In a Phase III trial, delamanid drug was found to be safe but the cure rate and mortality rate were not different between the group that received the delamanid drug for MDR-TB and the group that received a placebo. The culture conversion rate too did not show statistically significant difference at two or six months. The WHO has advised all national TB programmes to include delamanid only when patients cannot tolerate or show resistance to certain second-line TB drugs.
In what may turn out to be a huge disappointment, delamanid drug, approved for use in multidrug-resistant tuberculosis (MDR-TB) patients by the World Health Organisation in October 2014, did not show any statistically significant difference in successfully curing the disease or reducing the mortality rate compared with a dummy in a Phase III trial (Trial 213), WHO’s position statement (here and here) issued on January 15 says. However, the drug was found to be safe unlike many of the other second-line medicines used for MDR-TB treatment.
The 2014 interim guidance issued by the WHO on the use of the drug for treating MDR-TB patients was based on Phase IIb trial results and subject to review once Phase III trial results become available. In 2016, the delamanid interim policy was extended to cover children aged 6-17 years following a review of data from a six-month safety, efficacy, and pharmacokinetic trial of paediatric patients. A person is said to have MDR-TB when there is drug resistance to at least isoniazid and rifampicin, the two main first-line TB drugs.
After bedaquiline, delamanid is the second drug that was approved for use in MDR-TB patients by the WHO in recent times. the WHO approved the bedaquiline drug for use in MDR-TB patients in 2013 based on Phase IIb trial results. A Phase III trial of bedaquiline drug involving 200 participants is yet to conclude.
The randomised, double-blind, placebo-control trial using delamanid was conducted in seven countries — Estonia, Latvia, Lithuania, Republic of Moldova, Peru, the Philippines, and South Africa.
Though the trial did not confirm the efficacy findings of earlier studies, delamanid should be retained in country guidelines, national essential medicine lists and procurement options, says the WHO. But the MDR-TB treatment algorithms “may need adjustment” in view of the Phase III trial results.
In addition to optimised MDR-TB regimen, participants in the trial received either delamanid or a dummy for six months. At the end of 30 months of follow-up, 77.1% of MDR-TB patients who received delamanid drug were cured compared with 77.6% of those who received a placebo (dummy), and mortality was 5.3% in the delamanid group and 4.7% in the placebo group.
Though the Phase IIb trial showed increased culture conversion at two months, the Phase III trial did not show any statistically significant difference in culture conversion at two or six months.
When to use delamanid
As a result, the WHO has advised all national TB programmes to include delamanid to longer MDR-TB regimen only when patients cannot tolerate or show resistance to certain second-line TB drugs. “When an effective and well-tolerated longer MDR-TB regimen can be otherwise composed, the addition of delamanid may not be warranted,” the WHO says.
The conditions for using delamanid drug in patients remain the same — careful selection of patients who are likely to benefit, designing a longer MDR-TB regimen as recommended by the WHO, close monitoring of treatment response, and active TB drug-safety monitoring and management.