The most frequent adverse drug reactions ( > 10.0% of patients) during treatment with SIRTURO in the controlled trials were nausea, arthralgia, and headache. Additional adverse events reported in ≥ 10% of patients treated with SIRTURO and with a higher frequency than the placebo treatment group were hemoptysis and chest pain.
Clinical Studies Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.
Adverse drug reactions for SIRTURO were identified from the pooled safety data from 335 bedaquiline-exposed patients who received 8 weeks (Study 2) and 24 weeks (Studies 1 and 3) at the proposed dose. Studies 1 and 2 are randomized, double-blind, placebo-controlled trial in newly diagnosed patients with pulmonary MDR-TB. In both treatment arms, patients received SIRTURO or placebo in combination with other drugs used to treat MDR-TB. Study 3 is an ongoing, open-label, noncomparative study with SIRTURO administered as part of an individualized pulmonary MDR-TB treatment regimen in previously treated patients.
In Study 1 overall, 35.0% were Black, 17.5% were Hispanic, 12.5% were White, 9.4% were Asian, and 25.6% were of another race. Eight of 79 (10.1%) patients in the SIRTURO group and 16 of 81 (19.8%) patients in the placebo treatment group were HIV-infected. Seven (8.9%) SIRTURO-treated patients and six (7.4%) placebo-treated patients discontinued Study 1 because of an adverse event.
Table 1: Select Adverse Drug Reactions from Study 1 That Occurred More Frequently Than Placebo During Treatment with SIRTURO
|Adverse Drug Reactions||SIRTURO Treatment Group
|Placebo Treatment Group
|Nausea||30 (38.0)||26 (32.1)|
|Arthralgia||26 (32.9)||18 (22.2)|
|Headache||22 (27.8)||10 (12.3)|
|Transaminases Increased*||7 (8.9)||1 (1.2)|
|Blood Amylase Increased||2 (2.5)||1 (1.2)|
|Hemoptysis†||14 (17.7)||9 (11.1)|
|Chest Pain†||9 (11.4)||6 (7.4)|
|Anorexia†||7 (8.9)||3 (3.7)|
|Rash†||6 (7.6)||3 (3.7)|
|* Terms represented by 'transaminases increased' included transaminases increased, AST increased, ALT increased, hepatic enzyme increased, and hepatic function abnormal.
† Reported Adverse Events with a greater incidence in the SIRTURO treatment group but which were not identified as adverse drug reactions.
No additional unique ADRs were identified from the uncontrolled Study 3.
In Study 1, there was a statistically significant increased mortality risk by Week 120 in the SIRTURO treatment group compared to the placebo treatment group (9/79 (11.4%) versus 2/81 (2.5%), p-value=0.03, an exact 95% confidence interval of the difference [1.1%, 18.2%]). Five of the 9 SIRTURO deaths and the 2 placebo deaths were TB-related. One death occurred during the 24-week SIRTURO treatment period. The median time to death for the remaining eight subjects in the SIRTURO treatment group was 329 days after last intake of SIRTURO. The imbalance in deaths is unexplained; no discernible pattern between death and sputum conversion, relapse, sensitivity to other drugs used to treat TB, HIV status, and severity of disease was observed.
In Study 1, the mean increases in QTc, corrected using the Fridericia method, were greater in the SIRTURO treatment group compared to the placebo treatment group from the first week of treatment (9.9 ms at Week 1 for SIRTURO and 3.5 ms for placebo). The largest mean increase in QTc during the 24 weeks of SIRTURO treatment was 15.7 ms compared to 6.2 ms with placebo treatment (at Week 18). QT increases from baseline in the SIRTURO group persisted even after SIRTURO treatment was stopped. During the trial, there was no clear correlation of antecedent significant QT prolongation or clinically significant dysrhythmia in any of the subjects that died.
In Study 3, where patients with no treatment options received other QT-prolonging drugs used to treat TB, including clofazimine, concurrent use with SIRTURO resulted in additive QT prolongation, proportional to the number of QT prolonging drugs in the treatment regimen. Patients receiving SIRTURO alone with no other QT prolonging drug developed a mean QTcF increase over baseline of 23.7 ms with no QT segment duration in excess of 480 ms, whereas patients with at least 2 other QT prolonging drugs developed a mean QTcF prolongation of 30.7 ms over baseline, resulting in QTcF segment durations in excess of 500 ms in one patient.
There were no documented cases of Torsade de Pointes in the safety database [see WARNINGS AND PRECAUTIONS].
Hepatic-Related ADRs (Including Abnormalities In Serum Transaminases)
Hepatic ADRs developed in more SIRTURO-treated patients than those treated with other drugs used to treat TB.
Laboratory tests: In both Studies 1 and 2, reversible aminotransferase elevations of at least 3xULN developed more frequently in the SIRTURO treatment group (11/102 [10.8%] vs 6/105 [5.7%] in the placebo treatment group.
Reported adverse reactions: In Study 1, increased aminotransferases were reported in 7/79 (8.9%) patients in the SIRTURO treatment group compared to 1/81 (1.2%) patients in the placebo treatment group.