Trial 1

Trial 1 (NCT02333799) was an open-label trial conducted in three centers in South Africa in patients with pulmonary TB resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug (Population 1), or pulmonary TB resistant to isoniazid and rifampin, who were treatment-intolerant or non-responsive to standard therapy (Population 2). Fifty-six (51%) patients were HIV-positive. The patients received a combination regimen of Pretomanid Tablets, bedaquiline, and linezolid for 26 weeks (extended to 9 months in 2 patients) with 24 months of follow-up. The dosage of Pretomanid Tablets was 200 mg orally once daily. The dosage of bedaquiline was 400 mg orally once daily for 2 weeks followed by 200 mg 3 times per week for 24 weeks. The starting dose of linezolid was either 600 mg orally twice daily or 1,200 mg orally once daily. One hundred seven of the 109 patients enrolled were assessable for the primary efficacy analyses with two patients remaining in follow-up for the primary outcome assessment.

Treatment failure was defined as the incidence of bacteriologic failure (reinfection – culture conversion to positive status with a different M. tuberculosis strain), bacteriological relapse (culture conversion to positive status with the same M. tuberculosis strain), or clinical failure (an unfavorable status at, or before, end of treatment (EOT) or failing to attain culture negativity, or if the patient was withdrawn at or before EOT for clinical reasons including retreatment or changing treatment) through follow-up until 6 months after the EOT. Results are presented in Table 4. Of the 107 patients assessed, outcomes were classified as success for 95 (89%) patients and failure for 12 (11%) patients. The success rate significantly exceeded the historical success rates for TB resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug based on a literature review. The outcomes were similar in both HIV negative and HIV positive patients.

Trial 2

Trial 2 (NCT03086486) was a phase 3 partially blinded, randomized trial assessing the safety and efficacy of various doses and treatment durations of linezolid plus Pretomanid Tablets and bedaquiline in patients with pulmonary TB resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug, or pulmonary TB resistant to rifamycins and either a fluoroquinolone or a second line injectable antibacterial drug, or pulmonary TB resistant to isoniazid and rifampin who were treatment intolerant or non-responsive to standard therapy.

A total of 181 patients were randomized to receive one of 4 treatment regimens, of which 45 each received 1,200 mg or 600 mg linezolid orally plus Pretomanid Tablets and bedaquiline for 26 weeks, and 46 and 45 patients received 1,200 mg or 600 mg linezolid orally for 9 weeks (not an approved dosing regimen), followed by linezolid placebo for 17 weeks, respectively, plus Pretomanid Tablets and bedaquiline for 26 weeks. The dosage of Pretomanid Tablets was 200 mg orally once daily for 26 weeks. The dosage of bedaquiline was 200 mg daily for 8 weeks, followed by 100 mg daily for 18 weeks. 

Treatment failure was defined as the incidence of bacteriologic failure, bacteriologic relapse or clinical failure through follow-up until 6 months after the end of treatment, which was identical to the definition of treatment failure in Trial 1. 

The success rate in each treatment arm significantly exceeded the historical success rates for TB resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug based on a literature review used in Trial 1. When used in combination with Pretomanid Tablets and bedaquiline, linezolid 600 mg once daily for 26 weeks is preferred over linezolid 1,200 mg once daily for 26 weeks [see Dosage and Administration (2.2)]. 

Among the 90 patients receiving linezolid for 26 weeks, the mean age of the patients was 38 years old with 68% being males. Most patients were White (64%), and the remaining patients were Black (36%). Most patients had a current diagnosis (a stratification factor) of pulmonary TB resistant to rifamycins and either a fluoroquinolone or a second line injectable antibacterial drug (46%) or pulmonary TB resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug (44%), and the remainder were patients having pulmonary TB resistant to isoniazid and rifampin who were treatment intolerant or non-responsive to standard therapy (6% and 4%, respectively). The results are presented in Table 5 below.