Why RER-CTO?: The conduct of clinical trials requires competent ethics committee and regulatory authorities that can review clinical trial applications and monitor processes independently and efficiently ensuring the safety of clinical trial participants, and the integrity and reliability of the generated data. The capacity of most African regulatory authorities regarding clinical trial review and oversight is weak due to poor infrastructure, limited resources both human and financial, lack of expertise, un-conducive working framework and lack of systems adequately supported by technology. Collaboration between academia, international organizations, National ethics committees (NECs) and national regulatory authorities (NRAs) are mandatory to produce sustainable regulatory skills and functional clinical trial oversight systems. The RER-CTO consortium consists of a group of well reputable clinical trial researchers, regulatory authorities, ethics committees, universities and research institutes in Ethiopia, Tanzania, Norway, and Sweden. Our aim is to achieve ethics and regulatory excellence and harmonization in sub-Saharan Africa in clinical trial oversight (CTO) by improving the legal and policy framework by identifying gaps and making recommendations, improving regulatory and research ethics oversight capacity and capability by digitalising the clinical trial oversight systems and developing training programs to strengthen competency of relevant stakeholders, and strengthening local, regional, and international collaborations and coordination of NECs and NRAs for clinical trial oversight by developing joint clinical trial review guidelines. These efforts are geared towards increasing clinical trials in sub-Saharan Africa, standardization of clinical trial review and monitoring processes, and promoting ownership, efficiency, linkages for data sharing, transparency, and accountability of clinical trial review processes.

Every year, about a million children under 15 years are diagnosed with Tuberculosis (TB) worldwide, and about a quarter die. However, over 60% of children with TB remain undiagnosed, particularly in sub-Saharan Africa, which accounts for about 20% of the global burden of paediatric TB cases. In 2022, WHO issued an interim general recommendation to use integrated Treatment-Decision Algorithms (TDAs) to diagnose TB in children under 10 years. However, this recommendation was based on very low certainty of evidence. Therefore, we are seeking funding to address four objectives: 1) To compare the effectiveness of TDAs and the Standard of Care in routine clinical settings 2) To identify processes and contextual factors that influence the effectiveness and fidelity in the implementation of TDAs 3) To compare the costs, cost-effectiveness, and the population level impact of the TDA strategies on the burden of TB and 4) To validate the diagnostic performance (sensitivity, specificity, negative and positive predictive values) of the TDAs in various health system settings and clinical context. A four-year pragmatic open-label cluster randomized controlled trial will be conducted in 120 primary health facilities in Tanzania, Uganda, and DR Congo. The primary outcome is the proportion of children detected and initiated on TB treatment. About 60,000 children with presumptive TB will be screened. We anticipate that this project will yield results that address the issue of low detection rates of paediatric TB in sub-Saharan Africa and beyond, build research capacity in conducting implementation research in low-income countries, and foster networking and collaboration between the partner institutions.

PREPARE4VBD builds on the conviction that a true shift in our ability for early detection, prediction and control of vector-borne diseases (VBDs) of both livestock and humans in Africa and Europe, can only come from advancing a deep cross-organismal understanding of the features that allow VBDs to persist in endemic areas. We will therefore “cast the net wide” focusing on several VBDs and vector groups to explore synergistic opportunities for integrated and cost-effective approaches to optimize surveillance, prevention and control of VBDs. Specifically, we will address three vector groups (mosquitoes, ticks and snails) and a range of their diverse VBDs (Rift Valley Fever, ehrlichiosis, theileriosis and fasciolosis), to advance a broad, conceptual knowledge reaching beyond specific VBDs. We believe that only through a better understanding of what enables theVBDs and vectors to persist in their areas of origin, how they manage to spread or what allows some VBDs to successfully span the entire global North-South climatic gradient – will we gain the insights and actionable knowledge that enables us to predict the potential of VBDs to spread and establish in new areas. PREPARE will establish a truly multidisciplinary network of partner institutions in Europe and Africa, including leading capacities in mosquito- tick- and snail-borne diseases of livestock and humans. The partners cover a wide range of disciplines such as vector ecology, molecular biology, bioinformatics, metagenomics, climate change and predictive spatio-temporal modelling, epidemiology and One Health. Our suggested approach is proactive, focusing on better prevention of tick-, mosquito- and snail-borne diseases of livestock and humans, by increasing disease knowledge in Africa, developing improved tools for rapid detection and state-of-art model-based surveillance for early detection and forecasting to form a blueprint for best practices for optimized VBD surveillance strategies for the targeted diseases

Diabetes Mellitus (DM) contributes to an estimated 11.3% of adult deaths worldwide. Approximately 1 in 10 adults globally are estimated to have DM and the prevalence will rise significantly over the coming decades, especially in sub-Saharan Africa. People with DM have a three-fold increased risk of developing TB, and two-fold higher risk of dying from TB or experiencing treatment failure or recurrent disease, further threatening global TB control. As such, the growing burden of DM alongside the continuing TB epidemic have huge health and socio- economic impact. PROTID performs the first randomized controlled trial (RCT) globally to evaluate efficacy, safety, cost-utility and population impact of preventive treatment of TB preventive therapy for people with DM. It also examines gaps in diagnosis and management of DM and DM-TB in Uganda and Tanzania. Our results will guide global policy on TB prevention and management in people with DM, and this can have large socio-economic impact. In Africa, this is highly relevant given the double burden of DM and TB. In Europe, our results will be highly relevant for migrants and people living in eastern Europe, as both groups have a high burden of DM, latent tuberculosis infection (LTBI) and TB disease. PROTID’s results so far, and other advancements in the field, have already set clear research priorities beyond PROTID. PROTID is very well-positioned to take these forward, with strengthened leadership and research capacity in PROTID’s African partners embedded in a global research network, and its accumulated data on the largest and most-well characterized longitudinal cohort on DM and TB globally.

Diabetes is a common co-morbidity among people living with HIV. Since Oct 2021, we have been conducting a phase III randomised placebo-controlled trial of metformin among people living with HIV and pre-diabetes in Dar es Salaam, Tanzania (EDCTP RIA2018CO-2513). The aim is to test whether metformin can prevent progression to diabetes among people living with HIV. The primary endpoint is the time to diabetes. We had planned to enrol 2100 participants, follow-up for 3 years, and finish at the end of Dec 2024. COVID-19 resulted in severe delays to regulatory review. HIV care was decentralised away from health facilities to community posts to reduce COVID-19 risk, which led to much slower recruitment. We have now enrolled 1550 participants over the last 20 months. Less than 1% have been lost to follow-up. We will reach our target recruitment in Dec 2023 and will continue follow-up until Dec 2025. This will provide an average follow-up of 3 years per participant. Analyses of aggregated data to date show that glucose levels and weight have fallen over first 12 months among the trial cohort. Thus, we believe that trial will answer the research question by continuing follow-up until Dec 2025. In 2026, we will disseminate the findings to stakeholders and to the international bodies. We are collecting clinical, health economics, and qualitative data. The trial is being done as an equitable partnership between European and African researchers, and in partnership with Ministry of Health policy-makers and African patient representative bodies. We have good links with the African Centres for Disease Control, World Health Organisation (WHO-AFRO and Geneva offices), and Global Fund in order to inform policy considerations. Merck Pharma has provided medicinal products including the placebo.