Summary of STREAM and Delamanid phase III trial results and implications:

Transcription

1 Treating Patient, Not Disease: People-Centered Approach 7th TB Symposium Ministry of Health of the Kyrgyz Republic and Médecins Sans Frontières 1-2 March, 2018, BISHKEK, KYRGYZSTAN Summary of STREAM and Delamanid phase III trial results and implications: WHO rapid advice and next steps Ernesto Jaramillo Global TB Programme, WHO/HQ/LDR unit Geneva

2 Preliminary results of the STREAM 1 trial presented at UNION meeting in Mexico, October 2017 Study Arm Control arm N % N % Total assessed Favourable Unfavourable Difference in response (crude) 2.5% 95% confidence interval -6.9%, 11.8% Difference in response (standardised) 2.1% 95% confidence interval -6.9%, 11.2%

3 Shot taken from STREAM trial presentation at a URC-hosted meeting. Washington, DC, US, Jan, 2018

4 Shot taken from STREAM trial presentation at a URC-hosted meeting. Washington, DC, US, Jan, 2018

5 Treatment outcomes at 24 months, Trial 213 Delamanid trial results presented at UNION meeting in Mexico Outcome Delamanid + OBR Placebo + OBR Total N % N % N % Cured % % % Completed 12 4% 8 5% 20 4% Treatment failure 13 4% 6 4% 19 4% Lost to follow up 36 11% 20 12% 56 11% Died 14 4% 6 4% 20 4% Total there was an equal likelihood of serious TEAE in the delamanid and placebo arms (26.1% vs 27.6% respectively), of discontinuations due to adverse events (2.3% vs 1.8%) and hepatotoxicity (6.5% vs 7.1%). The principal cardiotoxicity signal from the initial Phase IIb trials was reproduced in the Phase III with QT-interval prolongation being more common in delamanid than the placebo group, albeit overall infrequent (3.5% vs 1.2% respectively).

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8 Scylla Charybdis Uncertainty MDR-TB epidemic

9 Scylla Charybdis Uncertainty MDR-TB epidemic Measurement of efficacy, safety, costs, patient and social acceptability is problematic and complex MDR-TB is deadly and transmissible; 52% global cure rate; transmission is main driver of MDR-TB epidemic

10 Scylla Charybdis Uncertainty MDR-TB epidemic Determining the efficacy, safety, costs, patient and social acceptability of a MDR-TB drug/regimen is problematic and complex MDR-TB is deadly and transmissible; 52% global cure rate; transmission is main driver of MDR- TB epidemic Results of delamanid phase III trial do not confirm efficacy of the drug in terms of treatment outcomes but do not rule it out neither

11 DELAMANID : WHO interim policy guidance (October 2014) Delamanid may be added to a WHO-recommended regimen in adult patients with pulmonary MDR-TB conditional recommendation, very low confidence in estimates of effect Subject to the following 5 conditions: 1. Proper patient inclusion 2. Treatment as per WHO recommendations 3. Treatment is closely monitored 4. Active pharmacovigilance in place 5. Patient informed consent obtained -> October 2016 : may be used in patients 6-17 years

12 Delamanid, 2018 Interim policy for adults (2014) based upon Phase IIb and observational data; policy in children (2016) on PK/PD data Phase III trial results communicated in October 2017: No difference in success rates compared with placebo arm. Safety profile reportedly manageable WHO policy: only add delamanid when regimen cannot otherwise be composed

13 Next steps

14 Off-label use the use of a pharmaceutical agent for an unapproved indication or in an unapproved age group, different dosage, duration or route of administration support to national programmes and clinicians in making decisions on use of bedaquiline and delamanid in individual patients Not intended to make a broadly applying set of recommendations. Describes when off label use is justified and under what conditions

15 Scylla Charybdis Uncertainty Determining the efficacy, safety, costs, patient and social acceptability is complex MDR-TB epidemic MDR-TB is deadly and transmissible; 52% global cure rate; transmission is main driver of MDR-TB epidemic Preliminary results of STREAM trial are not a proof of inferiority of shorter regimen in terms of treatment outcomes as compared to the longer regimen

16 Shorter MDR-TB regimen (1) Recommendation In patients with rifampicin-resistant TB or MDR-TB, who have not been previously treated with second-line drugs and in whom resistance to fluoroquinolones and second-line injectable agents has been excluded or is considered highly unlikely, a shorter MDR-TB regimen of 9 12 months may be used instead of a longer regimen

17 Shorter MDR-TB regimen (2) Main remarks Standardized regimen; limited modifications permissible 4-6 Km-Mfx-Pto-Cfz-Z-H high-dose -E / 5 Mfx-Cfz-Z-E Recommendation applies to adults, children, PLHIV Ideally, patients are tested for resistance to fluoroquinolones and second-line injectable drugs; not recommended in case of 2 nd line drug resistance, extrapulmonary disease and pregnancy

18 Choosing the treatment regimen in patients with confirmed MDR/RR-TB Confirmed resistance or suspected ineffectiveness to a medicine in the shorter MDR-TB regimen (except isoniazid resistance) Exposure to >1 second-line medicines in the shorter MDR-TB regimen for >1 month Intolerance to >1 medicines in the shorter MDR-TB regimen or risk of toxicity (e.g. drug-drug interactions) Pregnancy Extrapulmonary disease At least one medicine in the shorter MDR-TB regimen not available NO Shorter MDR-TB regimen FAILING REGIMEN, DRUG INTOLERANCE, RETURN AFTER INTERRUPTION >2 MONTHS, EMERGENCE OF AN EXCLUSION CRITERION YES Longer (individualized) MDR-TB regimens

19 adsm active and systematic clinical and laboratory assessment of patients on treatment with new TB drugs, novel MDR-TB regimens or XDR-TB regimens to detect, manage and report suspected or confirmed drug toxicities apps.who.int/iris/bitstream/10665/204465/1/who_htm_tb_ _eng.pdf

20 STREAM and Delamanid phase III trial results: Implications on patient care

21 Scylla Charybdis Uncertainty MDR-TB epidemic Determining the efficacy, safety, costs, patient and social acceptability is problematic and complex MDR-TB is deadly and transmissible; 52% global cure rate; transmission is main driver of MDR-TB epidemic; Both trials showed that 80% treatment success is reachable when treatment regimen is delivered with a patientcentred care approach

22 TB treatment AND patient-centred care are to work hand-in-hand!

23 Patient-centred care IS not the cherry on top of the cake

24 Patient-centred care is the heart of the cake

25 Update of Policy - Timeline Position statement delamanid January 2018 Position statement shorter regimen - February Guidelines for the treatment of INH-resistant TB - March Update of the Companion Handbook (consolidated with drug susceptible TB) May Release of MDR-TB treatment guidelines October Update of the Companion Handbook (consolidated with drug susceptible TB) January 2019

26 Single TB treatment handbook 2018

27 WAY OUT What risks Scylla and harms are you willing Charybdis to take, and commitments to make in order to survive when sailing in these deadly MDR-TB waters? epidemic Uncertainty Current weapons may save you, may not, and may even cause harm 240,000 deaths in 2016

28 Scylla Charybdis Uncertainty MDR-TB epidemic Both trials showed 80% MDR-TB treatment success when it was delivered with a patientcentred care approach There is reasonable evidence that delamanid and shorter regimen may add value to MDR-TB treatment in certain populations, with manageable risks, when delivered under patient-centred care

29 Scylla Charybdis Uncertainty MDR-epidemic 80% MDR-TB treatment success rate when regimen is delivered with patient-centred care Reasonable evidence that delamanid and shorter regimen may add value in certain populations under certain conditions THE WAY OUT Ensure there is political will to FULLY implement current WHO guidance, based on the best evidence available, and continue research to improve evidence

30 Ensure there is political will to FULLY implement current WHO guidance