SIRTURO® Clinical Trials

ADULT PATIENTS

Study 1

Study Design

A placebo-controlled, double-blind, randomized trial (Study 1) was conducted in patients with newly diagnosed sputum smear-positive with multi-drug resistant pulmonary Mycobacterium tuberculosis.

Patients were randomized to receive treatment with:

  • SIRTURO® (bedaquiline) and other drugs used to treat MDR-TB (SIRTURO® treatment group) (n=79); or
  • placebo plus other drugs used to treat MDR-TB (placebo treatment group) (n=81)

The other drugs used to treat MDR-TB consisted of a combination of 5 other antimycobacterial drugs:

  • ethionamide
  • kanamycin
  • pyrazinamide
  • ofloxacin
  • cycloserine/terizidone or available alternative

SIRTURO® was administered as 400 mg once daily for the first 2 weeks and as 200 mg 3 times per week for the following 22 weeks.

After the 24-week study drug (SIRTURO® or placebo) treatment phase, patients continued to receive their other drugs used to treat MDR-TB until a total treatment duration of 18 to 24 months was achieved, or at least 12 months after the first confirmed negative culture.

Sixty-seven patients randomized to SIRTURO® and 66 patients randomized to placebo had confirmed MDR-TB, based on susceptibility tests (taken prior to randomization) or medical history if no susceptibility results were available, and were included in the efficacy analyses.

Study Population

  • 63% Male
  • Median age 34 years
  • 35% Black
  • 15% HIV positive
  • Most patients had cavitation in one lung (62%)
  • Cavitation in both lungs was observed in 18% of patients

Results

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 2 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.
  • The table below shows the proportion of patients with sputum culture conversion after 24 weeks and 120 weeks of treatment with SIRTURO® or placebo in combination with other drugs used to treat MDR-TB.

Culture Conversion Status

Study 2

Study Design

Study 2 was a smaller placebo-controlled study designed similarly to Study 1, except that SIRTURO® or placebo was given for only 8 weeks instead of 24 weeks.

Patients were randomized to receive treatment with:

  • SIRTURO® and other drugs used to treat MDR-TB (SIRTURO® treatment group) (n=23); or
  • placebo and other drugs used to treat MDR-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 MDR-TB based on patients’ baseline Mycobacterium tuberculosis isolate obtained prior to randomization.

Results

At Week 8, compared to the placebo treatment group, the SIRTURO® treatment group had:

  • Decreased time to culture conversion
  • Improved culture conversion rates

At Weeks 8 and 24 respectively, 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)

Study 3

Study Design:

Study 3 was a Phase 2b, uncontrolled study to evaluate the safety, tolerability, and efficacy of SIRTURO® as part of an individualized MDR-TB treatment regimen in 233 patients with sputum smear positive (within 6 months prior to screening) pulmonary MDR-TB. Patients received SIRTURO® for 24 weeks in combination with antibacterial 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.

Pediatric Patients (5 years to less than 18 years of age)

The pediatric trial, (Study 4, NCT02354014), was designed as a single-arm, open-label, multi-cohort trial to evaluate the pharmacokinetics, safety and tolerability of SIRTURO® in combination with a background regimen in patients 5 to less than 18 years of age with confirmed or probable pulmonary MDR-TB infection.

Pediatric Patients (12 years to less than 18 years of age)

Fifteen patients ages 14 years to less than 18 years of age were enrolled in the first cohort. The median age was 16 years, 80% were female, 53% were Black, 33% were White and 13% were Asian. No patient 12 years to less than 14 years of age was enrolled in this cohort. SIRTURO® was administered as 400 mg once daily for the first 2 weeks and 200 mg 3 times/week for the following 22 weeks using the 100 mg tablet.

In the subset of patients with culture positive pulmonary MDR-TB at baseline, treatment with bedaquiline resulted in conversion to a negative culture in 75.0% (6/8 patients) at Week 24.

Pediatric Patients (5 years to less than 12 years of age)

Fifteen patients ages 5 years to 10 years of age were enrolled in the second cohort. The median age was 7 years, 60% were female, 60% were Black, 33% were White and 7% were Asian. No patient older than 10 years to less than 12 years of age was enrolled in this cohort. The body weight range was 14 kg to 36 kg; only 1 patient weighing 14 kg was enrolled. SIRTURO® was administered as 200 mg once daily for the first 2 weeks and 100 mg 3 times/week for the following 22 weeks using the 20 mg tablet.

In the subset of patients with culture positive pulmonary MDR-TB at baseline, treatment with bedaquiline resulted in conversion to a negative culture in 100% (3/3 patients) at Week 24.