Four months of quabodepistat, delamanid and bedaquiline: a non-inferiority signal in drug-susceptible TB

Design

Open-label, randomised, proof-of-concept non-inferiority phase 2b/c trial, six sites in South Africa

Population

122 adults aged 18 to 65 with newly diagnosed drug-susceptible pulmonary TB

Primary outcome

Sputum culture conversion by end of treatment; safety

Effect

96.0% pooled 4-month regimen vs 100% standard; difference -4.0% (80% CI -7.4 to 3.4)

This open-label, randomised phase 2b/c trial at six sites in South Africa enrolled 122 adults aged 18 to 65 with newly diagnosed drug-susceptible pulmonary tuberculosis. Participants received 4 months of delamanid and bedaquiline plus quabodepistat at 10, 30 or 90 mg daily, or 6 months of standard rifampicin, isoniazid, ethambutol and pyrazinamide. Quabodepistat is an investigational agent.

The primary end point was sputum culture conversion by the end of treatment. It occurred in 96.0% (96 of 100) of the pooled investigational group and 100% (21 of 21) of the standard group, a difference of -4.0% (80% CI -7.4 to 3.4), meeting non-inferiority on a 12% margin. By dose, conversion was 100%, 92.9% and 97.4%.

Grade 3 or higher adverse events occurred in 11 to 20% of investigational groups and 5% of the standard group. There were no serious adverse events attributed to trial drugs. One participant died of worsening tuberculosis, judged unrelated.

The design is proof of concept: a small open-label trial with an 80% interval, culture conversion at end of treatment, and no relapse follow-up reported in the abstract. The authors call it a promising signal that supports further studies.

• This regimen is investigational; standard six-month treatment remains the reference.
• Culture conversion at end of treatment is not relapse-free cure; that was not reported in the abstract.
• Grade 3 or higher adverse events were more frequent in the investigational groups (11% to 20% vs 5%).
• The trial excluded people over 65, children and, as stated, enrolled only drug-susceptible disease.
• Treatment-shortening regimens matter for programmes in India, where adherence over six months is a recurring problem.

Why it matters

A shorter all-oral regimen would address the cost of adherence over six months, which is a leading reason for treatment failure and loss to follow-up.

Don't overread it

It is a 122-patient, open-label, sponsor-funded phase 2b/c study that does not show relapse-free cure.

The statistics, in plain English

Non-inferiority here was judged on an 80% confidence interval with a 12-point margin, which is more lenient than the usual 95% interval, appropriate for proof of concept but not for changing practice. With only 21 control patients, one or two failures could shift the result materially.

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