768 DERIVED

• Nambozi M, Mulenga M, Halidou T, Tagbor H, Mwapasa V, Phiri LK, Kalanda G, Valea I, Traore M, Mwakazanga D, Claeys Y, Schurmans C, De Crop M, Menten J, Ravinetto R, Thriemer K, Van Geertruyden JP, Mutabingwa T, D'Alessandro U; Pregact Group. Safe and efficacious artemisinin-based combination treatments for African pregnant women with malaria: a multicentre randomized control trial. Reprod Health. 2015 Jan 15;12:5. doi: 10.1186/1742-4755-12-5.

  PMID: 25592254 DERIVED

MeSH Terms

Interventions

amodiaquine, artesunate drug combination; Artemether, Lumefantrine Drug Combination

Intervention Hierarchy (Ancestors)

Artemether; Artemisinins; Reactive Oxygen Species; Free Radicals; Inorganic Chemicals; Organic Chemicals; Lumefantrine; Fluorenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sesquiterpenes; Terpenes; Polycyclic Compounds; Drug Combinations; Pharmaceutical Preparations

Study Officials

• Umberto D'Alessandro, MD

  Institute Tropical Medicine Belgium and MRC Unit in The Gambia

  STUDY CHAIR

• Tinto Halidou, PharmD

  Centre Muraz

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 26, 2009
• First Posted: February 27, 2009
• Study Start: June 1, 2010
• Primary Completion: October 1, 2013
• Study Completion: April 1, 2015
• Last Updated: March 14, 2016

Record last verified: 2016-03

Locations

GH (3); BU (2); MA (1); ZA (1)