Improving Maternal heAlth by Reducing Malaria in African HIV Women (MAMAH)

Evaluation of the Safety and Efficacy of Dihydroartemisinin-piperaquine for Intermittent Preventive Treatment of Malaria in HIV-infected Pregnant Women

Trial to evaluate the safety and efficacy of DHA-PPQ for Intermittent Preventive Treatment (IPTp) in HIV-infected pregnant women receiving cotrimoxazole prophylaxis (CTXp) and antiretroviral (ARV) drugs and using long lasting insecticide treated nets will be conducted in Mozambique and Gabon where malaria and HIV infection are moderate to highly prevalent. In addition, the possibility for a PK interaction between DHA-PPQ and ARV drugs will be assessed in a sub-sample of participants. Women will receive ARV therapy according to national guidelines and their infants will be followed until one year of age to evaluate the impact of DHA-PPQ on MTCT-HIV.

Study Overview

• Status: Completed
• Conditions: HIV/AIDS; Pregnancy Related; Malaria
• Intervention / Treatment: Drug: Dihydroartemisinin-piperaquine (DHA-PPQ); Drug: Placebo Oral Tablet

Detailed Description

Background

Intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) is recommended for malaria prevention in HIV-uninfected women but it is contraindicated in those HIV-infected on cotrimoxazole prophylaxis (CTXp) due to potential adverse effects. A recent trial showed that an effective antimalarial added to CTXp and long-lasting insecticide treated nets (LLITNs) in HIV-infected pregnant women improves malaria prevention and maternal health. However, the antimalarial used -mefloquine- was not well tolerated and it was associated with an increase in HIV viral load at delivery and a two-fold increased risk of MTCT-HIV. These findings highlight the need to find alternative drugs with better tolerability and safety profile to prevent malaria in this vulnerable group and to further study the pharmacological interactions between antimalarials and antiretrovirals (ARVs).

Dihydroartemisinin-piperaquine (DHA-PPQ), because of its long half-life and good tolerability has been shown to improve antimalarial protection in HIV-uninfected pregnant women, constituting the most promising candidate for IPTp in HIV-infected pregnant women. However, there is limited information on the pharmacokinetics of DHA-PPQ with concomitant use of ARV drugs and CTX, particularly in pregnant women.

Objectives

1. To evaluate the safety, tolerability and efficacy of DHA-PPQ as IPTp for malaria prevention in HIV-infected pregnant women receiving daily CTXp and ARV drugs
2. To assess the effect of DHA-PPQ as IPTp on mother to child transmission of HIV
3. To study the effects of DHA-PPQ on the pharmacokinetics of clinically relevant doses of ARV drugs used for prevention of MTCT and treatment of HIV infection
4. To evaluate the effectiveness of CTXp in clearing malaria parasites in HIV-infected pregnant women

Methods

The trial has been designed as a randomized double blind placebo-controlled superiority trial to evaluate the safety and efficacy of DHA-PPQ as IPTp in HIV-infected pregnant women taking daily CTXp and ARV drugs. The trial sites are located in Central and South Eastern sub-Saharan Africa (Gabon and Mozambique), where HIV prevalence among pregnant women ranges from 6 to 29%.

Based on previous estimations at the study sites and assuming a prevalence of peripheral parasitaemia at delivery of 7.5% with CTXp, it is estimated that 298 women per arm will be required to detect with 80% power a significant (p<0.05) decrease of 5% or more in the prevalence of peripheral parasitaemia in the CTXp+IPTp-DHA-PPQ group. In order to allow for 10% losses to follow up, it is calculated that 332 women/study arm will need to be recruited (total n=664). Furthermore, assuming a 5% MTCT-HIV in the control group, this sample size will have an 80% power to detect at the 5% level of significance, 2.2 times difference in the risk of MTCT-HIV.

The trial will have two study arms; HIV-infected pregnant women participating in the trial will be randomized to receive either:

1. Monthly doses of IPTp-DHA-PPQ over three days plus daily ARVs and cotrimoxazole prophylaxis
2. Monthly doses of IPTp-placebo over three days plus daily ARVs and cotrimoxazole prophylaxis

Women will receive ARV therapy according to national guidelines and their infants will be followed until one year of age to evaluate the impact of DHA-PPQ on MTCT-HIV.

Participants will be asked to visit the ANC monthly and to deliver at the study health facilities. Adherence to CTX prophylaxis and ARV therapy, as well as use of the LLITNs use will be assessed monthly at the scheduled antenatal care (ANC) clinic visits.

Pharmacokinetic (PK) sub-study The possibility for a PK interaction between DHA-PPQ and ARV drugs will be assessed in a sub-sample of participants (n=200).

• Study Type: Interventional
• Enrollment (Actual): 666
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Raquel Gonzalez, MD, PhD; Phone Number: 4144 +34932275400; Email: raquel.gonzalez@isglobal.org
• Study Contact Backup: Name: Mireia Piqueras, PhD; Phone Number: 4141 +34932275400; Email: mireia.piqueras@isglobal.org

Study Locations

• Gabon
  • Lambaréné, Gabon
    • Centre de Recherches Médicales de Lambaréné (CERMEL)
• Mozambique
  • Manhiça, Mozambique
    • Centro de Investigação em Saúde de Manhiça (CISM)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

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

Exclusion Criteria:

• Residence outside the study area or planning to move out in the following 10 months from enrolment
• Gestational age at the first antenatal visit > 28 weeks of pregnancy
• Known history of allergy to CTX
• Known history of allergy or contraindications to DHA-PPQ
• Participating in other intervention studies

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IPTp-DHA-PPQ; Monthly IPTp-DHA-PPQ over three days plus daily ARVs and cotrimoxazole prophylaxis	Drug: Dihydroartemisinin-piperaquine (DHA-PPQ); Following physical examination, recruited women with more than 13 weeks of gestational age will receive IPTp-DHA-PPQ under supervision
Placebo Comparator: IPTp-Placebo; Monthly IPTp-placebo over three days plus daily ARVs and cotrimoxazole prophylaxis	Drug: Placebo Oral Tablet; Following physical examination, recruited women with more than 13 weeks of gestational age will receive IPTp-Placebo under supervision

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maternal parasitaemia at delivery	Presence of Plasmodium falciparum (P. falciparum) asexual parasites of any density in peripheral blood (determined by microscopy)	Delivery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of clinical malaria		On average six months follow up during pregnancy
Incidence of all-cause admissions		On average six months follow up during pregnancy
Incidence of all-cause outpatient attendances		On average six months follow up during pregnancy
Frequency and severity of adverse events		On average six months follow up during pregnancy
Mean haemoglobin concentration		At delivery
Prevalence of submicroscopic P. falciparum peripheral parasitaemia		At delivery
Prevalence of anaemia (Hb<11 g/dL)		At delivery
Prevalence of severe anaemia (Hb<7 g/dL)		At delivery
Mean CD4+ T cell counts levels		At delivery
Proportion of women with detectable HIV viral load		At delivery
Prevalence of placental P. falciparum infection		At delivery
Prevalence of P. falciparum peripheral parasitaemia at the post-partum visit		On average 42 days after end of pregnancy (post-partum visit)
Maternal mortality rate		On average six months follow up during pregnancy and 42 days after end of pregnancy (post-partum visit)
Prevalence of P. falciparum parasitaemia in cord blood		At birth
Prevalence of neonatal anaemia		Neonatal period ( in first 28 days of life)
Mean birth weight		At birth
Prevalence of low birth weight (<2500 g)		At birth
Mean gestational age at birth		At birth
Prevalence of prematurity		At birth
Prevalence of embryo and foetal losses		On average six months follow up during pregnancy
Prevalence of small for gestational age		At birth
Frequency of congenital malformations		At birth
Incidence of clinical malaria		During first year of life
Neonatal mortality rate		During neonatal period (during first 28 days of life)
Frequency of mother to child transmission of HIV at one and at 12 months of age		During first year of life
Infant mortality rate		During first year of life
Composite malaria outcome: proportion of participants with malaria infection diagnosed	Any malaria confirmed infection during follow up, delivery and post-partum period (blood smear, malaria PCR, placental infection)	From enrolment until one month after end of pregnancy (on average seven months of study follow up of women, depending on gestational age at inclusion)
Composite maternal malaria and anemia: proportion of particiapnts diganosed either with malaria or anemia		At delivery
Composite adverse pregnancy outcome	LBW, miscarriage, stillbirth, prematurity	Birth

Collaborators and Investigators

• Sponsor: Barcelona Institute for Global Health
• Collaborators: Medical University of Vienna; Centro de Investigação em Saúde de Manhiça; Centre de Recherche Médicale de Lambaréné; Medicines for Malaria Venture; Bernhard Nocht Institute for Tropical Medicine; Universität Tübingen
• Investigators: Study Director: Clara Menendez, MD, PhD, Barcelona Institute for Global Health

Publications and helpful links

General Publications

• Gonzalez R, Nhampossa T, Mombo-Ngoma G, Mischlinger J, Esen M, Tchouatieu AM, Pons-Duran C, Dimessa LB, Lell B, Lagler H, Garcia-Otero L, Zoleko Manego R, El Gaaloul M, Sanz S, Piqueras M, Sevene E, Ramharter M, Saute F, Menendez C. Evaluation of the safety and efficacy of dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria in HIV-infected pregnant women: protocol of a multicentre, two-arm, randomised, placebo-controlled, superiority clinical trial (MAMAH project). BMJ Open. 2021 Nov 23;11(11):e053197. doi: 10.1136/bmjopen-2021-053197.

Helpful Links

• EDCTP web page with basic information on the project
• Project webpage

Study record dates

Study Major Dates

• Study Start (Actual): September 18, 2019
• Primary Completion (Actual): July 19, 2022
• Study Completion (Actual): June 19, 2023

Study Registration Dates

• First Submitted: September 6, 2018
• First Submitted That Met QC Criteria: September 13, 2018
• First Posted (Actual): September 14, 2018

Study Record Updates

• Last Update Posted (Actual): July 19, 2023
• Last Update Submitted That Met QC Criteria: July 18, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Treatment; HIV; Pregnancy; Malaria; Prevention; Dihydroartemisinin-piperaquine
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Piperaquine; Artenimol
• Other Study ID Numbers: EDCTP- RIA2016MC-1613

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

The main findings of the clinical trial will be submitted for publication in a peer reviewed journal within 12 months of study completion through an open access mechanism, or otherwise made available publicly in compliance with H2020 open access requirements.

Primary project raw data will be published in the project website. This approach is taken to protect in particular the interests of the endemic country researchers and institutions and in acknowledgment of the primary research oversight by endemic country ethics review boards. At no stage will data containing personal information of research participants be released.

• IPD Sharing Time Frame: Project metadata will be made available in formal reports to key stakeholders as soon as possible and to the wider public within 12 months after the end of the project. The announcement of the availability of the project metadata will be posted in the project website.
• IPD Sharing Access Criteria: Open Access
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No