Study 1 (NCT00449644, Stage 2) was a placebo-controlled, double-blind, randomized trial conducted in patients with newly diagnosed sputum smear-positive pulmonary TB due to M. tuberculosisresistant to at least rifampin and isoniazid. Patients were randomized to receive a combination of SIRTURO or placebo with five other antimycobacterial drugs (i.e., ethionamide, kanamycin, pyrazinamide, ofloxacin, and cycloserine/terizidone or available alternative) for a total duration of 18 to 24 months or at least 12 months after the first confirmed negative culture. Treatment was 24 weeks of treatment with SIRTURO 400 mg once daily for the first two weeks followed by 200 mg three times per week for 22 weeks or matching placebo for the same duration. Overall, 79 patients were randomized to the SIRTURO arm and 81 to the placebo arm. A final evaluation was conducted at Week 120. 

Sixty-seven patients randomized to SIRTURO and 66 patients randomized to placebo had confirmed pulmonary TB due to M. tuberculosisresistant to at least rifampin and isoniazid, based on susceptibility tests (taken prior to randomization) or medical history if no susceptibility results were available, and were included in the efficacy analyses. Demographics were as follows: 64% of the study population was male, with a median age of 33 years, 38% were Black, 17% were Hispanic, 11% were White, 11% were Asian, and 24% were of another race; and 14% were HIV-positive (median CD4 cell count 446 cells/µL). Most patients had cavitation in one lung (62%); and 20% of patients had cavitation in both lungs. 

Time to sputum culture conversion was defined as the interval in days between the first dose of study drug and the date of the first of two consecutive negative sputum cultures collected at least 25 days apart during treatment. In this trial, the SIRTURO treatment group had a decreased time to culture conversion and improved culture conversion rates compared to the placebo treatment group at Week 24. Median time to culture conversion was 83 days for the SIRTURO treatment group compared to 125 days for the placebo treatment group. Table 8 shows the proportion of patients with sputum culture conversion at Week 24 and Week 120.

Study 2 (NCT00449644, Stage 1) was a smaller placebo-controlled study designed similarly to Study 1 except that SIRTURO or placebo was given for only eight weeks instead of 24 weeks. Patients were randomized to either SIRTURO and other drugs used to treat pulmonary TB due to M. tuberculosisresistant to at least rifampin and isoniazid (SIRTURO treatment group) (n=23) or placebo and other drugs used to treat TB (placebo treatment group) (n=24). Twenty-one patients randomized to the SIRTURO treatment group and 23 patients randomized to the placebo treatment group had confirmed pulmonary TB due to M. tuberculosisresistant to at least rifampin and isoniazid based on patients' baseline M. tuberculosisisolate obtained prior to randomization. The SIRTURO treatment group had a decreased time to culture conversion and improved culture conversion rates compared to the placebo treatment group at Week 8. At Weeks 8 and 24, the differences in culture conversion proportions were 38.9% [95% CI: (12.3%; 63.1%) and p-value: 0.004], 15.7% [95% CI: (-11.9%; 41.9%) and p-value: 0.32], respectively. 

Study 3 (NCT00910871) was a Phase 2b, uncontrolled study to evaluate the safety, tolerability, and efficacy of SIRTURO as part of an individualized treatment regimen in 233 patients with sputum smear positive (within 6 months prior to screening) pulmonary TB due to M. tuberculosisresistant to at least rifampin and isoniazid, including patients with isolates resistant to second-line injectables and/or fluoroquinolones. Patients received SIRTURO for 24 weeks in combination with antimycobacterial drugs. Upon completion of the 24-week treatment with SIRTURO, all patients continued to receive their background regimen in accordance with national TB program (NTP) treatment guidelines. A final evaluation was conducted at Week 120. Treatment responses to SIRTURO at Week 120 were generally consistent with those from Study 1. 

Study 4 (NCT02409290) was a Phase 3, open-label, multicenter, active-controlled, randomized trial to evaluate the efficacy and safety of SIRTURO, coadministered with other oral anti-TB drugs for 40 weeks in patients with sputum smear-positive pulmonary TB caused by M. tuberculosisthat was resistant to at least rifampin. Patients in whom the M. tuberculosisstrain was known to be resistant at screening to second-line injectable agents or fluoroquinolones were excluded from enrollment. When phenotypic susceptibility testing of the baseline isolates became available post-randomization, patients infected with M. tuberculosisresistant to either second-line injectable agents or fluoroquinolones were kept in the study, however, those with M. tuberculosisresistant to both second-line injectables and fluoroquinolones were discontinued from the study. 

Patients were randomized to one of four treatment arms:

  * Arm A (N=32), the locally used treatment in accordance with 2011 WHO treatment guidelines with a recommended 20-month duration
  * Arm B (N=202), a 40-week treatment of moxifloxacin (N=140) or levofloxacin (N=62), clofazimine, ethambutol, pyrazinamide, supplemented by injectable kanamycin, high-dose isoniazid and prothionamide in the first 16 weeks (intensive phase)
  * Arm C (N=211), a 40-week, all-oral treatment of SIRTURO, levofloxacin, clofazimine, ethambutol, and pyrazinamide, supplemented by high-dose isoniazid and prothionamide in the first 16 weeks (intensive phase)
  * Arm D (N=143), a 28-week treatment consisting of SIRTURO, levofloxacin, clofazimine, and pyrazinamide, supplemented by kanamycin injectable and a higher isoniazid dose for the first eight weeks (intensive phase)



SIRTURO was administered 400 mg once daily for the first two weeks and 200 mg three times a week for the following 38 weeks (in Arm C) or 26 weeks (in Arm D).

All patients were to be followed up until study completion at Week 132. During study conduct, enrollment in Arms A and D was stopped due to changes in the standard of care for TB treatment. Patients already randomized to these study arms were to complete their assigned treatment and follow-up.

The primary objective was to assess whether the proportion of patients with a favorable efficacy outcome in Arm C was noninferior to that in Arm B at Week 76.

The primary efficacy outcome measure was the proportion of patients with a favorable outcome at Week 76. A favorable outcome at Week 76 was defined as the last two consecutive cultures being negative, and with no unfavorable outcome. An unfavorable outcome at Week 76 was assessed as a composite endpoint, covering both clinical and microbiological aspects such as changes in TB treatment, all-cause mortality, at least one of the last two culture results positive, or no culture results within the Week 76 window. In case of treatment failure, recurrence or serious toxicity on the allocated treatment, salvage treatment that could include SIRTURO was provided, based on investigator judgment.

The modified intent-to-treat population (mITT) was the primary efficacy population and included all randomized patients with a positive sputum culture for M. tuberculosisthat was resistant to at least rifampin and not resistant to both second-line injectables and fluoroquinolones, based on susceptibility results (taken prior to randomization). A total of 196 and 187 patients were included in the mITT population in Arm C and Arm B, respectively. Overall, in both treatment arms, 62% were male of median age 33 years, 47% were Asian, 34% were Black, 19% were White, and 14% were HIV-coinfected. Most patients had lung cavitation (74%), with multiple cavities in 63% and 47% of patients in Arm C and Arm B, respectively. The baseline drug resistance profile of M. tuberculosisfor Arms C and B were as follows: 14% had resistance to rifampin while susceptible to isoniazid, 75% had resistance to rifampin and isoniazid, and 10% had resistance to rifampin, isoniazid, and either a second-line injectable or a fluoroquinolone. 

For efficacy analyses beyond Week 76, data collection was stopped at the point when the last recruited patient was projected to reach Week 96. The long-term efficacy data therefore include data up to at least Week 96 for all patients, and up to Week 132 for 146/196 (74.5%) patients in Arm C and 145/187 (77.5%) patients in Arm B.

Table 9 shows results for favorable and unfavorable outcomes at Week 76 and Week 132 in Study 4.