Ladron De Guevara, Mexico

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.

Platform Assessing Regimens and Durations In a Global Multisite Consortium for TB

Study Design: This will be a randomised, open-label, multicentre, seamless phase 2B (regimen selection) and 2C (duration randomisation), multi-arm multi-stage, platform clinical trial Overall objective: The overall objective is to identify novel drug regimen(s) with acceptable safety profile, non-inferior efficacy, and shortened treatment duration compared to the standard-of-care 24-week HRZE/HR regimen (isoniazid + rifampicin + pyrazinamide + ethambutol for 8 weeks then isoniazid + rifampicin for 16 weeks) that could be used to treat both rifampicin-susceptible and resistant TB. Specific sub-objectives: The objective of the Phase 2B stage is to identify novel regimens of 16 weeks' duration with acceptable safety profile and the greatest potential, based on assessment of quantitative sputum liquid culture and treatment failure/relapse, to progress to investigation of optimal treatment duration Amongst the regimens selected for progression from phase 2B to phase 2C stage, the objective is then to further evaluate the safety profile of these regimens and to identify the optimal treatment duration (between 8 and 16 weeks) based on unfavourable outcome to support advancement to future Phase 3 trials. Setting: Specialist TB clinics and research centres in sites across Europe, Asia, Africa and South America Population: Adults with newly diagnosed, rifampicin-susceptible pulmonary TB Duration: Individual participant participation will be for 72 weeks. The total duration of trial is 5 years. Interventions: Phase 2B: Participants will be randomised (1:1:1..1) to the following 12 arms (A-L) initially. Additional arms maybe added through protocol amendment. Control, standard-of-care regimen, given for 24 weeks A. Isoniazid + rifampicin + pyrazinamide + ethambutol for 8 weeks then isoniazid + rifampicin for 16 weeks Novel treatment regimens each given for 16 weeks B. Bedaquiline + delamanid + moxifloxacin C. Bedaquiline + delamanid + moxifloxacin + GSK306656 D. Bedaquiline + delamanid + pyrazinamide + GSK306656 E. Bedaquiline + delamanid + linezolid (for first 8 weeks) + GSK306656 F. Bedaquiline + pretomanid + moxifloxacin + GSK306656 G. Bedaquiline + delamanid + moxifloxacin + BTZ-043 H. Bedaquiline + delamanid + pyrazinamide + BTZ-043 I. Bedaquiline + delamanid + linezolid (for first 8 weeks) + BTZ-043 J. Bedaquiline + pretomanid + moxifloxacin + BTZ-043 K. Bedaquiline + moxifloxacin + pyrazinamide + BTZ-043 L. Bedaquiline + delamanid + GSK306656 + BTZ-043 There are two planned interim analyses of safety and efficacy data by an Independent Data Monitoring Committee in Phase 2B. The first interim analysis will occur when the last participant for arms to be included in the analysis, completes 16 weeks of treatment and all necessary data are available. The second interim analysis will occur when the last participant for arms to be included in the analysis completes to week 48 (from randomisation) and all necessary data are available. The IDMC will make recommendation to the Trial Steering Committee (TSC) and Asset Holders on the progression of regimens to Phase 2C. The TSC will make the final decision. Arm B (bedaquiline + delamanid + moxifloxacin) will not be considered for progression to 2C. Phase 2C: For regimens selected for progression (following interim phase 2B evaluation). Participants will be randomised to treatment durations of either 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks or to the 24-week standard-of-care regimen (as described above). Primary Efficacy Outcome Measure(s) - Phase 2B: rate of change in log10(TTP) over 0 to 12 weeks, where TTP is time to positivity measured in days from MGIT culture Phase 2C: Favourable/unfavourable status (binary) at week 48 from randomisation Safety Outcome Measures (Phase 2B and 2C) - The following outcomes will be reported up to week 26 from randomisation (unless otherwise stated): - Grade 3/4/5 adverse events (DAIDS grading scale) - Serious Adverse Events - Adverse Events of Special Interest - Regimen-related adverse events leading to withdrawal from the study - Adverse events leading to discontinuation of the regimen Number of Participants to be Studied: Up to 2500 overall - 700 in phase 2B and 1800 in phase 2C (distribution between phases depends on progression according to specified decision-making steps)

A Study of Camizestrant in ER+/HER2- Early Breast Cancer After at Least 2 Years of Standard Adjuvant Endocrine Therapy

This is a Phase III open-label study to assess if camizestrant improves outcomes compared to standard endocrine therapy in patients with ER+/HER2 - early breast cancer who completed definitive locoregional therapy (with or without chemotherapy) and standard adjuvant endocrine therapy (ET) for at least 2 years and up to 5 years. The planned duration of treatment in either arm of the study is 60 months. The eligible patients must have intermediate or high risk of recurrence, as defined by specified clinical and biologic criteria. Prior use of CDK4/6 inhibitors is permitted. The primary endpoint of the study is Invasive breast cancer-free survival (IBCFS) and main secondary endpoints include Invasive disease-free survival (IDFS), Distant relapse-free survival (DRFS), Overall survival (OS), Safety and Clinical Outcome Assessments (COAs). Patients will be followed for 10 years from randomization of the last patient.

A 52-Week Study of the Efficacy and Safety of BLU-5937 in Adults With Refractory Chronic Cough

The primary efficacy objective is to assess the effect of BLU-5937 on 24-hour cough frequency in adults with refractory chronic cough (including unexplained chronic cough) at 12 weeks.

A Pan-TB Regimen Targeting Host and Microbe

A Global Study of Volrustomig (MEDI5752) Plus Chemotherapy Versus Pembrolizumab Plus Chemotherapy for Participants With Metastatic Non-small Cell Lung Cancer.

Adult patients with a histologically or cytologically documented metastatic NSCLC, with tumors that lack activating EGFR, ALK, and ROS1 alterations are eligible for enrollment. Patients will be randomized in a 1:1 ratio to receive treatment with volrustomig + chemotherapy or pembrolizumab + chemotherapy. Tumor evaluation scans will be performed until disease progression as efficacy assessment. All patients will be followed for survival until the end of the study. An data monitoring committee (DMC) composed of independent experts will be convened to confirm the safety and tolerability of the proposed dose and schedule.

BTZ-043 Dose Evaluation in Combination and Selection

This open label, phase 2B, randomized controlled study will evaluate three experimental arms containing different doses of BTZ-043 in combination with bedaquiline and delamanid, in adult subjects with newly diagnosed, drug-sensitive pulmonary tuberculosis, in comparison with bedaquiline, delamanid and moxifloxacin, administered over 16 weeks. A total of 90 adult (≥ 18 years of age) participants will be enrolled. In case of a high number of dropouts or non-evaluable participants, it may be necessary to recruit more participants into the study. The participants will be randomly allocated to one of the three BTZ-containing experimental regimens or the moxifloxacin-containing comparator regimen: Arm 1: bedaquiline, delamanid, BTZ-043 500 mg (BDT500) Arm 2: bedaquiline, delamanid, BTZ-043 1000 mg (BDT1000) Arm 3: bedaquiline, delamanid, BTZ-043 1500 mg (BDT1500) Arm 4: bedaquiline, delamanid, moxifloxacin (BDM) In all arms, bedaquiline will be dosed at 400 mg once daily for 2 weeks, followed by 100 mg once daily for 14 weeks and delamanid will be dosed at 300 mg once daily for 16 weeks. Moxifloxacin will be dosed at 400 mg once daily in the comparator arm. After completion of 16 weeks of treatment, all participants will receive 8 weeks of continuation therapy with Rifampicin and Isoniazid.

Sisonke 2 - A COVID-19 Vaccine Boost Open Label Study.

Purpose To evaluate the effectiveness and safety of the single dose Ad26.COV2.S (Jansen) COVID-19 vaccine plus a homologous boost with Ad26.COV2.S (Janssen) COVID-19 vaccine among Sisonke participants as compared to unboosted Sisonke participants In addition the investigators will continue to evaluate VE of the Sisonke Boost compared to: i) Vaccinated populations pre boosts ii) Unvaccinated populations in South Africa. Study design Open-label, single-arm phase 3B vaccine implementation study Rationale South Africa is severely affected by the global COVID-19 epidemic, and following the initial prime vaccination among HCWs in the first 4 months of 2021. New data has demonstrated the safety and effectiveness of a booster dose given two months or more after the initial Ad26.COV2.S. This provides the rationale and feasibility for the evaluation of a homologous booster vaccine dose to the cohort of vaccinated Sisonke participants to inform the larger vaccine rollout. Study participants Sisonke participants age 18 and over working in the South African public and private health care sector (approx N=500 000) who were enrolled in Sisonke and have not subsequently had a further booster vaccine dose. Study sites Department of Health Vaccine Administration Sites across South Africa supported by the Sisonke (Together) (VAC31518COV3012) Trial Research Site Investigators and Study Staff Study duration Participants will receive a homologous Ad26.COV2.S (Janssen) booster dose of vaccine at least 6 months post the prime vaccination. The investigators will monitor outcomes utilising the DATCOV surveillance system and NHLS/NICD SARS COV-2 testing databases for up to 2 years post initial vaccination. Study products Ad26.COV2.S by Janssen administered as a single dose followed by a single booster injection. Primary objectives • To assess the effectiveness of Ad26.COV2.S vaccine as a homologous boost on severe COVID, hospitalizations and deaths in Sisonke participants as compared with the unboosted Sisonke populations. Secondary objectives To assess the effectiveness of Ad26.COV2.S vaccine as a homologous boost on severe COVID, hospitalizations and deaths in Sisonke participants as compared vaccinated and unvaccinated populations of essential workers in South Africa. - To estimate the incidence of symptomatic SARS CoV-2 infections in Sisonke participants following a boost compared with the unboosted Sisonke populations and general vaccinated and unvaccinated population in South Africa - To estimate booster dose uptake among Sisonke participants in South Africa - To monitor the genetic diversity of breakthrough SARS CoV-2 infections. - To monitor safety in the case of homologous boosts in Sisonke participants.

Remote Ischaemic Conditioning in STEMI Patients in 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 Africa. Study design: The RIC-AFRICA trial is a multi-centre, sham-controlled, randomised controlled trial (RCT) involving 1400 ST-segment elevation myocardial infarction (STEMI) patients presenting within ≤ 24 hours of myocardial infarction (MI) onset, across approximately 20 sites in 7 African countries (South Africa, Kenya, Sudan, Uganda, Mozambique, Senegal and Mauritius). 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 Africa, thereby potentially providing a low-cost, non-invasive therapy for improving health outcomes.

Phase 3 Inhaled Novaferon Study in Hospitalized Patients With Moderate to Severe COVID-19