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

NCT ID: NCT00852423

Last Updated: 2016-03-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 3428 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-06-30
• Study Completion Date: 2015-04-30

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.

Detailed Description

Malaria is the most important human parasitic disease. Although pregnant women are a high-risk group, they are almost systematically excluded from clinical trials, for fear of teratogenicity and embryotoxicity; thus, we generally lack sufficient information on the safety and efficacy of most antimalarials in pregnancy, as well as evidence-based recommendations for the prevention and treatment of malaria during pregnancy.

The WHO recommendation to use artemisinin combination therapy (ACT) in the 2nd and 3rd trimester is already implemented in several African countries. However, the documentation of their efficacy and safety in pregnancy is still limited, especially concerning the African contexts.

Therefore, we propose to test 4 fixed-dose combinations (artemether-lumefantrine, amodiaquine-artesunate, mefloquine-artesunate and dihydroartemisinin-piperaquine), to evaluate their efficacy and safety when administered to pregnant women (2nd and 3rd trimester) infected with P. falciparum. Explanatory variables will be collected for treatment failure (PCR-corrected) and for recurrent parasitaemia. The primary hypothesis tested will be the clinical equivalence (pair-wise non-inferiority) of the 4 treatment regimens with clinical equivalence defined as difference in treatment failure rates (PCR corrected) of 5% or less.

In addition, an attempt will be done to carry out in vitro testing at the time of recurrent infection. However, the success of the test will depend on the parasite density. In addition, blood samples collected on filter paper at day 0 and at day of recurrent parasitaemia will be genotyped for the search of known molecular markers related to drug resistance. Not all samples will be analyzed; rather these will be selected according to the therapeutic response so that the prevalence of molecular markers will be compared between treatment successes, true treatment failures and new infections.

Conditions

Malaria in Pregnancy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

DHAPQ

Three-day treatment with dihydroartemisinin-piperaquine

Group Type: EXPERIMENTAL

Dihydroartemisinin-piperaquine

Intervention Type: 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.

MQAS

Three-day treatment with mefloquine artesunate

Group Type: EXPERIMENTAL

Artesunate-mefloquine

Intervention Type: 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

AQAS

Three-day treatment with artesunate-amodiaquine

Group Type: ACTIVE_COMPARATOR

Artesunate-amodiaquine

Intervention Type: 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.

AL

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

Group Type: ACTIVE_COMPARATOR

Artemether-lumefantrine

Intervention Type: 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.

Interventions

Dihydroartemisinin-piperaquine

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.

Intervention Type: DRUG

Artesunate-mefloquine

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

Intervention Type: DRUG

Artesunate-amodiaquine

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.

Intervention Type: DRUG

Artemether-lumefantrine

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.

Intervention Type: DRUG

Other Intervention Names

DHAPQ, Eurartesim; MQAS; AQAS, artesunate-amodiaquine Winthrop®; AL, Coartem, Riamet

Eligibility Criteria

Inclusion Criteria

• 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").

Exclusion Criteria

• 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.)

• Minimum Eligible Age: 15 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

National Institute for Medical Research, Tanzania

OTHER_GOV

Sponsor Role: collaborator

Kwame Nkrumah University of Science and Technology

OTHER

Sponsor Role: collaborator

Centre Muraz

OTHER

Sponsor Role: collaborator

Kamuzu University of Health Sciences

OTHER

Sponsor Role: collaborator

Tropical Diseases Research Centre, Zambia

OTHER_GOV

Sponsor Role: collaborator

Institute of Tropical Medicine(KIT), Amsterdam

UNKNOWN

Sponsor Role: collaborator

Liverpool School of Tropical Medicine

OTHER

Sponsor Role: collaborator

Institute of Tropical Medicine, Belgium

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Umberto D'Alessandro, MD

Role: STUDY_CHAIR

Institute Tropical Medicine Belgium and MRC Unit in The Gambia

Tinto Halidou, PharmD

Role: PRINCIPAL_INVESTIGATOR

Centre Muraz

Locations

ISSR/Centre Muraz

Nanoro, , Burkina Faso

ISSR/Centre Muraz

Nazoanga, , Burkina Faso

Kwame Nkrumah University of Science & Technology, Kumasi

Ejisu Sekyere East, Ashanti Region, Ghana

Kwame Nrumah University of Science and Technology, Kumasi

Juaben Government Hospital, Ashanti Region, Ghana

Effiduase Government Hospital

Effiduase, , Ghana

College of Medicine, University of Malawi

Chikwawa District Hospital, Blantyre, Malawi

St Paul Hospital

Nchelenge, Nchelenge District, Zambia

Countries

Burkina Faso; Ghana; Malawi; Zambia

References

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.

Reference Type: RESULT

PMID: 26962727 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34627141 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 30922317 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 27895848 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 26088768 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 25592254 (View on PubMed)

Other Identifiers

ITMP0308

Identifier Type: -

Identifier Source: org_study_id