SIRTURO® Clinical Trials

Study 1

Study Design

A placebo-controlled, double-blind, randomized trial (Study 1) was conducted in newly diagnosed patients 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 subjects’ 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.

INDICATIONS AND USAGE

SIRTURO® (bedaquiline) is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in the treatment of adults (≥18 years) with pulmonary multi drug resistant tuberculosis (MDR TB). Reserve SIRTURO® for use when an effective treatment regimen cannot otherwise be provided. Administer SIRTURO® by directly observed therapy (DOT).

This indication is approved under accelerated approval based on time to sputum culture conversion. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Limitations of Use

Do not use SIRTURO® for the treatment of:

  • Latent infection due to Mycobacterium tuberculosis
  • Drug-sensitive tuberculosis
  • Extrapulmonary tuberculosis
  • Infections caused by non-tuberculous mycobacteria

The safety and efficacy of SIRTURO® in the treatment of HIV-infected patients with MDR-TB have not been established as clinical data are limited.

IMPORTANT SAFETY INFORMATION

WARNINGS: INCREASED MORTALITY; QT PROLONGATION

    Increased Mortality
  • An increased risk of death was seen in the SIRTURO® treatment group (9/79, 11.4%) compared to the placebo treatment group (2/81, 2.5%) in one placebo-controlled trial. Only use SIRTURO® when an effective treatment regimen cannot otherwise be provided.
    QT Prolongation
  • QT prolongation can occur with SIRTURO®. Use with drugs that prolong the QT interval may cause additive QT prolongation. Monitor ECGs. Discontinue SIRTURO® if significant ventricular arrhythmia or if QTcF interval prolongation of greater than 500 ms develops.

Warnings and Precautions

Increased Mortality

An increased risk of death was seen in the SIRTURO® treatment group. The imbalance in deaths is unexplained. No discernible pattern between death and sputum culture conversion, relapse, sensitivity to other drugs used to treat tuberculosis, HIV status, or severity of disease could be observed. Only use SIRTURO® when an effective treatment regimen cannot otherwise be provided.

QT Prolongation

SIRTURO® prolongs the QT interval. Obtain an ECG before initiation of treatment, and at least 2, 12, and 24 weeks after starting treatment with SIRTURO®. Obtain serum potassium, calcium, and magnesium at baseline and correct if abnormal. Monitor electrolytes if QT prolongation is detected.

SIRTURO® has not been studied in patients with ventricular arrhythmias or recent myocardial infarction.

The following may increase the risk for QT prolongation when patients are receiving SIRTURO®: use with other QT prolonging drugs including fluoroquinolones and macrolide antibacterial drugs and the antimycobacterial drug, clofazimine; a history of Torsade de Pointes; a history of congenital long QT syndrome; a history of or ongoing hypothyroidism; a history of or ongoing bradyarrhythmias; a history of uncompensated heart failure; serum calcium, magnesium, or potassium levels below the lower limits of normal

If necessary, bedaquiline treatment initiation could be considered in these patients after a favorable benefit risk assessment and with frequent ECG monitoring.

Discontinue SIRTURO® and all other QT prolonging drugs if the patient develops clinically significant ventricular arrhythmia or a QTcF interval of greater than 500 ms (confirmed by repeat ECG).

If syncope occurs, obtain an ECG to detect QT prolongation.

Hepatotoxicity

More hepatic-related adverse drug reactions were reported with the use of SIRTURO® plus other drugs to treat tuberculosis compared to other drugs used to treat tuberculosis without the addition of SIRTURO®. Alcohol and other hepatotoxic drugs should be avoided while on SIRTURO®, especially in patients with impaired hepatic function.

Monitor symptoms (such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, and hepatomegaly) and laboratory tests (ALT, AST, alkaline phosphatase, and bilirubin) at baseline, monthly while on treatment, and as needed. Test for viral hepatitis and discontinue other hepatotoxic medications if evidence of new or worsening liver dysfunction occurs. Discontinue SIRTURO® if:

  • aminotransferase elevations are accompanied by total bilirubin elevation greater than two times the upper limit of normal
  • aminotransferase elevations are greater than eight times the upper limit of normal
  • aminotransferase elevations are greater than five times the upper limit of normal and persist beyond two weeks

Drug Interactions

CYP3A4 Inducers/Inhibitors: Bedaquiline is metabolized by CYP3A4 and its systemic exposure and therapeutic effect may therefore be reduced during co-administration with inducers of CYP3A4. Avoid coadministration of strong CYP3A4 inducers such as rifamycins (i.e., rifampin, rifapentine, and rifabutin) or moderate CYP3A4 inducers such as efavirenz. Co-administration of SIRTURO® with strong CYP3A4 inhibitors may increase the systemic exposure to bedaquiline, which could potentially increase the risk of adverse reactions. Therefore, avoid the use of strong CYP3A4 inhibitors used for more than 14 consecutive days while on SIRTURO®, unless the benefit of treatment with the drug combination outweighs the risk. Appropriate clinical monitoring for SIRTURO®-related adverse reactions is recommended.

Adverse Reactions

Adverse reactions that occurred more frequently than placebo during treatment with SIRTURO® included: nausea (38% vs. 32%), arthralgia (33% vs. 22%), headache (28% vs. 12%), hemoptysis (18% vs. 11%), chest pain (11% vs. 7%), anorexia (9% vs. 4%), transaminases increased (9% vs. 1%), rash (8% vs. 4%), and blood amylase increased (3% vs. 1%).

Please see full Prescribing Information, including Boxed Warnings and Medication Guide, for more details.