Springdale, Arkansas

Post-Trial Tuberculosis Case Finding: A Substudy of CoVPN 3008

This observational substudy will involve participants from the CoVPN 3008 trial, regardless of their HIV status, to study tuberculosis (TB). At the start, all participants will be screened for TB, even if they have no symptoms. They will receive chest x-rays and provide sputum samples for TB testing using Xpert Ultra, smear microscopy, and culture. The study has two main groups. Group 1 includes participants with confirmed TB, and Group 2 includes participants without TB who will act as controls. Participants with confirmed TB will start treatment and have a first follow-up visit on Day 4 to reassess TB symptoms and collect blood samples. A second follow-up visit will take place at week 26 to evaluate their treatment progress, clinical outcomes, and TB status, ensuring they receive the necessary care. Participants without TB will have a single follow-up visit on Day 4 to reassess TB symptoms and collect blood samples. The study aims to identify potential biomarkers of TB by analyzing blood samples from both cases and controls, focusing on gene expression linked to TB, including hidden (subclinical) TB.

A Pan-TB Regimen Targeting Host and Microbe

DTG/3TC Fixed Dose Formulations for the Maintenance of Virological Suppression in Children with HIV Infection Aged 2 to <15 Years Old

This study will include 370 children and young people aged 2 to less than 15 years old who are living with HIV and are being treated with anti-HIV medicines for the first time. Participants will be split into two groups, by chance, by a process called "randomisation". One group will continue to receive the anti-HIV medicines already taken according to country-specific routine practice. The second group will change to the new combination of medicine, dolutegravir and lamivudine (with the combination written usually as "DTG/3TC"). Depending on the weight, participants in the second group will be able take the new medicine either as one tablet a day or as a small number of dispersible tablets that are also taken once a day. All children and young people in the study will have regular clinic assessments that are at a similar frequency to the clinic visits that participants would have outside of the study. Blood tests will be performed to check that the medicine is safe and, at some visits, participants and their carers will also be asked to answer some questions on how they feel about taking their medicine. All children and young people will be followed until the last participant who joins the study has been in the study for 96 weeks.

Evaluating the Safety and Immunogenicity of MTBVAC in Adolescents and Adults Living With and Without HIV in South Africa

This study will evaluate the safety and immunogenicity of MTBVAC in adolescents and adults living with and without HIV in South Africa. The study will be conducted in two parts (Part A and B). Part A will include two Cohorts (Cohort 1 and 2) and each Cohort will have four groups. Part B will have one Cohort which will also have four groups. Participants will be recruited into three cohorts (Cohorts 1-3) based on their HIV status and, for People Living With HIV, their CD4+ T cell count and WHO clinical stage prior to ART initiation/re-initiation. Within each cohort, they will be stratified into subgroups based on their IGRA status. For Cohorts 1 and 2 which will enroll simultaneously, participants will be randomized to receive MTBVAC or BCG according to the ratio of the planned sample sizes within the cohort; there is no placebo group in this trial. Enrollment of Cohort 3 will proceed if safety criteria are met for Cohorts 1 and 2, with randomization to MTBVAC and BCG. Participants in all groups will receive a single ID study product injection of 0.1 mL in volume and will be followed for 48 weeks.

Remote Ischaemic Conditioning in STEMI Patients in Sub-Saharan AFRICA

Background: Remote ischaemic conditioning (RIC) using transient limb ischaemia and reperfusion has been shown to reduce myocardial infarct size in animal studies and small proof-of-concept clinical studies in ST-segment elevation myocardial infarction (STEMI) patients. However, RIC failed to improve clinical outcomes in the large European CONDI-2/ERIC-PPCI multi-centre randomised clinical trial. Potential reasons for this failure include the low-risk patients recruited into the study and the fact that patients received timely and optimal reperfusion therapy by primary percutaneous coronary intervention. The RIC-AFRICA trial will investigate whether RIC can improve clinical outcomes in higher-risk STEMI patients treated by thrombolysis in sub-Saharan Africa. Study design: The RIC-AFRICA trial is a multi-centre, sham-controlled, double-blinded, randomised controlled trial (RCT) involving 1200 ST-segment elevation myocardial infarction (STEMI) patients presenting within ≤ 24 hours of myocardial infarction (MI) onset, across approximately 20 sites in four sub-Saharan African countries (South Africa, Kenya, Sudan and Uganda). Patients will be randomised to receive either RIC or sham control initiated prior to thrombolysis and applied daily for the next 2 days. The RIC protocol will comprise four 5-minute cycles of inflation (to 20mmHg above systolic blood pressure) and deflation of an automated pneumatic cuff placed on the upper arm. The sham control protocol will comprise four 5-minute cycles of low-pressure inflation (to 20mmHg) and deflation by a visually identical pneumatic cuff. The primary composite endpoint will be all-cause death and new-onset heart failure at 30-days post STEMI. Patients presenting with STEMI and deemed ineligible for the RIC AFRICA RCT because they present >24 hours from MI onset but less than 72 hours, will be recruited into the observational arm of the study with the same endpoints as the trial. Implications: The RIC-AFRICA trial will determine whether RIC can reduce rates of death and prevent heart failure in higher-risk STEMI patients treated by thrombolytic therapy in sub-Saharan Africa, thereby potentially providing a low-cost, non-invasive therapy for improving health outcomes.

Reducing Mortality in Adults With Advanced HIV Disease (REVIVE)

All participants in the REVIVE trial will be randomized (1:1) at the time of study entry to receive azithromycin prophylaxis or placebo for 28 days and will be followed for 24 weeks to determine the primary outcome measure. Total follow up duration will be 48 weeks.

A Randomised, Multi-centre, Double-blind, Phase 3 Study to Observe the Effectiveness, Safety and Tolerability of Molnupiravir Compared to Placebo Administered Orally to High-risk Adult Outpatients With Mild COVID-19 Receiving Local Standard of Care in South Africa

This is a multi-centre, double-blind, phase 3 study to observe the effectiveness, safety, and tolerability of molnupiravir 800 mg administered 12-hourly for five days in adult patients with mild COVID-19 at the time of enrolment, who are at risk of progression to severe disease, compared to a placebo. Patients with recent onset of COVID-19 symptoms will be screened to assess eligibility for enrolment. Confirmation of SARS-CoV-2 infection will be performed through rapid antigen detection using the LumiraDx point of care diagnostic platform. Approximately 4000 eligible patients will be enrolled and will be randomised in a 1:1 manner to start treatment with either molnupiravir or a placebo on the same day. Patients will record their symptoms (through a self-administered questionnaire) and self-observed vital signs daily for 10 days from the time of enrolment and will be contacted by study team personnel on Days 3, 6 and 10 to monitor their well-being. Adverse event and concomitant medication data will be collected. A final end-of-study follow-up visit will be conducted on Day 29. An independent Data and Safety Monitoring Board (DSMB) will be convened for this study with expertise in COVID-19 or respiratory viruses, and emerging epidemics. The purpose of the DSMB is to monitor the study for safety and operational futility. In addition to the usual, regular, required reporting to SAHPRA, the investigator anticipates that additional reporting will be required by the Clinical Trials Committee, noting the severity of the 3rd and 4th waves, the level of ''breakthrough'' infections in the context of high background comorbidities, and the urgent interest in this class of drugs.

Study to Assess Efficacy and Safety of M72/AS01E-4 Mycobacterium Tuberculosis (Mtb) Vaccine in Adolescents and Adults