E Cape, South Africa

A Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Obinutuzumab in Adolescents With Active Class III or IV Lupus Nephritis and the Safety and PK of Obinutuzumab in Pediatric Participants

A Phase III Study to Investigate the Efficacy and Safety of Baxdrostat in Combination With Dapagliflozin on CKD Progression in Participants With CKD and High Blood Pressure.

A Study to Evaluate the Treatment Response and Safety of Two Dose Regimens of Subcutaneous Amlitelimab Monotherapy Compared With Treatment Withdrawal in Participants Aged 12 Years and Older With Moderate-to-severe Atopic Dermatitis

A Study to Assess Adverse Events and Change in Disease Activity From Intravenous (IV) and Subcutaneous (SC) Lutikizumab in Adult Participants With Active Ulcerative Colitis

To Evaluate Mucosal and Systematic Immune Response to Acute Respiratory Tract Infections of South African Children

This observational cohort study will include children aged 0-13 years with acute respiratory tract infections who present to Tygerberg Hospital (TBH) for routine care. Key routine care data, including vaccination history, detailed medical history, and treatments received during hospital admission (such as oxygen therapy, antiviral medication, antibiotics, or other supportive drugs), will be documented in case report forms (CRFs). South Africa has a high burden of tuberculosis and HIV infection, and it is important to study respiratory tract infections in this population. Children aged 0-13 years will be recruited from Tygerberg Hospital (TBH), which functions as a regional referral center for the surrounding health sub-districts, including Northern, Tygerberg, Khayelitsha, and Eastern, collectively serving over 30% of the metropolitan population (3.5 million residents). Additionally, TBH acts as a tertiary-level referral center for paediatric emergencies, infectious diseases, and pulmonology. Children with acute respiratory symptoms who present to TBH will be enroled in the study, provided they have been hospitalised for less than 72 hours, consent has been obtained from both the caregiver and child (where applicable), and there are no medical contraindications to collecting respiratory samples. This study will be implemented within routine care services and clinical and laboratory data collected for routine care will be used for research. The research team will collect additional data and samples. Additional samples collected at enrolment will include blood, mucus, and saliva. Additional saliva samples will be taken on the second and third days of hospital admission, as well as at discharge. About one and a half teaspoons of blood will be taken on enrolment to perform the following tests: 1. Antibody analysis 1. Antibodies targeting common respiratory pathogens, as well as polyreactive (non-specific) antibodies 2. Total IgM/IgG/IgA 2. PAXgene for transcriptomics. Transcriptomics is the study of all the RNA molecules (called the transcriptome) in a cell, tissue, or organism at a given time. It helps scientists understand which genes are active (turned on) and how much they are being used. Nasopharyngeal aspirates will be used to collect mucus. A thin tube will be inserted into one nostril to the back of the throat and the mucus will be sucked up into a tube. Polymerase chain reaction (PCR) will be used to look for common respiratory viruses. Samples will also be saved for later metagenomic sequencing (looking for all the viruses, bacteria and fungi that are present in the sample). Saliva will be collected at enrolment, on the second and third day of admission and at discharge, by leaving a cottonwool sample in the mouth until it is soaked. The antibodies in saliva will be compared to those in the blood. In addition, mucosal immune markers such as cytokines will be measured. Baseline and follow-up questionnaires will collect detailed clinical information. 1. Standard symptomatology questionnaires 1. Signs and symptoms of presenting illness will be recorded, including upper and lower respiratory tract symptoms and fever. Previous medical history of respiratory symptoms including recurring respiratory symptoms, chronic illnesses (including TB and HIV) and the use of chronic medication. 2. Constitutional factors including gender, birth weight, gestational age at birth, HIV exposure status and family history of asthma or atopy. 3. Environmental factors including TB exposure, tobacco smoke exposure during and after pregnancy, and indoor cooking. 4. Nutritional status information regarding diet, and growth preceding hospitalisation as evidenced in the Road-To-Health Card. 5. Microbiome-specific questions, birth history, diet. 2. Quality of life (QoL, standard measure by age cohort). Standardised health-related quality of life questionnaire Statistical Analysis: The investigators intend to enrol between 200-300 South African children (see power calculation below). This will allow the use of a targeted protein marker approach in combination with antibody measurements (IgA + IgG) and pathogen detection (multiplex PCR). Simultaneous measurement of multiple biomarkers allows the analysis of interactions between innate and adaptive immune immunity and pathogen density at the mucosal level. The total number of children will be divided into discovery and validation cohorts. The discovery cohort included an age- and sex-balanced cohort of 80 children: 40 with a severe course and 40 with relatively mild infection (80/80 already included). The results from all markers are used to create a classification model that selects a limited number of markers that are then tested in the here proposed second independent validation cohort of a minimum of 236 children with an acute RTI (see power calculation below). Markers with a persistently high discriminatory value in the validation cohort will be compared for performance against standard clinical diagnostic measurements in serum (including CRP) for their performance in assessing severity and the potential need for antibiotic treatment. Initial data from analysed work allows for the following power calculation: Power calculation: For the discovery cohorts, 40 children per group is needed to achieve 80% power for each of n=100 tests (individual test alpha = 0.00090) to detect an actual mean difference of 0.6 with expected SD per group 0.6, applying a false discovery rate (FDR) of 0.010 using a two-sided Mann-Whitney U test.10,11 For the inclusion of the here proposed validation cohort, there is an anticipated 25% severe infections and an alternative AUC of 0.85 - 0.90. Conservatively taking an AUC of 0.77 under the alternative hypothesis, a sample of 59 is needed from the severe group and 138 from the mild group to reject the same null hypothesis AUC of 0.65 with 80% power. Thus, there is a need to include a minimum total of (100/25*59) = 236 children in the acute RTI validation cohort. By anticipating a 10% dropout rate, the minimum total number of children that is aimed to include is 260 (up to 300 inclusions in the case of a higher-than-expected dropout rate). IBM SPSS Statistics software (SPSS Statistics for Windows; IBM, Armonk, NY) and or STATA will be used for analysis. Demographic and clinical characteristics will be described using standard statistical analysis methods. The descriptive data will be presented as percentages and medians ± interquartile range, or numbers with percentages.Ethical considerations The study will be conducted according to South African and internationally accepted ethical standards, including the Declaration of Helsinki and the South African Good Clinical Practice Guidelines (SA GCP). An annual progress report with intermediate results will be submitted to the Ethics committee and funders. In addition, records will be available to HREC for inspection (quality assurance and compliance with regulations), while always maintaining participant confidentiality. Informed consent and assent Parents/ legal guardians, or in special cases caregivers, of the child, will be required to give informed consent for the child's participation in the study. Legal guardians will be required to produce documentation to prove legitimate guardianship. In some cases, we will allow a primary caregiver to give informed consent. This will be considered when there are no parents or legal guardians around and the caregiver has a clear history of being the primary caregiver of the child. In addition, this exception will be discussed with the HREC committee. Oral and written information about the study and study procedures will be given, together with the consent form in the preferred language (English, Afrikaans, isiXhosa). An interpreter will be used if necessary. Children > 7 years of age will also have to sign assent for the study. The child/ parent/legal guardian/ caregiver will be able to withdraw the child from the study at any time point, without this adversely affecting the standard care. A copy of the signed Informed Consent/Assent Form along with a copy of the most recent approved Patient Information Sheet will be given to the study participant. An original signed and dated consent form will be retained in the Investigator Site File (ISF) and a copy will be placed in the medical notes. This consent, and ethical approval, covers the future laboratory analysis of blood and respiratory samples taken during this study. Privacy and confidentiality The identity of all study subjects will be protected by adhering to all SA GCP guidelines on data handling and storage. Storage of paper data During the data collection phase, paper-based data will be stored in fire-resistant locked cabinets in a dedicated, locked room. They will be transported in locked bags/boxes to and from research sites/rooms. After data collection has been completed and the database is clean and locked for analysis, all paper-based data will be securely archived either offsite with a company that specializes in archival, or onsite in a dedicated storage space in fire-resistant cabinets. This will be for the duration required by SA GCP. The longest required timeline will be taken as the archival time. Once this time is completed, the PI will be asked to authorize the destruction of all paper-based forms. Data-management At recruitment, each patient will be assigned a unique anonymous study barcode. All documents and samples related to a single participant will be marked with the participant's unique barcode. No identifying data will appear on the samples. Only the consent form and demographic form (containing the subject's contact details necessary for follow-up tracing) will have the subject's personal information linked to the barcode- these documents will be stored separately from the other documents in a locked cabinet at DTTC. Samples will be stored in dedicated freezers at the DTTC, where technical and maintenance support is available on a 24-hour basis. All data will be stored without personal identifiers; lab personnel will be blinded to clinical and personal data. Data will be stored on protected servers at DTTC with limited access by the database manager, PI and selected co-investigators only. No other genetic testing will be performed unless permission is requested and granted from the HREC. Potential harm/ risk Overall, the procedures in this proposed work have minimal risk to study participants. Routine care procedures are carried out by qualified health care professionals according to the Health Professions Council of South Africa (HPCSA). Routine care data and sample collection All procedures (CXR, HIV testing and respiratory sample collection) are standard of care and are routinely recommended and performed in the study setting to investigate children with respiratory illness, with limited patient risk. Respiratory sampling: NPAs or NPSs cause mild discomfort and a minimal risk of nosebleeds. After instilling a few drops of sterile saline solution into both nostrils, mucus is aspirated from the posterior nasopharynx using a soft cannula attached to a mucus extractor. The procedure lasts a couple of minutes. For NPA collection, the suction machine is set at a pressure that will not cause major trauma to the mucosal lining of the nose and throat. Suction pressures by age, according to the American Association for Respiratory Care (AARC) Guidelines for appropriate sub-atmospheric nasotracheal suctioning pressures, will be followed: Neonates: 60 - 80 mm Hg (0.079- 0.10 Bar) Infants: 80 - 100 mm Hg (0.079- 0.13 Bar) Children: 100 - 120 mm Hg (0.13- 0.15 Bar) All procedures of this proposed research are minimally invasive with very limited risk for the participants. The study personnel will be committed to minimising risks to the child at all times. The study nurse will be trained in all study investigations and will follow strict standard operating procedures with the help of a research assistant. The collection of NPAs will take place in a well-ventilated room, and particulate N95 respirators and goggles or protective eye screens will be worn throughout the procedure to protect parents and healthcare providers from possible respiratory pathogen (including TB) aerosolization. Radiology: Chest radiographs (CXR) will only be taken at enrolment if clinically indicated. The total radiation dose per child is approximately 0.05 mSv (depending on age and including antero-posterior and lateral films), which is roughly equivalent to 30 days of background environmental exposure (Duke University Radiation Safety Committee, IRB Protocol Radiation Risk Statements. Website: http://www.safety.duke.edu/RadSafety). Phlebotomy: Children may experience pain associated with phlebotomy. A maximum of three attempts will be made to obtain the venous blood specimen. Arterial blood specimens will not be obtained. The study nurse and physician will be experienced and trained to perform phlebotomy. Additionally, local analgesia and distracters such as toys and music will be used to minimize stress experienced by children. The HREC guideline for the SOP for researchers will be used when determining what volume of blood can be used for research purposes. Internationally accepted and NIH research guidelines regarding study involvement of children dictate that children should provide no more than 3% of total blood volume per 24-hour period (www.irb.pitt.edu/Guidance/Bloodwithdrawpediatrics.pdf). Thus, venous blood specimens provided by study participants are generally considerably less than the recommended guidelines. For children weighing less than 5kg, the blood draw for serum will be restricted to 1.5ml. This will still enable sufficient serum for the primary aim of the study, but there will be less for storage for planned future work. To minimize risk and in consideration of culturally accepted norms, we will exclude children who weigh < 2.5 kg. Ill children who are on intravenous rehydration infusions or anaemic (Hb<8.5), will have the initial procedures deferred. Cost to parent/legal guardian All study procedures will be paid for from study funds i.e. there will be no cost to the study participant or their family. The parent/legal guardian will receive a small payment for participation in the study (time and inconvenience) while seen in hospital. The South African Health Product Regulatory Authority Clinical Trial Participant Time, Inconvenience and Expense (TIE) Compensation Model will be adhered to, and the enrolment will likely last <3 hours and consequently reimbursement for time will be ± 150 ZAR for enrolment. The enrolment and sampling will occur at TBH during hospital admission only. Child and caregiver are not expected to come back. Infection control measures Safe handling of bio-hazardous material All team members involved in obtaining biological specimens will be trained in the safe handling of such materials. Sharps used for blood taking will be disposed of safely and rapidly into a dedicated sharps container. All laboratory facilities linked to the proposed work are well-established and accredited to work with bio-hazardous materials. Protection from potentially infectious respiratory secretions All team members involved in obtaining NPAs from study participants will wear N95 respirator masks, which will be fit tested once yearly on all staff. The procedures will be undertaken in a dedicated sampling room with an extraction fan and according to DTTC infection control SOP.

A Study to Investigate the Efficacy and Safety of Tezepelumab in Adult Participants With Moderate to Very Severe COPD (D5241C00007)

This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel group study to evaluate the safety and efficacy of tezepelumab in adults with moderate to very severe chronic obstructive pulmonary disease (COPD) receiving inhaled maintenance therapy and having had at least 2 moderate, or 1 severe, COPD exacerbations in the 12 months prior to Visit 1. Subjects will receive monthly subcutaneous injection of one of two different doses of tezepelumab, or placebo, with a maximum treatment duration of 76 weeks and a minimum of 52 weeks. The study also includes a off-treatment safety follow-up period of 12 weeks.

A Study on the Safety and Immune Response of a Urinary Tract Infection (UTI) Vaccine in Adults 18-64 Years of Age and Clinical Efficacy in Females 18-64 Years of Age

This clinical trial consists of 2 parts. Part 1 will consist of antigen dose-escalation (start with least dose with gradual increase in dose) Safety Lead-In (SLI) in healthy participants. Part 2 (Proof of Principle [PoP]) will start after the safety review of all safety data in Part 1 and will consist of participants with history of at least 1 episode of urine culture confirmed E. coli UTI in the last 12 months prior to the study intervention administration.

Telemedicine Contraceptive Counselling (TECC) Versus Standard Care

Overall purpose of the PILOT and RCT: This research project aims to increase access and uptake of contraception after abortion through the systematic development and testing of a new telemedicine service for contraceptive counselling (TECC). The investigators will perform a pilot study in South Africa, and multicenter randomized controlled trial in South Africa and Kenya with the following specific aims: 1. To design and test a user-friendly online service for contraceptive counseling informed by systematic research into the preference and experience of women in our study setting. 2. To compare uptake of long-acting reversible contraception (LARC) after TECC and in-person contraceptive counseling. 3. To compare rates of choice, uptake, and continuation of LARC or any contraceptive, satisfaction, preference for counseling, recurrent unintended pregnancy, and recurrent abortion after TECC and in-person contraceptive counseling. PILOT STUDY Objective: To assess the acceptability of a new online e-health service for contraceptive counselling i.e., telemedicine contraceptive counseling (TECC) Design: A mixed methods pilot study developing and testing a new TECC service preceding a randomized controlled trial Setting and duration: The study will take place at Mitchell's Plain's community health center (CHC) in Western Cape, between February November 2023 and December 2023. Study population: 30 women seeking abortion either medical or surgical, ≥ 18 years of age, able to communicate and understand spoken and written English, with private access to a smartphone, and willing to participate in the study Recruitment and consent: Recruitment, informed consent, baseline interview and randomization will take place at the clinics by one of two experienced field workers, fluent in English and isiXhosa/Afrikaans. Intervention: Participants will test the TECC service while waiting at the clinic to see the nurse for their abortion consultation. A follow-up survey will be sent out and completed by phone if necessary at 2 weeks after enrolment in the study. Out of these 30 women, approximately 10 (or until data saturation is achieved) will participate in semi-structured in-depth interviews regarding their experience of using the TECC service. Primary outcome collected at 2 weeks Main outcome variable will be a compound variable reflecting the proportion of women who choose a method after completing the TECC intervention and report 1) being satisfied or very satisfied with the service (affective attitude), 2) understanding the content and purpose of the intervention (coherence), 3) feeling confident in their ability to use the service (self-efficacy), 4) experiencing the service as easy to use (burden), 5) assessing service as likely to be of use in the community (effectiveness) Secondary outcomes collected at 2 weeks 1. Contraceptive method chosen by type (%) 2. Choice of LARC (%), defined as choice of an IUD or a subdermal implant for contraception 3. Change of method with respect to previous use (%) Qualitative component Data collection - qualitative component Data will be collected through semi structured in depth interviews (IDIs), held in person or by phone after the second quantitative data collection point. The sample size is estimated to be until data saturation or up to 10 interviews. The interview guide for the IDIs will be developed to capture measures of the acceptability of the TECC service according to Sekhon et al.'s framework, i.e. how participants feel about the intervention (affective attitude), how much effort is required to participate in the intervention (burden), how well the intervention fits with the participants value system (ethicality), how well the intervention is understood (coherence), what benefits must be given up to utilize the intervention (opportunity costs), how likely the intervention is to work (perceived effectiveness), and the participants confidence in being able to use the intervention (self-efficacy). Emphasis will be on enhancing the quantitative findings and gaining a more comprehensive understanding of the acceptability of the TECC intervention. Especially aspects of the framework that are more difficult to explore quantitatively, such as ethicality and opportunity costs will be explored. Questions will be open ended, allowing new themes to emerge from the data, and the interview guide may be adapted to accommodate and explore themes emerging in the interviews. RANDOMIZED CONTROLLED TRIAL Objective: Setting: Population: 510 women seeking abortion either medical or surgical, < 13+0 weeks gestation, ≥18 years of age, able to communicate and understand spoken and written English, with private access to a smart phone, and willing to participate in the study. Recruitment and consent: Recruitment, informed consent, baseline interview and randomization will take place at the clinics by one of two experienced field workers, fluent in English and isiXhosa/Afrikaans. RCT: Participants will be randomly assigned to either standard care or TECC. 1. Standard care: Contraceptive counselling with clinic nurse. 2. TECC: While waiting for their abortion consultation with the clinic nurse, participants will use their phones to complete a contraceptive counseling session through the TECC service. Outcome measures: The investigators will compare effectiveness and acceptability of the service between the telemedicine and the standard care arm. Follow-up will through links ot online surveys in RedCap at 12 weeks, 6 months and 12 months after the initial consultation. Primary outcome at 12 weeks Uptake of LARC, defined as uptake of an IUD or a subdermal implant for contraception, within 12 weeks Secondary outcomes at 12 weeks 1. choice of LARC 2. uptake of any contraception 3. choice or uptake of new method with regards to previous use 4. satisfaction with TECC service (using a a multi-question validated scale) 5. Rated use of service for decision making (using a multi-question validated scale) 6. Degree of agency in decision making (using a a multi-question validated scale) 7. preference for counselling Secondary outcomes at 6 months 1. continued use of LARC 2. continued use of any contraception 3. recurrent unintended pregnancy 4. recurrent abortion Secondary outcomes at 12 months 1. continued use of LARC 2. continued use of any contraception 3. recurrent unintended pregnancy 4. recurrent abortion 5. Change of method at any timepoint up to 12 months 6. Reason for change of method

Vaginal Microbiome Research Consortium for Africa

This investment forms part of the BMGF Calestous Juma Scientific Leadership (CJSL) Fellowship to Dr Jo-Ann Passmore, to pilot VMRC4Africa and establish a collaborative regional network with African partners and Centres of Excellence with capacity and expertise to conduct clinical trials and vaginal microbiome research in Africa. With this CJSL Fellowship investment, Dr Passmore and her collaborators aim to enrol parallel cohorts of women from two sites in two African countries (South Africa: Desmond Tutu HIV Foundation [DTHF] and Kenya Medical Research Institute [KEMRI]) to evaluate detailed temporal fluctuations in vaginal microbiota in young, generally healthy women from Southern and Eastern Africa. These parallel cohorts will be intensively followed for 10 weeks, to create detailed profiles of vaginal microbial community state types (CSTs; by 16S rRNA gene sequencing) and fungal communities [by internal transcribed spacer (ITS) sequencing], to identify women with stable Lactobacillus-dominated microbiota, with no evidence of genital inflammation. Through the establishment of an "African vaginal microbiome biorepository", the intention will be to create a biobank from which to ultimately select geographically diverse Lactobacillus crispatus strains with health promoting characteristics that can be co-formulated into live biotherapeutic products (LBPs) to treat bacterial vaginosis (BV) for women globally.

A Study to Investigate the Effect of Baxdrostat on Ambulatory Blood Pressure in Participants With Resistant Hypertension

This is a Phase III, multicentre, randomised, double-blind, placebo-controlled, parallel group study to evaluate the safety, tolerability and the effect of 2 mg baxdrostat versus placebo, administered once a day (QD) orally, on the reduction of ambulatory SBP in participants with rHTN, defined as BP targets not being achieved in an individual despite the use of at least 3 antihypertensive agents of different classes (at maximum tolerated dose in the judgement of the Investigator), one of which is a diuretic.