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

• Treatment Failure (PCR adjusted) [ Time Frame: Day 63 ] [ Designated as safety issue: No ]
• Safety profiles including significant changes in relevant laboratory values [ Time Frame: Until delivery ] [ Designated as safety issue: Yes ]

• Treatment Failure(PCR adjusted) [ Time Frame: Day 28 ] [ Designated as safety issue: No ]
• Safety profiles including significant changes in relevant laboratory values [ Time Frame: One year after delivery ] [ Designated as safety issue: Yes ]

• Time to failure [ Time Frame: Case by case ] [ Designated as safety issue: No ]
• PCR unadjusted treatment failure [ Time Frame: Day 63 ] [ Designated as safety issue: No ]
• Gametocyte carriage (gametocyte-weeks) [ Time Frame: Case by case ] [ Designated as safety issue: No ]
• Asexual parasite clearance time [ Time Frame: Days to 2 consecutive negative blood slides. ] [ Designated as safety issue: No ]
• Gametocytaemia (prevalence and density) [ Time Frame: Day 7, 14, 21, 28 and 63 after treatment ] [ Designated as safety issue: No ]
• Haemoglobin changes [ Time Frame: Days 14, 28, 42 and 63 ] [ Designated as safety issue: Yes ]
• The presence of acute, chronic or past infection of the placenta (prevalence) [ Time Frame: Delivery ] [ Designated as safety issue: Yes ]
• Mean birth weight and prevalence of low birth weight newborns [ Time Frame: Delivery ] [ Designated as safety issue: Yes ]
• In vitro vitro and search of molecular markers related to drug resistance [ Time Frame: At the time of recurrent infection ] [ Designated as safety issue: Yes ]
• Determination of the PK profile of MQ, AQ and PQ (on 120 women/treatment) [ Time Frame: Case by case ] [ Designated as safety issue: No ]

• PCR unadjusted treatment failure [ Time Frame: Day 28 ] [ Designated as safety issue: No ]
• PCR unadjusted treatment failure [ Time Frame: Day 63 ] [ Designated as safety issue: No ]
• PCR Adjusted treatment failure [ Time Frame: Day 63 ] [ Designated as safety issue: No ]
• Asexual parasite clearance time [ Time Frame: Days to 2 consecutive negative blood slides. ] [ Designated as safety issue: No ]
• Gametocytaemia (prevalence and density) [ Time Frame: Day 7, 14, 21, 28 and 63 after treatment ] [ Designated as safety issue: No ]
• Haemoglobin changes [ Time Frame: Days 7, 14 and 28 and 63 ] [ Designated as safety issue: Yes ]
• The presence of acute, chronic or past infection of the placenta (prevalence) [ Time Frame: Delivery ] [ Designated as safety issue: Yes ]
• Mean birth weight and prevalence of low birth weight newborns [ Time Frame: Delivery ] [ Designated as safety issue: Yes ]

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.

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.

• Drug: 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.
  Other Name: DHAPQ, Eurartesim
• 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
  Other Name: MQAS
• 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.
  Other Name: AQAS, artesunate-amodiaquine Winthrop®
• 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.
  Other Name: AL, Coartem, Riamet

• Experimental: DHAPQ
  Three-day treatment with dihydroartemisinin-piperaquine
  Intervention: Drug: Dihydroartemisinin-piperaquine
• Experimental: MQAS
  Three-day treatment with mefloquine artesunate
  Intervention: Drug: Artesunate-mefloquine
• Active Comparator: AQAS
  Three-day treatment with artesunate-amodiaquine
  Intervention: Drug: Artesunate-amodiaquine
• Active Comparator: AL
  Three day treatment with artemether-lumefantrine (Coartem(R)
  Intervention: Drug: Artemether-lumefantrine

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.)

• National Institute for Medical Research, Tanzania
• Kwame Nkrumah University of Science and Technology
• Centre Muraz
• University of Malawi College of Medicine
• Tropical Diseases Research Centre, Zambia
• Institute of Tropical Medicine(KIT), Amsterdam
• Liverpool School of Tropical Medicine