The results of a National Institutes of Health-funded phase 2 study indicate the new tuberculosis (TB) drugs delamanid and bedaquiline, when combined, have only a modest effect on the electrical activity of the heart, US, South African, and Peruvian researchers have reported.
In the phase 2 randomised controlled trial, patients in South Africa and Peru with multidrug-resistant or rifampicin-resistant TB were randomised 1:1:1 to receive bedaquiline, delamanid, or both for 24 weeks. The two new drugs are considered critical components of a shorter, less toxic regimen for multidrug-resistant and rifampicin-resistant TB, but the cardiac and microbiologic safety of combining the two has not been well-established.
Both drugs are known to cause modest QTc prolongation, which can lead to an irregular heartbeat and increase the risk of sudden cardiac arrest, but the combined effect on QTc-related cardiac risk is unknown.
A total of 84 participants were enrolled in the trial from August 2016 through July 2018, with 28 in each treatment group and patients with higher-than-normal QTc values excluded. The primary endpoint was mean QTc change from baseline, as measured by electrocardiogram.
The mean change in QTc from baseline was 12.3 milliseconds (ms) in the bedaquiline group (95% confidence interval [CI], 7.8 to 16.7), 8.6 ms in the delamanid group (95% CI, 4.0 to 13.1), and 20.7 ms in the combined group (95% CI, 16.1 to 25.3). There were no grade 3 or 4 (life-threatening) QTc prolongation events, and the maximum QTc increase seen was similar for bedaquiline plus delamanid versus bedaquiline alone.
"These results are reassuring and provide evidence of the safety of concurrent bedaquiline and delamanid use in patients with multidrug-resistant or rifampicin-resistant tuberculosis," the authors wrote.
In addition, exploratory analysis found high rates of 8-week culture conversion in all groups, with early and sustained culture results seen in the combined treatment group. The authors said this is an encouraging sign that the combined treatment is effective but noted that the finding needs to be confirmed in larger clinical trials.
QT effects of bedaquiline, delamanid, or both in patients with rifampicin-resistant tuberculosis: a phase 2, open-label, randomised, controlled trial
Kelly E Dooley, Susan L Rosenkranz, Francesca Conradie, Laura Moran, Richard Hafner, Florian von Groote-Bidlingmaier, Javier R. Lama, Justin Shenje, Jorge De Los Rios, Kyla Comins, Joel Morganroth, Andreas H Diacon, Yoninah S Cramer, Kathleen Donahue, Gary Maartens, the AIDS Clinical Trials Group (ACTG) A5343 DELIBERATE Study Team
Published in The Lancet Infectious Diseases on 12 February 2021
Bedaquiline and delamanid are the first drugs of new classes registered for tuberculosis treatment in 40 years. Each can prolong the QTc interval, with maximum effects occurring weeks after drug initiation. The cardiac safety and microbiological activity of these drugs when co-administered are not well-established. Our aim was to characterise the effects of bedaquiline, delamanid, or both on the QTc interval, longitudinally over 6 months of multidrug treatment, among patients with multidrug-resistant or rifampicin-resistant tuberculosis taking multidrug background therapy.
ACTG A5343 is a phase 2, open-label, randomised, controlled trial in which adults with multidrug-resistant or rifampicin-resistant tuberculosis receiving multidrug background treatment were randomly assigned 1:1:1 by centrally, computer-generated randomisation, by means of permuted blocks to receive bedaquiline, delamanid, or both for 24 weeks. Participants were enrolled at TASK in Cape Town and the South African Tuberculosis Vaccine Initiative in Worcester, both in South Africa, and Hospital Maria Auxiliadora in Peru. Individuals with QTc greater than 450 ms were excluded. HIV-positive participants received dolutegravir-based antiretroviral therapy. Clofazimine was disallowed, and levofloxacin replaced moxifloxacin. ECG in triplicate and sputum cultures were done fortnightly. The primary endpoint was mean QTcF change from baseline (averaged over weeks 8–24); cumulative culture conversation at week 8-24 was an exploratory endpoint. Analyses included all participants who initiated study tuberculosis treatment (modified intention-to-treat population). This trial is registered with ClinicalTrials.gov, NCT02583048 and is ongoing.
Between Aug 26, 2016 and July 13, 2018, of 174 screened, 84 participants (28 in each treatment group, and 31 in total with HIV) were enrolled. Two participants did not initiate study treatment (one in the delamanid group withdrew consent and one in the bedaquiline plus delamanid group) did not meet the eligibility criterion). Mean change in QTc from baseline was 12·3 ms (95% CI 7·8–16·7; bedaquiline), 8·6 ms (4·0–13·1; delamanid), and 20·7 ms (16·1–25·3) (bedaquiline plus delamanid). There were no grade 3 or 4 adverse QTc prolongation events and no deaths during study treatment. Cumulative culture conversion by week 8 was 21 (88%) of 24 (95% CI 71–97; bedaquiline), 20 (83%) of 24 (65–95; delamanid), and 19 (95%) of 20 (79–100; bedaquiline plus delamanid) and was 92% (77–99) for bedaquiline, 91% (76–99), for delamanid, and 95% (79–100) for bedaquiline plus delamanid at 24 weeks.
Combining bedaquiline and delamanid has a modest, no more than additive, effect on the QTc interval, and initial microbiology data are encouraging. This study provides supportive evidence for use of these agents together in patients with multidrug-resistant or rifampicin-resistant tuberculosis with normal baseline QTc values.
Division of AIDS, National Institutes of Health.
The Lancet Infectious Disease study (Open access)