Evaluating newly approved drugs in combination regimens for multidrug-resistant tuberculosis with fluoroquinolone resistance (endTB-Q): study protocol for a multi-country randomized controlled trial.

BACKGROUND: Treatment for fluoroquinolone-resistant multidrug-resistant/rifampicin-resistant tuberculosis (pre-XDR TB) often lasts longer than treatment for less resistant strains, yields worse efficacy results, and causes substantial toxicity. The newer anti-tuberculosis drugs, bedaquiline and delamanid, and repurposed drugs clofazimine and linezolid, show great promise for combination in shorter, less-toxic, and effective regimens. To date, there has been no randomized, internally and concurrently controlled trial of a shorter, all-oral regimen comprising these newer and repurposed drugs sufficiently powered to produce results for pre-XDR TB patients. METHODS: endTB-Q is a phase III, multi-country, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of a treatment strategy for patients with pre-XDR TB. Study participants are randomized 2:1 to experimental or control arms, respectively. The experimental arm contains bedaquiline, linezolid, clofazimine, and delamanid. The control comprises the contemporaneous WHO standard of care for pre-XDR TB. Experimental arm duration is determined by a composite of smear microscopy and chest radiographic imaging at baseline and re-evaluated at 6 months using sputum culture results: participants with less extensive disease receive 6 months and participants with more extensive disease receive 9 months of treatment. Randomization is stratified by country and by participant extent-of-TB-disease phenotype defined according to screening/baseline characteristics. Study participation lasts up to 104 weeks post randomization. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 324 participants across 2 arms affords at least 80% power to show the non-inferiority, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per-protocol populations. DISCUSSION: This internally controlled study of shortened treatment for pre-XDR TB will provide urgently needed data and evidence for clinical and policy decision-making around the treatment of pre-XDR TB with a four-drug, all-oral, shortened regimen. TRIAL REGISTRATION: ClinicalTrials.Gov NCT03896685. Registered on 1 April 2018; the record was last updated for study protocol version 4.3 on 17 March 2023.

Setting up pharmacovigilance based on available endTB Project data for bedaquiline.

SETTING: Active pharmacovigilance (PV) is recommended for TB programmes, notably for multidrug-resistant TB (MDR-TB) patients treated with new drugs. Launched with the support of UNITAID in April 2015, endTB (Expand New Drug markets for TB) facilitated treatment with bedaquiline (BDQ) and/or delamanid of >2600 patients in 17 countries, and contributed to the creation of a central PV unit (PVU).OBJECTIVE: To explain the endTB PVU process by describing the serious adverse events (SAEs) experienced by patients who received BDQ-containing regimens.DESIGN: The overall PV strategy was in line with the 'advanced´ WHO active TB drug safety monitoring and management (aDSM) system. All adverse events (AEs) of clinical significance were followed up; the PVU focused on signal detection from SAEs.RESULTS and CONCLUSION: Between 1 April 2015 and 31 March 2019, the PVU received and assessed 626 SAEs experienced by 417 BDQ patients. A board of MDR-TB/PV experts reviewed unexpected and possibly drug-related SAEs to detect safety signals. The experts communicated on clusters of risks factors, notably polypharmacy and off-label drug use, encouraging a patient-centred approach of care. Organising advanced PV in routine care is possible but demanding. It is reasonable to expect local/national programmes to focus on clinical management, and to limit reporting to aDSM systems to key data, such as the SAEs.

Pharmacokinetic Evidence from the HIRIF Trial To Support Increased Doses of Rifampin for Tuberculosis.

Rifamycins exhibit concentration-dependent killing of Mycobacterium tuberculosis; higher exposures potentially induce better outcomes. We randomized 180 tuberculosis patients in Peru to receive rifampin at 10, 15, or 20 mg/kg/day. A total of 168 had noncompartmental pharmacokinetic analyses; 67% were sampled twice, and 33% were sampled six times. The doses administered were well tolerated. The median area under the concentration-time curve from 0 to 6 h (interquartile range) was 24.9 (17.6 to 32.1), 43.1 (30.3 to 57.5), or 55.5 (35.7 to 73.2) h · µg/ml. The median maximum drug concentration in serum in the experimental arms reached the target of 8 µg/ml. Continued investigation of higher rifampin doses is warranted. (This study has been registered at ClinicalTrials.gov under registration no. NCT01408914.).