Clinical Research Directory

Training Protocol on the Natural History of Tuberculosis

Background: \- Tuberculosis (TB) is an infectious disease that affects numerous people worldwide. Researchers are interested in actively recruiting individuals with TB for research and treatment studies. Objectives: \- To collect blood and other samples to study the natural history of tuberculosis. Eligibility: \- Individuals 2 years of age and older who have either active or latent tuberculosis. Design: * Latent TB patients: Participants will have a single study visit with a physical examination and medical history, and will provide blood samples for testing. * Active TB patients: Participants will have an initial visit with a physical examination and medical history, and will provide blood samples for testing. Participants will also provide sputum samples if required, and may have an optional skin punch biopsy to collect a sample of skin tissue for study. * Treatment for active TB will be provided as part of this protocol. * Active TB participants may be asked to return for study visits every 1-2 months while receiving treatment.

Pharmacokinetic Study to Evaluate Anti-mycobacterial Activity of TMC207 in Combination With Background Regimen (BR) of Multidrug Resistant Tuberculosis (MDR-TB) Medications for Treatment of Children/Adolescents With Pulmonary MDR-TB

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (explores what the body does to the drug), and anti-mycobacterial activity of bedaquiline (TMC207) in children and adolescents (0 months to less than \[\<\] 18 years of age) diagnosed with confirmed or probable pulmonary multidrug resistant tuberculosis (MDR-TB), in combination With a Background Regimen (BR) of MDR-TB Medications.

Bioneer Q-RFIA Clinical Evaluation

Robust evidence on the clinical diagnostic accuracy and operational characteristics of the Bioneer Accupower Q-RFIA PCR kit on IRON qPCR is required to comprehensively evaluate validity of the Bioneer RFIA assay to support both global and national policy decision-making. The rapid diagnosis and appropriate treatment of M/XDR-TB is essential to prevent significant morbidity, mortality and further transmission of disease. The FQ are key components of the new bedaquiline-containing 6-9 month regimen, and so it is necessary to rule-out resistance to these compounds prior to treating patients with the shorter regimen. Currently there are no WHO endorsed test that can diagnose MTB and identify resistance to both first and second-line drugs in a single assay cartridge with integrated sample preparation.

Program for Rifampicin-Resistant Disease With Stratified Medicine for Tuberculosis

PRISM-TB is an international, seamless, multicenter, open-label, randomized, controlled, pragmatic, stratified medicine, treatment shortening, multi-arm multi-stage (MAMS), noninferiority Phase 2/3 clinical trial for fluoroquinolone-susceptible multidrug-resistant/rifampin-resistant pulmonary tuberculosis (FQ-S MDR/RR-TB). In Stage 1, participants will be randomized among one of three treatment arms (one control and two experimental). Following the interim analysis (at the end of Stage 1) based on DOOR outcome comparisons and the entirety of the data, one of the four possible experimental strategies will be identified and continue into Stage 2. In Stage 2, participants will be randomized among one of two treatment arms (one control and one experimental). The trial objective is to identify, among participants with fluoroquinolone-susceptible multidrug-resistant/rifampicin-resistant tuberculosis (FQ-S MDR/RR-TB), the preferred BPaLM strategy of 13 or 17 weeks for participants stratified to receive shorter treatment and 17 or 24 weeks for participants stratified to receive longer treatment, as defined by a prespecified stratification algorithm, and to evaluate whether this BPaLM strategy has noninferior efficacy to the control strategy at Week 73.

Linezolid Dosing Strategies in Drug-Resistant TB

The purpose of the study is to evaluate the efficacy (how well the medicines work) and tolerability (whether participants stop treatment because of side effects from a drug or treatment) of an anti-TB treatment regimen that compares two doses of linezolid (LZD), combined with bedaquiline (BDQ), delamanid (DLM), and clofazimine (CFZ). This study will also measure the level of these medicines in the participants' blood.

Efficacy and Tolerability of Bedaquiline, Delamanid, Levofloxacin, Linezolid, and Clofazimine to Treat MDR-TB

Multidrug-resistant tuberculosis (MDR-TB) is tuberculosis (TB) that is resistant to at least isoniazid and rifampicin, the two most important anti-TB drugs. It occurs in 3.6% of newly diagnosed TB patients in the world and 17% of patients who have been previously treated. In 2017, approximately 600,000 people were estimated to have acquired MDR-TB. However, only 25% of persons with MDR-TB were diagnosed and started on treatment, reflecting inadequate diagnostic capacity and lack of TB treatment capacity. In this multicenter, randomized, partially blinded, four-arm, phase 2 study, the investigators will examine the efficacy and safety of an all-oral regimen of bedaquiline, delamanid, levofloxacin, linezolid, and clofazimine given for 16, 24, 32 or 40 weeks

Strengthening Evidence on Optimal Multidrug-resistant Tuberculosis Treatment Regimens

This is a multisite prospective cohort study of patients with multidrug- or rifampin-resistant tuberculosis who are treated with an all-oral shortened regimen under routine program conditions in one of three countries (Peru, Lesotho, Kazakhstan).

Registry on the Effectiveness and Safety of the 9-month MDR-END Treatment Regimen in Korean Patients with FQ-sensitive MDR-TB (MDR-END Registry)

This study is to evaluate the effectiveness and safety of a 9-month MDR-END regimen as a treatment for fluoroquinolone-sensitive multidrug resistant pulmonary tuberculosis in the real-world clinical setting. It will be conducted as a non-interventional, prospective, single group, multicenter design. Subjects who are considered to meet the inclusion /exclusion criteria will receive MDR-END regimen for 9 months (or 12 months) during the treatment period according to the 5th edition of the Korean Guidelines for Tuberculosis, and will be followed-up for 12 months after the end of treatment.

Hotspots, Households and Hospitals: Enhanced Drug-resistant Tuberculosis Case Finding in Namibia

Poor case management, pharmacokinetic variability and on-going transmission have fostered the drug-resistant tuberculosis (DR-TB) epidemic leading to a global estimated number of \>500,000 new multidrug resistant (MDR) TB cases per year, of which roughly 10% are extensively drug resistant (XDR). Namibia is a high TB burden country with an incidence rate of 446/100,000 in 2016; about 11,000 new cases per year. 3.9% of new cases and 8.7% of previously treated cases have MDR-TB. Whole genome sequencing (WGS) has recently been applied to interrogate the complete genetic code of Mycobacterium tuberculosis (Mtb) strains. WGS can be used to infer relationships between identified strains as well as determine genomic variations involved in resistance development. The specific aims of the H3TB study are to: (i) characterise the DR-TB epidemic, in terms of clinical, epidemiological, geospatial, social network and laboratory data, to identify transmission hotspots in three regions of Namibia, (ii) evaluate the feasibility of targeted case finding intervention strategies to improve DR-TB control in highly affected populations and (iii) develop a transmission model to investigate the potential impact of the case finding intervention strategies on DR-TB incidence in Namibia. A prospective surveillance study started in January 2020, which includes all DR-TB cases in Namibia, and which will nest H3TB. Data collection tools and other study implementation tools have been designed and implemented. The study team is working in close collaboration with the National Institute of Pathology, where all DR-TB cases from the country are registered, to ensure all possible cases are captured. This is important for the identification of transmission hotspots. After HREC and MOHSS approval, individuals with GeneXpert® MTB/RIF rifampicin-resistant samples and a positive Mtb culture from three regions in Namibia will be included in a transmission hotspot identification study. Preliminary data have shown that DR-TB clusters exist in these regions. Clinical, epidemiological, geospatial, social network and laboratory data (GeneXpert® MTB/RIF, culture, drug sensitivity tests) will be collected. WGS capacity has been established at the UNAM research laboratory, where WGS will be performed on the samples of H3TB participants; results will be validated at the Research Center Borstel in Germany. These study results in conjunction with a systematic review and meta-analysis will inform the design of case finding interventions which will be evaluated through a mixed-methods feasibility study conducted at high transmission areas (hotspots, households and hospitals). Data from these studies and the TB programme will be used to develop the model which will include a health economics component. The study will strengthen DR-TB diagnosis, surveillance and control, inform DR-TB case finding policy in Namibia and regionally, inform resource allocation by identifying high transmission areas and create preliminary data to design a large scale DR-TB case finding intervention.

Test to Treat TB: Impact of Sputum Sequencing-guided Individualised Therapy on Outcomes in Drug-resistant Tuberculosis

Resistance to anti-tuberculosis drugs is a continually growing problem. Multidrug-resistant tuberculosis (MDRTB) is resistance to at least rifampicin and isoniazid, and extensively drug-resistant TB is additional resistance to a fluoroquinolone and a second injectable line drug. Methods currently employed in testing for resistance are inadequate and a contributing factor to the 40-50% MDR-TB treatment success rate. Current drug susceptibility testing methods are slow for most drugs, taking weeks. Rapid molecular methods such as the line probe assays, e.g. Hain GenoType MDRTBplus and sl, provide resistant calls to only a limited number of drugs, and are often less useful in smear negative patients. Molecular technologies such as sequencing can provide a comprehensive readout of drug resistance and are able to detect resistant populations at very low levels (≤1%), thus enabling individualized therapy. This can be done directly from sputum. Targeted sequencing amplifies regions of genomic DNA associated with resistance prior to sequencing. Rapid analytic software is used to process the raw sequence data, identify resistance causing mutations and provide a readout of clinically relevant information. However, the feasibility, and more importantly the impact, of this approach has not been evaluated in a clinical trial to establish proof of concept. Aim 1: To conduct a randomised controlled trial to determine the impact of sputum-based targeted sequencing in detecting resistance to second-line TB drugs compared to the current programmatic standard of care (Hain MDRTBplus/sl and adjunct phenotypic drug susceptibility testing) when used to inform of treatment for MDR-TB. Aim 2: To compare currently available drug resistant sequencing pipelines for diagnostic accuracy, sensitivity, specificity and predictive value as compared to culture based phenotypic drug susceptibility testing. Aim 3: To compare the feasibility, accuracy, turn-aroundtime, and cost implications of the above-mentioned diagnostic approaches.