Evaluating the Safety, Tolerability, and Pharmacokinetics of Bedaquiline and Delamanid, Alone and in Combination, For Drug-Resistant Pulmonary Tuberculosis

This study evaluated the safety, tolerability, and pharmacokinetics of the anti-tuberculosis (TB) drugs bedaquiline (BDQ) and delamanid (DLM), alone and in combination, among participants (with or without HIV co-infection) taking multidrug treatment for multidrug-resistant tuberculosis (MDR-TB) or rifampin-monoresistant TB (RR-TB).

Bedaquiline (BDQ) and delamanid (DLM) are two newly approved anti-TB drugs and are both well tolerated. However, the combined effect of these two drugs has not been studied. Combining these two drugs, together with other anti-TB drugs, may improve outcomes for people with MDR-TB or RR-TB. The purpose of this study was to evaluate the safety, tolerability, and pharmacokinetics of BDQ and DLM, alone and in combination, among participants (with or without HIV co-infection) taking multidrug treatment for MDR-TB or RR-TB, and specifically to evaluate the effect of these drugs on the heart.

Participants were randomly assigned to one of three arms: participants in Arm 1 received BDQ, participants in Arm 2 received DLM, and participants in Arm 3 received BDQ and DLM. All participants received their assigned study drugs for 24 weeks together with multidrug background treatment (MBT) for MDR-TB or RR-TB (not provided by the study). HIV-infected participants also received dolutegravir, to be used in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) until study completion. NRTIs were not provided by the study. At study entry participants were initially required to be hospitalized for 2 months, however after an interim analysis, the period of hospitalization was shortened to 2 weeks.

Study visits occurred at entry, each week for 8 weeks after study entry, every other week until week 24, and at weeks 28, 36, 48, 60, 72, 84, 96 and 128. Visits included physical examinations, blood collection, urine collection, sputum sample collection, hair sample collection, chest x-rays, pregnancy testing, electrocardiograms (ECGs), and adherence questionnaires.

Participants were also asked to take part in an optional cerebrospinal fluid sampling study that entailed a lumbar puncture, to be done at weeks 8 or 24.