Protecting Households from Newly Diagnosed Multi-drug Resistant Tuberculosis (MDR-TB) Patients: A Study on Delamanid (DL

1. A5300B/IMPAACT2003B Presentation for DR-TB STAT 29th August 2019 ACTG: Gavin J Churchyard, Sue Swindells IMPAACT: Anneke C Hesseling, Amita Gupta Protecting Households On Exposure to Newly Diagnosed Index Multidrug-Resistant Tuberculosis Patients (A5300B/I2003B/PHOENIx)

2. Study Sites *12701 Gaborone (Botswana, Gaborone)2 *12101 Chagas (Brazil, Rio de Janeiro)₁ 30022 Gheskio-INLR (Haiti, Port-au-Prince)2 *31730 Gheskio-IMIS (Haiti, Port-au-Prince)2 *11701 CART (India, Chennai)1 *31441 BJMC (India, Pune)₂ 12601 AMPATH (Kenya, Eldoret)1 *11301 Barranco (Peru, Lima)1 *11302 San Miguel (Peru, Lima)₁ 31985 Socios (Peru, Lima)1,ᵖs 31981 De La Salle (Philippines, Dasmarinas) 1,ᵖs *11101 WITS HJH (South Africa, Johannesburg)₁ *11201 Durban International (South Africa, Durban) 1 *12301 Soweto (South Africa, Johannesburg) 1 31684 The Aurum Institute (South Africa, Rustenburg) 1,ᵖs *31718 TASK Applied Science (South Africa, Bellville)2 *31790 Desmond Tutu TB Centre (South Africa, Cape Town)3 *31792 UCTLI (South Africa, Cape Town)1 *31793 SATVI (South Africa, Cape Town)2 *31976 PHRUMatlosana (South Africa, Klerksdorp)2,ᵖs 5118 KCMC (Tanzania, Moshi)4 *5116 ChiangraiPrachanukroh Hospital (Thailand, Chiang Mai)4 5115 Siriraj Hospital, Mahidol University (Thailand, Bangkok) 4 31802 Thai Red Cross (Thailand, Bangkok)1 12401 JCRC (Uganda, Kampala)₁ 30293 MU-JHU Research Collaboration (Uganda, Kampala)3 30313 Parirenyatwa (Zimbabwe, Harare)1 _____________ *Participated in feasibility study ᵖs Protocol Specific Site ₁ ACTG,₂ACTG / IMPAACT,₃IMPAACT, ₄IMPAACT – NICHD

3. MDR TB in Household Contacts • MDR TB contacts have a high risk of TB infection and disease • Vast majority of MDR TB in children arises from household transmission • Systematic review of observational studies of DR TB contacts • 4–8% develop incident TB (first 12-24 mos) • 44–72% of incident TB are drug-resistant • No tests for differentiating latent MDR vs. susceptible TB infection • 19.1 million (0.3%) estimated with MDR LTBI • PHOENIxFeasibility study • Of 1007 HHCs • 12% had TB disease • 72% had LTBI Shah et al. CID. 2014; Cain KP et al. Int J Tuberc Lung Dis 2010, Knight Lancet ID 2019; Gupta et al. CID. 2019

4. WHO 2014 TPT GuidelinesResearch Gaps • The potential role of new drugs with good sterilization properties should be investigated • There remains an urgent need for trials of TB preventive therapy for HH contacts of MDR TB patients, particularly for those at high risk including HIV-infected, TST+ and young children to inform international evidence-based recommendations, especially from placebo-controlled trials

5. WHO 2018 Consolidated Guidelines for Programmatic Management of LTBI • In high-risk HHCs of MDR TB patients, preventive treatment may be based on individualised risk assessment and sound clinical justification. (New, Conditional recommendation, low quality of evidence) • Treatment should be based on DST of source case • Confirmation of infection with LTBI tests is required • Informed consent is required • Close monitoring for TB disease for 2 years required • Recommendation must not affect RCTs of PT for MDR-TB HHCs on ethical grounds

6. Efficacy of Drugs in a Murine Model of LTBI Mouse studies suggest that PA824 (nitroimidazole) has similar efficacy in treating LTBI as INH H=isoniazid; R=rifampin; L=levofloxacin; M=moxifloxacin; J=bedaquiline; Pa=pretonamid; U=sutezolid

7. Delamanid (DLM) • Is a nitroimidazole • Potent against intracellular and dormant M.tb • DLM 200mg once daily results in DLM levels above the MIC in adults

8. DelamanidDrug-Drug Interaction Potential with ART • DLM has minimal DDI potential reported to date • DLM investigated in combination with EFV, TDF, LPV/r, INSTIs • EFV and TDF did not affect DLM exposure • Although LPV/r increases DLM and major metabolites, dose adjustment not required • Dolutegravir and raltegravir do not affect DLM exposure • DLM did not impact ART exposure

9. Overview • PHOENIx MDR TB Protocol • Study Objectives • Design • Study population • Schedule of events • Adherence, PK, economic assessment • Safety • Conclusion

10. A5300B/I2003B Study Hypothesis Treating HIV-infected and other child, adolescent and adult household contacts of MDR TB patients, including pre-XDR TB and XDR TB, who are at high risk of developing TB with delamanid (DLM) will substantially reduce the risk of developing TB, compared to standard-dose isoniazid (INH)

11. Objectives Primary Objectives Among HIV-infected and child, adolescent, and adult household (HH) contacts of MDR TB patients at high risk of developing TB, to compare: • The efficacy of DLM vs. INH for preventing confirmed or probable active TB • The safety of DLM vs. INH for the treatment of presumed LTBI with MDR TB

12. Objectives Secondary Objectives To compare DLM vs INH with respect to: • Efficacy and safety by • HIV status • High-risk group (HIV+, children, LTBI+) • Efficacy in preventing • Confirmed MDR TB • All-cause mortality • Confirmed or probable TB and all-cause mortality

13. Objectives Secondary Objectives To compare DLM vs INH with respect to: • Grade 3 or higher adverse events • Drug-susceptibility pattern & WGS of the index patient vs. incident TB cases • To describe the intensive PK and safety of DLM administered once daily in children <5 years old To evaluate • Risk factors for confirmed/probable TB in HHCs • Possible modifiers of the difference in risk between study arms

14. Objectives Exploratory Objectives • To establish a sample repository • To discover and/or validate relevant host biomarkers and correlates of incident TB using multiomic approaches • To explore whether efficacy, safety, and/or PK of DLM and INH are associated with polymorphisms in human genes (NAT2, CYP2B6)

15. Objectives Exploratory Objectives • To describe the number of women HHCs who become pregnant while on DLM or INH and characterize their pregnancy and birth outcomes • To assess adherence and the electronic drug monitoring (EDM) device for DLM and INH • To evaluate DLM vs. INH with respect to • Cost-effectiveness • Health-related QoL in HHCs • To compare efficacy, PK findings, and adherence across sites and geographic regions

16. Study Design • Multi-center, cluster-randomized, superiority trial • Cluster = eligible high risk contacts from same HH • HHs randomized 1:1 to DLM or INH • Randomization stratified by site • All eligible HHCs in same HH receive the same treatment (enrollment of all HHC not required) • “Active” control • INH (and DLM) will be active against community-acquired (drug-susceptible) infection in HH contacts

17. Sample Size / Power • Total of 5,178 participants are estimated to be enrolled • 1,726 Index cases • 3,452 high risk HHCs, assuming 2 contacts per index case • Sample size will provide 90% power to detect a 50% relative reduction in cumulative proportion with confirmed/probable active TB by 96 weeks from 5% in the INH control arm to 2.5% in the DLM arm with Type I error rate of 0.05

18. Study population Index case: An adult (18 years and older) with confirmed pulmonary MDR TB who has started appropriate treatment within the past 90 days • ConfirmedRIF & INH resistance by phenotypic or genotypic DST by • Adequate source documentation from a licensed/nationally approved referral laboratory • Using a DAIDS-approved laboratory that operates according to GCLP guidelines and participates in an appropriate EQA program.

19. Study population Household contacts • A HHC is generally a person who lives in the same dwelling unit and shares the same housekeeping arrangements as the index case and who reports >4 hours shared indoor airspace in a week within 90 days prior to the index case starting MDR TB treatment

20. Study population High risk household contacts • Newborns to children <5 years old regardless of TST/IGRA or HIV status • Adults and children ≥5 years of age that are • HIV-infected or HIV-uninfected but immunosuppressed regardless of TST/IGRA status • TST positive (≥5mm) and/or IGRA positive whose HIV status is negative, indeterminate or unknown and who are not non-HIV immunosuppressed

21. Study Regimens Arm A: • DLM daily for 26 weeks • Adults: DLM 200 mg daily • Children: weight-banded dosing • DLM dosing in <6 yrolds will be evaluated using real time PK, modelling & safety evaluation

22. Study Regimens Arm B: • INH daily for 26 weeks • Adults and children ≥24kg: 300 mg once daily • Children <24kg: 10-15mg/kg up to 300 mg/day once daily • Pyridoxine will be per local guidelines • INH and DLM will be distributed through the NIAID CRPMC • Pyridoxine will be procured locally by study sites

23. Schedule of EventsHousehold contacts

24. Schedule of EventsHousehold contacts

25. Run-in-phase(Assessing site feasibility) Feasibility of identifying index MDR TB cases, enrolling high-risk HHCs and implementing TB preventive therapy • Each site will have a run-in phase which will include 10 index cases and all eligible high risk HHC • Site feasibility will be assessed when enrolment / follow-up target (4 weeks) is reached • Sites may continue enrolment during assessment • Mycobacterial results of the first 10 index cases screened to be reviewed

26. Adherence monitoring • Participant self-report • EDM data on all participants • PK for adherence (INH in urine; DLM in blood) • Near real-time testing during run-in phase • Batched testing thereafter in randomly selected cohort (and TB cases) prior to each DSMB review • % non-adherence based on missing PK samples and undetectable drug: <50% stopping guideline

27. Adherence support • A RPI methodology will be used to optimize acceptance and operational performance of the EDM device at all study sites • Electronic drug monitoring (EDM) activities • Data feedback & adherence counselling at each dispensing visit • Lapses in opening events • Text reminders, phone calls • Home visits if required • Tailored counselling

28. Sparse Pharmacokinetic and Adherence Analyses • Samples will be collected during study drug administration for adherence monitoring • Blood (DLM) or urine (INH) will be collected at weeks 4, 12, and 24 from all participants • If applicable, samples will also be collected at the time of suspected TB & premature study discontinuation • A case-cohort evaluation of drug exposure will be conducted to inform study outcomes at the end of the study

29. Intensive Pharmacokinetic Analyses • To assess DLM once daily weight-based dosing in children ≤5years of age, at ~week 8: • 20 children between ages 0-24 months • 20 children >24 months through 5 years of age • Blood samples will be collected at pre-dose (hour 0), 2, 4, 6 and 8 hours post-dose • Data analyzed in near real time & related to safety • If results suggest a dose adjustment is necessary, up to 20 additional children will be enrolled to verify dose • Intensive PK at selected sites with pediatric capacity

30. Economic evaluation • Patient costs and HRQoL will be assessed as part of the routine study survey, administered at baseline, week 16, 20, and week 96 • Patient costs, HRQoL outcomes & QALYs will be estimated for individual patients • Incremental cost effectiveness will be estimated using study & published data • Future cost effectiveness post trial will be estimated using a Markov model

31. Safety Issues • Common adverse events • DLM: GI upset, QTc prolongation, hepatotoxicity • INH: hepatotoxicity, seizures, peripheral neuropathy, psychosis, hypersensitivity rash • Safety data will be reviewed • 6-monthly by DAIDS (all participants) • Monthly by DAIDS MO (pediatric participants) • Risk benefit ratio considers healthy participants at risk of TB (and MDR-TB) disease progression

32. Safety Issues • Women who become pregnant on INH or DLM will discontinue INH or DLM and continue to be followed on study • All pregnant women will be followed for pregnancy & infant outcomes

33. Intensive safety monitoring LFTs (Total bili, AST, ALT) & creatinine • For the first 500 HHCs enrolled additional LFTs & creatinine will done according to SOE • Sites will be notified when 500 HHCs have been enrolled. • ECG monitoring for QTc prolongation • 1st 500: At screening and weeks 4, 8, 12, 16 & 26 • After 1st 500: At screening and weeks 8, 26 • ECGs will be read centrally; central pediatric cardiologist available for clinical advice and management

34. Conclusions • HIV-infected and uninfected household contacts are at high risk of developing TB and death • RCTs are urgently needed to inform global policy and to guide implementation of global MDR TB preventive therapy • PHOENIx study will compare the efficacy and safety of DLM vs INH in HHCs of MDR TB patients

35. The PHOENIx has risen! • First sites activated in Brazil June 7, 2019 & Botswana on June 11, 2019 • First index case enrolled 13th June 2019 • 3 years accrual and 2 years of follow-up

36. Acknowledgements All sites, communities and collaborators ACTG and IMPAACT Networks