Bedaquiline and delamanid safe when given together to treat drug resistant TB

QT interval prolongation effects of bedaquiline (BDQ) and delamanid (DLM) given together were no more than additive in a study looking at cardiac safety of the combined use of these drugs in people with multidrug resistant (MDR)-TB.

BDQ and DLM are the first drugs from two new classes approved for TB in over 40 years. Both are recommended by WHO for treatment of MDR-TB by WHO.

Both drugs’ metabolites prolong  the QT interval. Peak QT effects are at 16–18 weeks for BDQ and 8 weeks for DLM. The cardiac safety of these drugs given together as part of a regimen to treat MDR-TB has not been previously studied.

DELIBERATE was a phase 2, randomised, open-label, three arm pharmacokinetic and safety trial. Adults with MDR-TB, receiving multidrug background treatment (MBT), were randomised 1:1:1 to receive BDQ, DLM or both (BDQ + DLM) for 24 weeks.

The primary objective was to compare mean change from baseline in QTcF (in ms; averaged over weeks 8–24) when BDQ and DLM are given together to the mean change when each drug is given alone.

People with QTcF >450 ms or CD4 count <100 cells/mm³ were excluded. Clofazamine was not permitted and moxifloxacin was switched to levofloxacin. HIV positive participants received dolutegravir-based ART.

Three electrocardiograms (ECG) were performed at baseline, every two weeks for 24 weeks, then week 28.

A core laboratory blinded to treatment arm calculated QTcF. The study defined grade 3 QTcF prolongation as >500ms or >480 ms with increase from baseline >60 ms. Grade 4 was life-threatening dysrhythmia.

Sites were in South Africa and Peru. Gary Maartens from the University of Cape Town presented these findings on behalf of the DELIBERATE investigators.

Eighty-four participants were enrolled. Most (75%) were men, median age was 35 years and 37% were HIV positive.

Mean baseline QTcF and standard deviations in the BDQ, DLM and BDQ + DLM arms were respectively: 398 (24), 404 (19) and 391 (14).

Of 74 participants with QTc data, mean change in QTcF from baseline in the respective arms was: 11.9 (95% CI 7.4 to 16.5), 8.6 (95% CI 4.0 to 13.2) and 20.7 (95% CI 16.1 to 25.4).

The investigators concluded that the combined effect on the QTcF interval of co-administration of BDQ and DLM is clinically modest and no more than additive.

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The investigators also noted the caveat that this was a carefully-screened population not receiving other DR-TB drugs that have significant QT prolongation effects (clofazimine and moxifloxacin).