On January 15, 2018, the World Health Organization's (WHO) Global Tuberculosis Programme has released a Position Statement19 on the use of delamanid in treatment of multidrug-resistant tuberculosis (MDR-TB), following an expedited review of the phase III randomized controlled trial results by Otsuka Pharmaceutical, released at the 48th UNION World Conference on Lung Health in Mexico. Based on the results of this trial, the WHO is advising national TB programmes and other stakeholders to only add delamanid to a longer MDR-TB regimen when the regimen cannot be composed according to WHO recommendations, eg. when drug intolerability or drug resistance requires changes. When an effective and well-tolerated longer MDR-TB regimen can be otherwise composed, the addition of delamanid may not be warranted20.
Background
Delamanid was approved for use in multidrug-resistant tuberculosis (MDR-TB) patients by the WHO in October 201421, by issuing an interim policy guidance on the use of this novel medicine developed by Otsuka Pharmaceutical. The interim policy guidance stated that 'delamanid may be added to a MDR-TB regimen in adult patients with pulmonary TB' conditional upon: i) careful selection of patients likely to benefit; ii) patient informed consent; iii) adherence to WHO recommendations in designing a longer MDR-TB regimen; iv) close monitoring of clinical treatment response; and v) active TB drug-safety monitoring and management (aDSM). Further in 2016, the delamanid interim policy by WHO 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 patients22.
Phase III Clinical Trial of Delamanid
The purpose of this trial was to determine whether delamanid is effective in the treatment of Multidrug-resistant Tuberculosis (MDR TB) in combination with other MDR TB medications during 6 months of treatment. This trial was the first-ever MDR-TB treatment study of its kind to be completed and reported and its findings were thus much-awaited. The trial conformed to whigh scientific standards, as guided by an extensive and detailed study protocol, and with broad geographical distribution of study sites in seven countries (Estonia, Latvia, Lithuania, Republic of Moldova, Peru, the Philippines, and South Africa).
Trial participants received either delamanid or a placebo for six months, added to an optimised, longer background MDR-TB regimen designed according to WHO recommendations. Participants were randomised to receive either delamanid or placebo in a 'blinded' fashion, i.e neither they nor the treating physicians were aware of whether the medicine added to the MDR-TB regimen was active delamanid or an inactive placebo.
Trial Results
Efficacy Results
- There was no clinically relevant or statistically significant difference between the delamanid and placebo study arms in treatment success: At 30 months' follow-up, 77.1% of participants receiving delamanid achieved sustained cure versus 77.6% of participants receiving placebo.
- There was no clinically-relevant or statistically significant difference in all-cause mortality between the two study arms: at 30 months' follow-up mortality was 5.3% in the delamanid group and 4.7% in the placebo group.
Safety Results
- There was no significant difference in treatment-emergent adverse events (TEAEs) between participants receiving delamanid and those receiving placebo. No new or significant drug-drug interactions between delamanid and antiretroviral (ARV) drugs were observed,
The overall, cure and mortality rates were similar in trial participants who received delamanid and in those who received the placebo on top of the optimised background MDR-TB regimen. The trial thus did not confirm the efficacy findings of earlier studies. However, no additional or new safety concerns were identified, providing reassurance of the safety of delamanid relative to many of the other second-line medicines used for MDR-TB treatment.
Study Conclusions
Delamanid in the present trial did not show any statistically significant difference in successfully curing the disease or reducing the mortality rates compared with a placebo in this Phase III human clinical trial. However, the drug was found to be safe unlike many of the other second-line medicines used for MDR-TB treatment.
WHO's revised Advise on usage of Delamanid
- WHO is advising national TB programmes and other stakeholders to add delamanid to a longer MDR-TB regimen only when the regimen cannot be composed according to WHO recommendations, eg. when drug intolerability or drug resistance requires changes. When an effective and well-tolerated longer MDR-TB regimen can be otherwise composed, the addition of delamanid may not be warranted.
- The decision to use delamanid in such regimens should be made by treating clinicians based on individual patient assessment and well-established considerations for composition of MDR-TB regimens including drug susceptibility profiles, drug intolerability and safety, risk-benefit and ethics.
- The conditions for delamanid use in individual patients remain the same, i.e. i) careful selection of patients likely to benefit; ii) patient informed consent; iii) adherence to WHO recommendations in designing a longer MDR-TB regimen; iv) close monitoring of clinical treatment response; and v) active TB drug-safety monitoring and management (aDSM).
- Use of delamanid in the shorter MDR-TB regimen under programmatic conditions is not recommended by WHO given the lack of data.
- Delamanid should be retained in country guidelines, national essential medicine lists and procurement options. MDR-TB treatment algorithms may need adjustment in view of the Trial 213 outcomes.
- Research on the role of delamanid in MDR-TB treatment should continue; particularly, its use in MDR-TB regimens compromised by drug resistance or drug intolerability should be pursued.
Delamanid in India
Delamanid in India was approved by the Central Drugs Standard Control Organization (CDSCO) India in August 2017. It has been approved for the use as part of an appropriate combination regimen for pulmonary multi-drug resistant tuberculosis (MDR-TB) in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability23. Further in the Subject Expert Committee (SEC) meeting, the experts of Antimicrobial and Antiviral SEC committee recommended based on the examination of the data on global clinical trials conducted and approval by EU and Japan for this drug, and risk benefit analysis, the committee recommended for waiver of local clinical trial as this drug is required as an unmet need in emergency for the treatment of MDR/XDR-TB in adult. Further, the Committee recommended for approval of the drug in the conditional access programme through Revised National Tuberculosis Control Program (RNTCP)24.
Conclusion
The bacteria that causes tuberculosis (TB) can develop resistance to the antimicrobial drugs used to cure the disease. Multidrug-resistant TB (MDR-TB) is a form of TB that does not respond to even isoniazid and rifampicin, the 2 most powerful anti-TB drugs. MDR-TB is a complex form of disease and is difficult to treat with limited treatment option. In this scenario, results from the phase III clinical studies on Delamanid, have been hugely disappointing.
Footnotes
19 http://www.who.int/tb/features_archive/WHO_statement_use_delamanid_MDR_TB/en/
20 http://www.who.int/entity/tb/publications/2018/WHOPositionStatementDelamanidUse.pdf
21 http://apps.who.int/iris/bitstream/10665/137334/1/WHO_HTM_TB_2014.23_eng.pdf
22 http://apps.who.int/iris/bitstream/10665/250614/1/9789241549899-eng.pdf
23 http://www.cdsco.nic.in/forms/list.aspx?lid=2034&Id=11
24 http://www.cdsco.nic.in/writereaddata/MOM%20of%20SEC%20Antimicrobial%20and%20Antiviral%2014_06_2017%20(Website)%20(1).pdf
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