Improving maternal and infant health by reducing malaria risks in African women: evaluation of the safety and efficacy of dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria in HIV-infected pregnant women

Fundación Privada Instituto de Salud Global Barcelona (ISGlobal) with partners from Austria, Gabon, Germany, and Mozambique

Project Coordinator: Prof. Clara Menéndez Santos, ISGlobal, Spain
Starting date: 1 March 2018
Grant amount: EUR 2,985,000
Grant agreement: RIA2016MC-1613

Malaria infection during pregnancy is an important driver of maternal and neonatal health especially among HIV-infected women. In Africa, at least one million pregnancies are co-infected with malaria and HIV annually. The interaction between the two infections is particularly deleterious in pregnancy, leading to increased risk of malaria and HIV viral load, which may increase the frequency of mother to child transmission of HIV (MTCT-HIV). 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).

The project includes six work packages (WPs). Two of them (WP1 and WP6) relate to the Project Management and Communication, Advocacy and Exploitation activities, whereas WP2, and 3 comprise the main research tasks, and 4 and 5 will address Capacity Building and Networking actions. ISGlobal, as overall Project Coordinator leads the aforementioned WPs 1 and 6. WP4 is coordinated by Dr Ghyslain Mombo-Ngoma (CERMEL, Gabon) and will have the support of Dr Heimo Lagler (Medical University of Vienna, Austria).

The activities included in this work package will contribute to achieving the project objectives through collaboration between the European and African partners involved to develop the technical capacity and infrastructure required to carry out clinical trials for malaria control. Opportunities for capacity building will occur throughout the entire project in an integrated way. More specifically, this work package will:

Further information can be found on the MAMAH project webpage

Clinical evaluation of AntimalarialS tri-therapy with AtovAquone Proguanil for malaria treatment in African children (ASAAP)

Kwame Nkrumah University of Science and Technology (KNUST), Kumasi, Ghana with partners from Benin, Burkina Faso, France, Gabon, Germany, and Mali

Project coordinator: Dr. Oumou Maiga-Ascofare (KNUST), Ghana
Starting date: 01 March 2019
Duration: 48 months
EDCTP grant amount: EUR 7,642,364
Grant agreement: RIA2017MC-2022

ASAAP is a 48-month lasting clinical trial research to evaluate the efficacy, safety, tolerability and pharmacokinetics of a new antimalarial drug combination, with particular focus on its successful application in one of the largest and most vulnerable demographics of Africa – i.e. children 0-5 years old. The overall aim is to develop new antimalarial treatments by combining existing, efficacious medicines for treatment of malaria in African children by promoting African and European research collaboration and strengthening the capacity of African institutions to conduct clinical research.

ASAAP is part of the European and Developing Countries Clinical Trials Partnership 2 (EDCTP2) program supported by the European Union (EU) and receives funding from the German Federal Ministry of Education and Research (BMBF) and the National Institut of Health and Medical Research in France (INSERM).

The project is being led and coordinated by Dr. Oumou Maiga-Ascofaré of the BNITM in Hamburg, Germany and the KCCR in Kumasi, Ghana under the authority of the Kwame Nkrumah University of Science and Technology (KNUST), in collaboration with:

Further information can be found on the EDCTP webpage

A phase II and III clinical trial programme to assess safety, efficacy and transmission-blocking properties of the new antimalarial KAF156 combined with a new formulation of lumefantrine in children and adults with uncomplicated Plasmodium sp. malaria in West and Central Africa

Université des Sciences, des Techniques et des Technologies de Bamako (USTTB), Bamako, Mali, with partners from Burkina Faso, France, Gabon, Germany, the Netherlands, Niger, Sweden, Switzerland, and United Kingdom

Project coordinator: Prof. Abdoulaye Djimdé (USTTB, Mali)
Starting date: 01 March 2019
Duration: 60 months
EDCTP grant amount: EUR 10,000,000
Grant agreement: RIA2017T-2018

WANECAM is the West African Network for Clinical Trials of Antimalarial drugs. This network is being supported by grants from the European &Developing Countries Clinical Trials Partnership (EDCTP). The WANECAM 2 project aims to accelerate the development of the Ganaplacide/lumefantrine combination for the treatment of uncomplicated malaria by conducting clinical trials in four countries in West and Central Africa: Burkina Faso, Gabon, Mali and Niger.

Moreover, and very importantly, the project includes activities around capacity building (e.g. training and infrastructure development) to improve the capabilities in West African countries to develop new antimalarial drugs. The aim is to advance the development of a much-needed new antimalarial therapy while strengthening clinical trial development capabilities in Africa. The WANECAM 2 project includes participants from West Africa and Europe and is coordinated by Prof Djimde from the University of Bamako. See a full list of our collaborators.

Further information can be found on the WANECAM2 website or on the EDCTP webpage.

Portfolio approach to developing the next generation of malaria treatments for Africa (“PAMAFRICA”)

This proposal presents leading drug candidates from the MMV-partnership portfolio, plus reformulations of licensed medicines, to be evaluated in clinical trials. A consortium-driven program will be undertaken, with the aim of delivering 4 key outcomes – a single-dose cure and an injectable cure for severe malaria, both for evaluation in confirmatory Phase III studies, and a treatment for neonates, along with a significant increase in African research capacity. Additional partner benefits include leadership development, community engagement, and networking and team-building, driven through European-African and intra-African collaborations. The consortium partners will include CISM Manhiça (Mozambique), CERMEL (Gabon), University of Tübingen, IS Global, Novartis, Merck and others, and be led by MMV who will also guarantee 50% of the co-funding.

COORDINATOR
Medicines for Malaria Venture, Switzerland, Timothy Wells
PARTICIPANTS
University of Tübingen, Germany, Peter Kremsner Barcelona Institute for Global Health (IS Global), Spain, Quique Bassat Centro de Investigação em Saude de Manhiça (CISM), Mozambique, Eusebio Macete Centre de Recherches Médicales de Lambaréné (CERMEL), Gabon, Ghyslain Mombo-Ngoma Novartis Pharma AG-Basel, Switzerland, David Hughes
EDCTP contribution: €21.9M
Total budget: €44M
Duration: 60 months

A Phase 2 Interventional, Multicenter, Randomized Open Label Study to Determine the Effective and Tolerable Dose of KAF156 and Lumefantrine Solid Dispersion Formulation in Combination, Given Once Daily for 1, 2 and 3-days to Adults and Children With Uncomplicated Plasmodium Falciparum Malaria

Purpose:
This study aims to determine the most effective and tolerable dose at the shortest dosing regimen of the investigational drug KAF156 in combination with a solid dispersion formulation of lumefantrine (LUM-SDF) in adult/adolescent and pediatric patients with uncomplicated P. falciparum malaria. There is unmet medical need for anti-malarial treatment with new mechanism of action to reduce probability of developing resistance, and for duration shorter than 3 days of treatment and/or reduced pill burden.

A Phase 2, Multi-center, Randomized, Open-label, Dose-escalation Study to Determine Safety of Single (QD) and Multiple (3 QD) Doses of KAE609, Given to Adults With Uncomplicated Plasmodium Falciparum Malaria.

Purpose:
KAE609 will be evaluated primarily for hepatic safety of single and multiple doses in sequential cohorts with increasing doses. This study aims to determine the maximum safe dose of the investigational drug KAE609 in malaria patients.

To Evaluate the Efficacy of a Single Dose Regimen of Ferroquine and Artefenomel in Adults and Children With Uncomplicated Plasmodium Falciparum Malaria (FALCI).

Primary Objective:
To determine whether a single dose combination of OZ439 (Artefenomel)/FQ (Ferroquine) is an efficacious treatment for uncomplicated Plasmodium falciparum malaria in adults and children. Secondary Objectives:

Study to Investigate the Clinical and Parasiticidal Activity and Pharmacokinetics of Different Doses of Artefenomel and Ferroquine in Patients With Uncomplicated Plasmodium Falciparum Malaria
Primary Objective:

To show the contribution of OZ439 to the clinical and parasiticidal effect of OZ439/FQ combination by analyzing exposure-response of OZ439 measured by Day 28 polymerase chain reaction (PCR)-corrected adequate clinical and parasitological response (ACPR) for the effect and the AUC of OZ439 as PK predictor.
Secondary Objective(s):

Safety and efficacy of different albendazole-based treatment regimens to reduce microfilaraemia in subjects infected by Loa loa in an endemic area of Gabon: a randomised controlled open-label pilot study

Treatment options for loiasis, a filarial disease caused by infection with Loa loa, are currently limited by the very few drugs of any known efficacy and the risk of severe adverse reactions in patients with high microfilarial loads. Optimisation of regimens for the safe reduction of L. loa microfilaria could contribute to reduction of disease transmission, as well as facilitating elimination campaigns for lymphatic filariasis and onchocerciasis in co-endemic areas.

This randomised controlled open-label pilot study will explore the efficacy, sustainability and safety of three albendazole-based treatment regimens for reducing L. loa microfilaraemia in infected subjects in an endemic region of Gabon. Adult male subjects with L. loa microfilarial loads <50,000 mf/mL identified within the ongoing loiasis epidemiology study (BuDiLoLo) in Tsamba-Magotsi department will be eligible for inclusion following provision of written informed consent>.
Pan African Clinical Trials Registry: PACTR201807197019027.

Efficacy and safety of Ivermectin for the treatment of Plasmodium falciparum infections in asymptomatic Gabonese adults

Ivermectin has a potent anti-parasitic and anti-insecticide activity against many organisms including ecto- and endoparasites in animals and in humans. Malaria, a mosquito-borne disease caused by parasites of the genus Plasmodium, remains the most important parasitic disease in humans worldwide. It has been shown that ivermectin can reduce transmission of Plasmodium parasites by its activity against blood-sucking mosquitoes, but recent in vitro data suggests that ivermectin has also and effect on the erythrocytic stages of P. falciparum, but in vivo data are lacking.

Besides its insecticidal activity, the excellent safety profile of ivermectin, which has been used for decades in mass drug administration programs, and a different mechanism of action compared to other antimalarials make ivermectin an interesting candidate for malaria control and elimination campaigns. This dose escalation study is designed to assess the activity of ivermectin on the parasitaemia of asymptomatic P. falciparum infections.

The aim of this study is to investigate whether ivermectin is safe at a 3x300 µg/kg treatment course and can reduce or clear parasitaemia in participants infected with P. falciparum assessed by thick blood smear microscopy.
Primary Objective(s): To assess the safety and tolerability of single- and multiple ascending doses of iver-mectin in volunteers with asymptomatic P. falciparum infection. To assess the efficacy of ivermectin in participants with asymptomatic P. falciparum infection.
Secondary Objective(s): To compare efficacy of ivermectin 200μg/kg single dose versus two-day 200µg/kg treatment versus three-day 200μg/kg treatment versus three-day 300µg/kg treatment. To compare efficacy of ivermectin three-day 300µg/kg treatment compared to placebo. To compare safety and tolerability of ivermectin 200μg/kg single dose versus two-day 200µg/kg treatment versus three-day 200μg/kg treatment versus three-day 300µg/kg treatment.
Pan African Clinical Trials Registry: PACTR201908520097051

A randomized controlled trial comparing the effectiveness of Individual vs. Household Treatment for Scabies in Lambaréné, Gabon

Background It is unclear whether individual treatment of scabies is similarly effective compared to household treatment. This study therefore compared these two treatment strategies with topical benzyl benzoate for treating scabies in Lambaréné and surroundings in Gabon.

Methods Subjects presenting with uncomplicated scabies were randomized into either the Individual Treatment group, where only the affected subjects received treatment, or the Household Treatment group, where all family members were treated in parallel to the affected subjects regardless of signs and symptoms. The primary endpoint was clinical cure after 28 days; the secondary endpoint was the proportion of affected household members per household after 28 days.

Improved Integrated Maternal and Child Survival through Malaria and HIV Prevention
Gabon Malaria and AIDS Control (GMAC) project

The Gabon Malaria and AIDS (GMAC) project proposed by Medical Care Development International (MCDI) and selected public health research institutes aims to improve the delivery of WHO recommended prevention, testing, treatment and tracking of malaria and HIV/AIDS at the health facilities in 10 communities in the Nyanga province, one of the least developed in Gabon.

Through this project, MCDI prioritizes malaria and HIV prevention amongst the highest risk groups, consisting of pregnant women and infants. Interventions include the targeted distribution of mosquito bed nets to women attending the antenatal care (ANC) facilities, as well as the provision of intermittent preventive treatment of malaria during pregnancy (IPTp) and prevention of the mother-to-child transmission (PMTCT) of HIV through implementing PTMCT. A population of about 52 000 inhabitants is covered by the interventions in the Nyanga province. The communities include Tchibanga, Moabi, Mayumba, Mulengui-Binza, Mabanda, Murindi and Ndenguilila.

Goals and Objectives:
The overall goal of the project is to improve the quality and availability of malaria and HIV control services in five communities in Nyanga province, reducing mother-to-child transmission of HIV/AIDS and decreasing malaria cases and deaths among pregnant women and children under five years of age as well as in the general population.

Outputs:
The project outputs are: