Improving Maternal heAlth by Reducing Malaria in African HIV Women

Malaria Clinical Trial

— MAMAH  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03671109
• Other study ID #: EDCTP- RIA2016MC-1613
• Status: Completed
• Phase: Phase 3
• Start date: September 18, 2019
• Est. completion date: June 19, 2023

Study information

• Verified date: July 2023
• Source: Barcelona Institute for Global Health
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 666
• Est. completion date: June 19, 2023
• Est. primary completion date: July 19, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: N/A and older

Eligibility

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

Related Conditions & MeSH terms

• HIV/AIDS
• Malaria
• Pregnancy Related

Intervention

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 Oral Tablet
Following physical examination, recruited women with more than 13 weeks of gestational age will receive IPTp-Placebo under supervision

Locations

Country	Name	City	State
Gabon	Centre de Recherches Médicales de Lambaréné (CERMEL)	Lambaréné
Mozambique	Centro de Investigação em Saúde de Manhiça (CISM)	Manhiça

Sponsors (7)

Lead Sponsor	Collaborator
Barcelona Institute for Global Health	Bernhard Nocht Institute for Tropical Medicine, Centre de Recherche Médicale de Lambaréné, Centro de Investigação em Saúde de Manhiça, Medical University of Vienna, Medicines for Malaria Venture, Universität Tübingen

Countries where clinical trial is conducted

Gabon,  Mozambique, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maternal parasitaemia at delivery	Presence of Plasmodium falciparum (P. falciparum) asexual parasites of any density in peripheral blood (determined by microscopy)	Delivery
Secondary	Incidence of clinical malaria		On average six months follow up during pregnancy
Secondary	Incidence of all-cause admissions		On average six months follow up during pregnancy
Secondary	Incidence of all-cause outpatient attendances		On average six months follow up during pregnancy
Secondary	Frequency and severity of adverse events		On average six months follow up during pregnancy
Secondary	Mean haemoglobin concentration		At delivery
Secondary	Prevalence of submicroscopic P. falciparum peripheral parasitaemia		At delivery
Secondary	Prevalence of anaemia (Hb<11 g/dL)		At delivery
Secondary	Prevalence of severe anaemia (Hb<7 g/dL)		At delivery
Secondary	Mean CD4+ T cell counts levels		At delivery
Secondary	Proportion of women with detectable HIV viral load		At delivery
Secondary	Prevalence of placental P. falciparum infection		At delivery
Secondary	Prevalence of P. falciparum peripheral parasitaemia at the post-partum visit		On average 42 days after end of pregnancy (post-partum visit)
Secondary	Maternal mortality rate		On average six months follow up during pregnancy and 42 days after end of pregnancy (post-partum visit)
Secondary	Prevalence of P. falciparum parasitaemia in cord blood		At birth
Secondary	Prevalence of neonatal anaemia		Neonatal period ( in first 28 days of life)
Secondary	Mean birth weight		At birth
Secondary	Prevalence of low birth weight (<2500 g)		At birth
Secondary	Mean gestational age at birth		At birth
Secondary	Prevalence of prematurity		At birth
Secondary	Prevalence of embryo and foetal losses		On average six months follow up during pregnancy
Secondary	Prevalence of small for gestational age		At birth
Secondary	Frequency of congenital malformations		At birth
Secondary	Incidence of clinical malaria		During first year of life
Secondary	Neonatal mortality rate		During neonatal period (during first 28 days of life)
Secondary	Frequency of mother to child transmission of HIV at one and at 12 months of age		During first year of life
Secondary	Infant mortality rate		During first year of life
Secondary	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)
Secondary	Composite maternal malaria and anemia: proportion of particiapnts diganosed either with malaria or anemia		At delivery
Secondary	Composite adverse pregnancy outcome	LBW, miscarriage, stillbirth, prematurity	Birth

External Links

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