Clinical trial NCT03671109: Improving Maternal heAlth by Reducing Malaria in African HIV Women
Official title: Evaluation of the Safety and Efficacy of Dihydroartemisinin-piperaquine for Intermittent Preventive Treatment of Malaria in HIV-infected Pregnant Women
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Malaria
HIV/AIDS
Pregnancy Related
Keywords: Malaria
Dihydroartemisinin-piperaquine
HIV
Pregnancy
Treatment
Prevention
Lead sponsor: Barcelona Institute for Global Health
Sponsor class: OTHER
Collaborators: name: Medicines for Malaria Venture
name: Universität Tübingen
name: Centre de Recherche Médicale de Lambaréné
name: Medical University of Vienna
name: Bernhard Nocht Institute for Tropical Medicine
name: Centro de Investigação em Saúde de Manhiça
First posted: 2018-09-14
Enrollment: 666
Sex: FEMALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Superiority clinical trial
Primary purpose: PREVENTION

Brief 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.

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).

Eligibility criteria: 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

Primary outcomes:
measure: Maternal parasitaemia at delivery
timeFrame: Delivery
Secondary outcomes:
measure: Incidence of clinical malaria
timeFrame: On average six months follow up during pregnancy
measure: Incidence of all-cause admissions
timeFrame: On average six months follow up during pregnancy
measure: Incidence of all-cause outpatient attendances
timeFrame: On average six months follow up during pregnancy
measure: Frequency and severity of adverse events
timeFrame: On average six months follow up during pregnancy
measure: Mean haemoglobin concentration
timeFrame: At delivery
measure: Prevalence of submicroscopic P. falciparum peripheral parasitaemia
timeFrame: At delivery
measure: Prevalence of anaemia (Hb<11 g/dL)
timeFrame: At delivery
measure: Prevalence of severe anaemia (Hb<7 g/dL)
timeFrame: At delivery
measure: Mean CD4+ T cell counts levels
timeFrame: At delivery
measure: Proportion of women with detectable HIV viral load
timeFrame: At delivery
measure: Prevalence of placental P. falciparum infection
timeFrame: At delivery
measure: Prevalence of P. falciparum peripheral parasitaemia at the post-partum visit
timeFrame: On average 42 days after end of pregnancy (post-partum visit)
measure: Maternal mortality rate
timeFrame: On average six months follow up during pregnancy and 42 days after end of pregnancy (post-partum visit)
measure: Prevalence of P. falciparum parasitaemia in cord blood
timeFrame: At birth
measure: Prevalence of neonatal anaemia
timeFrame: Neonatal period ( in first 28 days of life)
measure: Mean birth weight
timeFrame: At birth
measure: Prevalence of low birth weight (<2500 g)
timeFrame: At birth
measure: Mean gestational age at birth
timeFrame: At birth
measure: Prevalence of prematurity
timeFrame: At birth
measure: Prevalence of embryo and foetal losses
timeFrame: On average six months follow up during pregnancy
measure: Prevalence of small for gestational age
timeFrame: At birth
measure: Frequency of congenital malformations
timeFrame: At birth
measure: Incidence of clinical malaria
timeFrame: During first year of life
measure: Neonatal mortality rate
timeFrame: During neonatal period (during first 28 days of life)
measure: Frequency of mother to child transmission of HIV at one and at 12 months of age
timeFrame: During first year of life
measure: Infant mortality rate
timeFrame: During first year of life
measure: Composite malaria outcome: proportion of participants with malaria infection diagnosed
timeFrame: 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)
measure: Composite maternal malaria and anemia: proportion of particiapnts diganosed either with malaria or anemia
timeFrame: At delivery
measure: Composite adverse pregnancy outcome
timeFrame: Birth
Other outcomes:
Locations:
city: Lambaréné
country: Gabon
facility: Centre de Recherches Médicales de Lambaréné (CERMEL)
city: Manhiça
country: Mozambique
facility: Centro de Investigação em Saúde de Manhiça (CISM)
Study officials:
affiliation: Barcelona Institute for Global Health
name: Clara Menendez, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Gonzalez R, Nhampossa T, Mombo-Ngoma G, Mischlinger J, Esen M, Tchouatieu AM, Mendes A, Figueroa-Romero A, Zoleko-Manego R, Lell B, Lagler H, Stoeger L, Dimessa LB, El Gaaloul M, Sanz S, Mendez S, Piqueras M, Sevene E, Ramharter M, Saute F, Menendez C; MAMAH study group. Safety and efficacy of dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria in pregnant women with HIV from Gabon and Mozambique: a randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2024 May;24(5):476-487. doi: 10.1016/S1473-3099(23)00738-7. Epub 2024 Jan 12.
citation: 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.