Clinical trial NCT00852423: Safe and Efficacious Artemisinin-based Combination Treatments for African Pregnant Women With Malaria
Official title: Safe and Efficacious Artemisinin-based Combination Treatments for African Pregnant Women With Malaria
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Malaria in Pregnancy
Keywords: Malaria in pregnancy
Sub-saharan Africa
Treatment
Artemisinin containing Therapy
Efficacy
Safety
Lead sponsor: Institute of Tropical Medicine, Belgium
Sponsor class: OTHER
Collaborators: name: National Institute for Medical Research, Tanzania
name: Kwame Nkrumah University of Science and Technology
name: Centre Muraz
name: Kamuzu University of Health Sciences
name: Tropical Diseases Research Centre, Zambia
name: Institute of Tropical Medicine(KIT), Amsterdam
name: Liverpool School of Tropical Medicine
First posted: 2009-02-27
Enrollment: 3428
Sex: FEMALE
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.)

Primary outcomes:
measure: Treatment Failure (PCR adjusted)
timeFrame: Day 63
measure: Safety profiles including significant changes in relevant laboratory values
timeFrame: Until delivery
Secondary outcomes:
measure: Time to failure
timeFrame: Case by case
measure: PCR unadjusted treatment failure
timeFrame: Day 63
measure: Gametocyte carriage (gametocyte-weeks)
timeFrame: Case by case
measure: Asexual parasite clearance time
timeFrame: Days to 2 consecutive negative blood slides.
measure: Gametocytaemia (prevalence and density)
timeFrame: Day 7, 14, 21, 28 and 63 after treatment
measure: Haemoglobin changes
timeFrame: Days 14, 28, 42 and 63
measure: The presence of acute, chronic or past infection of the placenta (prevalence)
timeFrame: Delivery
measure: Mean birth weight and prevalence of low birth weight newborns
timeFrame: Delivery
measure: In vitro vitro and search of molecular markers related to drug resistance
timeFrame: At the time of recurrent infection
measure: Determination of the PK profile of MQ, AQ and PQ (on 120 women/treatment)
timeFrame: Case by case
Other outcomes:
Locations:
city: Nanoro
country: Burkina Faso
facility: ISSR/Centre Muraz
city: Nazoanga
country: Burkina Faso
facility: ISSR/Centre Muraz
city: Ejisu Sekyere East
country: Ghana
facility: Kwame Nkrumah University of Science & Technology, Kumasi
state: Ashanti Region
city: Juaben Government Hospital
country: Ghana
facility: Kwame Nrumah University of Science and Technology, Kumasi
state: Ashanti Region
city: Effiduase
country: Ghana
facility: Effiduase Government Hospital
city: Chikwawa District Hospital
country: Malawi
facility: College of Medicine, University of Malawi
state: Blantyre
city: Nchelenge
country: Zambia
facility: St Paul Hospital
state: Nchelenge District
Study officials:
affiliation: Institute Tropical Medicine Belgium and MRC Unit in The Gambia
name: Umberto D'Alessandro, MD
role: STUDY_CHAIR
affiliation: Centre Muraz
name: Tinto Halidou, PharmD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.