Evaluation of Alternative Antimalarial Drugs for Malaria in Pregnancy (MiPPAD)

• ClinicalTrials.gov Identifier: NCT00811421
• Recruitment Status: Completed
• First Posted: December 19, 2008
• Last Update Posted: March 20, 2014
• Sponsor: Hospital Clinic of Barcelona
• Collaborators: Barcelona Centre for International Health Research; Institute of Tropical Medicine, University of Tuebingen; Institut de Recherche pour le Developpement; Université d'Abomey-Calavi; Albert Schweitzer Hospital; Kenya Medical Research Institute; Ifakara Health Institute; Centro de Investigacao em Saude de Manhica; Vienna School of Clinical Research (VSCR), Austria.; Centers for Disease Control and Prevention; Malaria in Pregnancy Consortium
• Information provided by: Hospital Clinic of Barcelona

Study Description

Brief Summary:

The study aims at comparing the safety, tolerability and efficacy of Mefloquine (MQ) to Sulfadoxine-Pyrimethamine (SP) as Interment Preventive Treatment in pregnancy (IPTp) for the prevention of malaria effects on the mother and her infant.

Condition or disease	Intervention/treatment	Phase
Pregnancy; Malaria; HIV Infections	Drug: Sulphadoxine-pyrimethamine; Drug: Mefloquine (full dose); Drug: Mefloquine (split dose); Drug: placebo; Drug: mefloquine	Not Applicable

Detailed Description:

The current recommendation by the World Health Organization (WHO) to prevent malaria infection in pregnancy in areas of stable malaria transmission relies on:

• Prompt and effective case management of malaria illness
• The use of intermittent preventive treatment (IPTp) with at least 2 treatment doses of sulfadoxine-pyrimethamine (SP) and
• The use of insecticide treated nets (ITNs)

However, the spread of parasite resistance to SP, particularly in eastern Africa, and the significant overlap in some regions of malaria transmission and high prevalence of HIV infection, have raised concerns about the medium and long-term use of SP for IPTp.

HIV infection increases susceptibility to malaria and may reduce the efficacy of interventions. The evaluation of alternative antimalarials for IPTp is thus urgently needed also involving HIV infected women.

Of all the current available alternative antimalarial drugs, mefloquine (MQ) is the one that offers the most comparative advantages to SP.

A randomized multicenter trial will be conducted in 4 sites in Africa (Benin, Gabon, Tanzania and Mozambique) in order to compare the safety and efficacy of SP versus MQ as IPTp in the context of ITNs. In addition, MQ tolerability will be also evaluated by comparing the administration of MQ as a single intake with its administration as split dose in two days. In total 4716 pregnant women will be enrolled at the antenatal clinic (ANC) and will be followed until the infant is one year old.

Besides, in those countries where HIV prevalence in pregnant women is > 10%, MQ-IPTp will be compared to Placebo-IPTp in HIV infected pregnant women receiving cotrimoxazole (CTX) prophylaxis. This trial will be double blinded and will be carried out in Kenya, Tanzania and Mozambique. It will involve 1070 pregnant women that will be followed until the infant is 2 months old.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 5820 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Official Title: Evaluation of the Safety and Efficacy of Mefloquine as Intermittent Preventive Treatment of Malaria in Pregnancy
• Study Start Date: September 2009
• Actual Primary Completion Date: December 2012
• Actual Study Completion Date: December 2013

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Trial 1: IPTp-SP+LLITNs; HIV-negative pregnant women receiving 2 doses of IPTp (500mg of sulfadoxine and 25 mg of pyrimethamine) in the context of long lasting Insecticide Treated Nets (LLITNs)	Drug: Sulphadoxine-pyrimethamine; SP oral administration (500mg sulphadoxine and 25mg pyrimethamine) as IPTp at the 1st and 2nd Antenatal Clinic visit
Experimental: Trial 1: IPTp-MQ (full dose) + LLITNs; HIV-negative pregnant women receiving 2 full doses of IPTp (15 mg/Kg) in the context of long lasting Insecticide Treated Nets (LLITNs)	Drug: Mefloquine (full dose); MQ oral administration (15 mg/Kg) on 1 day at the 1st and 2nd Antenatal Clinic visit as IPTp
Experimental: Trial 1: IPTp-MQ (split dose)+LLITNs; HIV-negative pregnant women receiving 2 doses of MQ as IPTp split dose over 2 days (15mg/kg) in the context of long lasting Insecticide Treated Nets (LLITNs	Drug: Mefloquine (split dose); MQ oral administration (15 mg/kg) split dose over 2 days at the 1st and 2nd ANC visit as IPTp
Experimental: Trial 2: CTX+IPTp-Placebo+LLITNs; HIV-positive pregnant women receiving 3 doses of IPTp (placebo) in the context of long lasting Insecticide Treated Nets (LLITNs)	Drug: placebo; MQ-placebo oral administration at the 1st, 2nd and 3rd Antenatal Clinic visit as IPTp
Experimental: Trial 2: CTX + IPTp-MQ+ LLITNs; HIV-positive pregnant women receiving 3 doses of IPTp (15 mg/Kg) in the context of long lasting Insecticide Treated Nets (LLITNs)	Drug: mefloquine; MQ oral administration (15 mg/Kg) at the 1st and 2nd Antenatal Clinic visit as IPTp

Outcome Measures

Primary Outcome Measures :

1. Trial 1 (IPTp MQ vs IPTp SP): Low birth weight. [ Time Frame: day 0, birth ]
2. Trial 2 (CTX+IPTp MQ vs. CTX+IPTp placebo): Peripheral parasitaemia. [ Time Frame: day 0, delivery ]

Secondary Outcome Measures :

1. Trial 1: Prevalence of placental P. falciparum infection. Prevalence of moderate maternal anaemia at delivery. [ Time Frame: day 0, delivery ]
2. Trial 2: Prevalence of placental P. falciparum infection. Prevalence of low birth weight babies (< 2500 g). [ Time Frame: day 0, birth ]

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

Trial 1:

• Permanent resident in the area
• Gestational age at the first antenatal visit ≤ 28 weeks
• Signed informed consent
• Agreement to deliver in the study site's maternity(ies) wards

Trial 2:

• Permanent resident in the area.
• Gestational age at the first antenatal visit ≤ 28 weeks
• HIV seropositive (after voluntary counseling and testing)
• Indication to receive CTX prophylaxis (according to the national guidelines)
• Signed informed consent
• Agreement to deliver in the study site's maternity(ies) wards.

Exclusion Criteria:

Trial 1:

• Residence outside the study area or planning to move out in the following 18 months from enrollment
• Gestational age at the first antenatal visit > 28 weeks of pregnancy
• Known history of allergy to sulfa drugs or mefloquine
• Known history of severe renal, hepatic, psychiatric or neurological disease
• MQ or halofantrine treatment in the preceding 4 weeks
• HIV infection
• Participating in other studies

Trial 2:

• Residence outside the study area or planning to move out in the following 10 months from enrollment
• Gestational age at the first antenatal visit > 28 weeks of pregnancy
• Known history of allergy to CTX or MQ
• Known history of severe renal, hepatic, psychiatric or neurological disease
• MQ or halofantrine treatment in the preceding 4 weeks

Contacts and Locations

Locations

Benin

Faculté des Sciences de la Santé (FSS), Université d'Abomey Calavi

Allada, Benin

Gabon

Medical Rsearch Unit (MRU), Albert Schweitzer Hospital

Lambaréné, Gabon

Kenya

Kenya Medical Research Institute (KEMRI)/ CDC

Kisumu, Kenya

Mozambique

Centro de Investigaçao em Saúde da Manhiça (CISM)

Manhiça, Maputo, Mozambique

Tanzania

Ifakara Health Institute (IHI)

Dodoma, Tanzania

Sponsors and Collaborators

Hospital Clinic of Barcelona

Barcelona Centre for International Health Research

Institute of Tropical Medicine, University of Tuebingen

Institut de Recherche pour le Developpement

Université d'Abomey-Calavi

Albert Schweitzer Hospital

Kenya Medical Research Institute

Ifakara Health Institute

Centro de Investigacao em Saude de Manhica

Vienna School of Clinical Research (VSCR), Austria.

Centers for Disease Control and Prevention

Malaria in Pregnancy Consortium

Investigators

• Principal Investigator: Clara Menendez, MD, PhD; Barcelona Centre for International Health Research

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Mireku MO, Davidson LL, Zoumenou R, Massougbodji A, Cot M, Bodeau-Livinec F. Consequences of prenatal geophagy for maternal prenatal health, risk of childhood geophagy and child psychomotor development. Trop Med Int Health. 2018 Aug;23(8):841-849. doi: 10.1111/tmi.13088. Epub 2018 Jun 22.

Moya-Alvarez V, Ouédraogo S, Accrombessi M, Cot M. High folate levels are not associated with increased malaria risk but with reduced anaemia rates in the context of high-dosed folate supplements and intermittent preventive treatment against malaria in pregnancy with sulphadoxine-pyrimethamine in Benin. Trop Med Int Health. 2018 Jun;23(6):582-588. doi: 10.1111/tmi.13064. Epub 2018 May 21.

Ndam NT, Mbuba E, González R, Cisteró P, Kariuki S, Sevene E, Rupérez M, Fonseca AM, Vala A, Maculuve S, Jiménez A, Quintó L, Ouma P, Ramharter M, Aponte JJ, Nhacolo A, Massougbodji A, Briand V, Kremsner PG, Mombo-Ngoma G, Desai M, Macete E, Cot M, Menéndez C, Mayor A. Resisting and tolerating P. falciparum in pregnancy under different malaria transmission intensities. BMC Med. 2017 Jul 17;15(1):130. doi: 10.1186/s12916-017-0893-6.

González R, Rupérez M, Sevene E, Vala A, Maculuve S, Bulo H, Nhacolo A, Mayor A, Aponte JJ, Macete E, Menendez C. Effects of HIV infection on maternal and neonatal health in southern Mozambique: A prospective cohort study after a decade of antiretroviral drugs roll out. PLoS One. 2017 Jun 2;12(6):e0178134. doi: 10.1371/journal.pone.0178134. eCollection 2017.

Mireku MO, Davidson LL, Boivin MJ, Zoumenou R, Massougbodji A, Cot M, Bodeau-Livinec F. Prenatal Iron Deficiency, Neonatal Ferritin, and Infant Cognitive Function. Pediatrics. 2016 Dec;138(6). pii: e20161319. Epub 2016 Nov 17.

Mombo-Ngoma G, Mackanga JR, González R, Ouedraogo S, Kakolwa MA, Manego RZ, Basra A, Rupérez M, Cot M, Kabanywany AM, Matsiegui PB, Agnandji ST, Vala A, Massougbodji A, Abdulla S, Adegnika AA, Sevene E, Macete E, Yazdanbakhsh M, Kremsner PG, Aponte JJ, Menéndez C, Ramharter M. Young adolescent girls are at high risk for adverse pregnancy outcomes in sub-Saharan Africa: an observational multicountry study. BMJ Open. 2016 Jun 29;6(6):e011783. doi: 10.1136/bmjopen-2016-011783.

Bodeau-Livinec F, Glorennec P, Cot M, Dumas P, Durand S, Massougbodji A, Ayotte P, Le Bot B. Elevated Blood Lead Levels in Infants and Mothers in Benin and Potential Sources of Exposure. Int J Environ Res Public Health. 2016 Mar 11;13(3). pii: E316. doi: 10.3390/ijerph13030316.

Rupérez M, González R, Mombo-Ngoma G, Kabanywanyi AM, Sevene E, Ouédraogo S, Kakolwa MA, Vala A, Accrombessi M, Briand V, Aponte JJ, Manego Zoleko R, Adegnika AA, Cot M, Kremsner PG, Massougbodji A, Abdulla S, Ramharter M, Macete E, Menéndez C. Mortality, Morbidity, and Developmental Outcomes in Infants Born to Women Who Received Either Mefloquine or Sulfadoxine-Pyrimethamine as Intermittent Preventive Treatment of Malaria in Pregnancy: A Cohort Study. PLoS Med. 2016 Feb 23;13(2):e1001964. doi: 10.1371/journal.pmed.1001964. eCollection 2016 Feb.

Mireku MO, Davidson LL, Koura GK, Ouédraogo S, Boivin MJ, Xiong X, Accrombessi MM, Massougbodji A, Cot M, Bodeau-Livinec F. Prenatal Hemoglobin Levels and Early Cognitive and Motor Functions of One-Year-Old Children. Pediatrics. 2015 Jul;136(1):e76-83. doi: 10.1542/peds.2015-0491. Epub 2015 Jun 8.

Sicuri E, Fernandes S, Macete E, González R, Mombo-Ngoma G, Massougbodgi A, Abdulla S, Kuwawenaruwa A, Katana A, Desai M, Cot M, Ramharter M, Kremsner P, Slustker L, Aponte J, Hanson K, Menéndez C. Economic evaluation of an alternative drug to sulfadoxine-pyrimethamine as intermittent preventive treatment of malaria in pregnancy. PLoS One. 2015 Apr 27;10(4):e0125072. doi: 10.1371/journal.pone.0125072. eCollection 2015.

González R, Desai M, Macete E, Ouma P, Kakolwa MA, Abdulla S, Aponte JJ, Bulo H, Kabanywanyi AM, Katana A, Maculuve S, Mayor A, Nhacolo A, Otieno K, Pahlavan G, Rupérez M, Sevene E, Slutsker L, Vala A, Williamsom J, Menéndez C. Intermittent preventive treatment of malaria in pregnancy with mefloquine in HIV-infected women receiving cotrimoxazole prophylaxis: a multicenter randomized placebo-controlled trial. PLoS Med. 2014 Sep 23;11(9):e1001735. doi: 10.1371/journal.pmed.1001735. eCollection 2014 Sep.

González R, Mombo-Ngoma G, Ouédraogo S, Kakolwa MA, Abdulla S, Accrombessi M, Aponte JJ, Akerey-Diop D, Basra A, Briand V, Capan M, Cot M, Kabanywanyi AM, Kleine C, Kremsner PG, Macete E, Mackanga JR, Massougbodgi A, Mayor A, Nhacolo A, Pahlavan G, Ramharter M, Rupérez M, Sevene E, Vala A, Zoleko-Manego R, Menéndez C. Intermittent preventive treatment of malaria in pregnancy with mefloquine in HIV-negative women: a multicentre randomized controlled trial. PLoS Med. 2014 Sep 23;11(9):e1001733. doi: 10.1371/journal.pmed.1001733. eCollection 2014 Sep.

• Responsible Party: Professor Clara Menendez Santos, Barcelona Centre for International Health Research (CRESIB), Spain
• ClinicalTrials.gov Identifier: NCT00811421 History of Changes
• Other Study ID Numbers: IP.07.31080.002
• First Posted: December 19, 2008
• Last Update Posted: March 20, 2014
• Last Verified: March 2014

Keywords provided by Hospital Clinic of Barcelona:

Malaria; Pregnancy; HIV; Prevention; Malaria prevention

Additional relevant MeSH terms:

Malaria; Protozoan Infections; Parasitic Diseases; Pyrimethamine; Sulfadoxine; Fanasil, pyrimethamine drug combination; Mefloquine; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents; Anti-Infective Agents; Folic Acid Antagonists; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents, Urinary; Renal Agents