ACTG TB Transformative Science Group Protocol updates, Union NAR Meeting February 23, 2019

Transcription

1 ACTG TB Transformative Science Group Protocol updates, Union NAR Meeting February 23, 2019 Gavin J. Churchyard, Chair Kelly Dooley, Vice Chair

2 Overview TB TSG scientific agenda Protocol overview New Directions Conclusions

3 The TB TSG Scientific Agenda TB TREATMENT SHORTENING: To identify regimens to shorten Drug-Susceptible TB treatment to 3 months in patients with and without HIV MDR-TB TREATMENT: To identify regimens to shorten and reduce the toxicity of treatment for MDR TB treatment in patients with and without HIV PREVENTIVE THERAPY: To identify regimens to shorten treatment for latent TB to 1 month and for MDR-TB infection to 6 months; to improve TB preventive therapy in PLHIV TB/HIV CO-TREATMENT: To optimize the treatment of TB/HIV co-infection and evaluate and minimize drug-drug interactions TRANSFORMATIVE SCIENCE: Pharmacology, Biomarkers, Laboratory monitoring and diagnostics, Preclinical studies (animal models) SPECIAL POPULATION, UNMET MEDICAL NEED: To identify regimens for the treatment of TB meningitis

4 Status of TB TSG protocols / proposals Studies completed A5279 (BRIEF TB) A5338 (DMPA/Rif/EFV) Enrollment completed A5343 (DELIBERATE, BDQ-DLM Study) A5349 (TBTC S31) To open soon/in development A5300B (Phoenix main study) A5356 (LZD DLM study) A5362 (CLO-FAST) A5372 (RPT-DTG/RPT-TAF PK study) A5373 (F.I.R.S.T.) A5384 (IMAGINE-TBM) Enrolling A5312 (High-dose INH for MDR-TB) A5302 (Biobank for Biomarkers)

5 Studies completed

6 TB Prophylaxis: Daily rifapentine + INH for 4 weeks ACTG A5279, the BRIEF TB trial Design: Multicenter, randomized, open-label, phase III clinical trial Drugs: Rifapentine 600 mg + Isoniazid 300 mg DAILY x 28 days (vs. 9H) Sample size: 3000 participants Population: HIV-infected individuals 13 years old and no evidence of active TB Stratification: 1) CD4+ cell count at entry (<100, , and >250 cells/mm 3 ) 2) ART use at entry (Yes/No 50% on ART at entry) ART: Efavirenz or nevirapine based ART permitted while on RPT/INH Duration: 3 years (156 weeks) after the last participant is enrolled CROI 2017, Abstract LB37 6

7 Time to endpoint 1HP 9H 1HP was non-inferior to 9H, had fewer AEs, and was more likely to be completed 1HP was non-inferior to 9H, had fewer AEs, and was more likely to be completed

8 Transformative Science: A5338 Depo-Provera with HIV &TB treatment Study Group: yo F with HIV/TB, normal ovarian function and not pregnant - Stable on ART: EFV + NRTIs 4 weeks - On continuation phase of TB treatment (INH and RIF) - No DMPA or other injectable HC w/in 180 days prior to entry - On no other HC w/in 30 days and no drugs known to induce/inhibit CYP3A4 system Day 0 Safety bloods DMPA PK Pregnancy test CD4 HIV-1 RNA Week 2 Week 4 DMPA PK Progesterone Levels Week 6 Week 8 Safety bloods Pregnancy test Week 10 Week 12 DMPA Clinical assessments & adherence assessment every 2 weeks Viral load at entry and week 12

9 Enrolment completed

10 MDR-TB-- A5343, the DELIBERATE trial DESIGN: DURATION: Randomized, open-label, three arm pharmacokinetic and safety trial 24 weeks on study treatment, followed by 18 months of follow-up. SAMPLE SIZE: 84 participants POPULATION: Men and women age 18 or older, with pulmonary drug resistant TB (MDR-TB) receiving multidrug background regimen (MBR)* Participants with HIV receive study-provided dolutegravir REGIMEN*: Arm 1: Bedaquiline 400 mg QD for two weeks, followed by 200 mg thrice-weekly for 22 weeks. Arm 2: Delamanid 100 mg BID for 24 weeks Arm 3: Both bedaquiline and delamanid (same doses as in Arms 1 & 2) *standard-course or short-course WHO Rx; FQ is levofloxacin; CFX not allowed; LZD substituted instead of BDQ for injectable when needed)

11 Study Schema Look for results at CROI Weeks 1-24: Study treatment Weeks 25+: Standard MDR-TB Treatment Bedaquiline + MBT Multidrug Background Treatment Delamanid + MBT Multidrug Background Treatment Bedaquiline + Delamanid + MBT ECG assessments, sparse PK sampling = intensive PK Baseline ECGs Week 2 Week 8 Week 24 ECG and sparse PK every 2 weeks to 24 weeks, then once at 28 weeks

12 Drug-susceptible TB: TBTC 31/ACTG 5349: Protocol Summary High-dose rifapentine Schematic of Study Design: Screen for eligibility Key P=rifapentine R=rifampin M=moxifloxacin E=ethambutol H=isoniazid Z=pyrazinamide Regimen 1 (control regimen) 2RHZE/4RH (26 weeks) Enroll Randomize 1:1:1 Regimen 2 (investigational) 2PHZE/2PH (17 weeks) Participant follow-up: 18 months after treatment assignment Regimen 3 (investigational) 2PHZM/2PHM (17 weeks) Total enrolled: 2,516 Timeline: First enrollment 25 January Last enrollment 30 October Completion of study treatment - May Primary efficacy and safety endpoints analysis (12-months) - Q Completion of follow up - May Secondary analysis (18-months endpoints) Q Analysis of Outcome Measures Primary at 12 months; secondary at 18 months

13 Enrolling

14 Isoniazid: What s the right dose for patients with MDR-TB? Revised Design of A5312 Group 1: Dose-ranging M. tuberculosis with inha mutation INH-resistant TB MIC data (bug) Apply treatment INH 5, 10, or 15 mg/kg (drug) Group 3: Previously MIC only; now Rx arms M. tuberculosis with katg mutation Apply treatment INH 15 or 20 mg/kg Group 2: Positive Control Arm Standard INH dosing Drug-sensitive TB Apply treatment INH 5mg/kg (drug) Measure 7-day Early Bactericidal Activity (EBA) Individual INH PK Individual INH PK 7-day EBA Treatment response Measure 7-day Early Bactericidal Activity (EBA) NAT2 metabolizer genotype (host) Treatment response Define Target AUC/MIC (based on positive control arm, max effect in experimental arms) Monte Carlo simulation using MIC, NAT2, AUC to determine dose required to achieve targets. Look for top-line results Groups 1 & 2 at CROI

15 TB Transformative Sciences Studies Study Description Status A5302 BioBank for Surrogate Marker Research for TB (B- SMART) (with TB Alliance and TBTC (CTB2)) Screening temporarily closed. To reopen Co-enrollment into this Biobank will extend to other ACTG studies, including A5300B/I2003B (PHOENIx) A5356 (Linezolid Delamanid Study) A5362 (The CLO-FAST Study) A5373 (F.I.R.S.T.) All ACTG specimens from now on will revert to ACTG storage and BRI specimen repository.

16 To open

17 TB Preventative Therapy A5300B/IMPAACT2003B Protecting Households On Exposure to Newly Diagnosed Index Multidrug-Resistant Tuberculosis Patients (A5300B/I2003B/PHOENIx) Protocol update Washington 19 th June 2018 Protocol Chairs ACTG: GJ Churchyard, S Swindells IMPAACT: AC Hesseling, A Gupta

18 Study Design Multi-center, cluster-randomized, superiority trial Cluster = eligible high risk contacts from same HH HH s randomized 1:1 to DLM or INH Randomization stratified by site All eligible HHCs in same HH receive the same treatment Active control INH (and DLM) will be active against community-acquired (drug-susceptible) infection in HH contacts

19 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 non-hiv 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

20 Drug-resistant TB Protocols Study Description Status A5356 MDR TB Linezolid Delamanid Study Open summer 2019 Study regimens Arm A: Oral LZD 600 mg daily + DLM 100 mg twice daily + OBT (excl. injectables) for 24 wks Arm B: Oral LZD 1200mg alternate days + DLM 100mg tbd + OBT (excl. injectables) for 24 wks Sample size: reduced to 120 participants

21 In Development

22 Drug susceptible TB Treatment Studies Study Description Status A5362 CLO-Fast Clofazimine- and Rifapentine-Containing Treatment Shortening Regimens in Drug-Susceptible Tuberculosis Projected to open Clofazimine approved for procurement under the Global Fund s Expert Review Panel (ERP) while it undergoes WHO Prequalification. GDF finalizing the price and terms Current approved shelf-life is short (only 18 months).

23 INH-monoresistant TB: Fighting Isoniazid Resistant Strains of Tuberculosis (FIRST) A5373 Screening/Randomization Arm 1 Daily HD-INH, RIF, PZA, EMB (plus pyridoxine) for 26 weeks Arm 2 Intensive phase: Daily LFX, RIF, PZA, EMB for 8 weeks Arm 2 Continuation phase: Daily RIF and LFX for 18 weeks 48 weeks follow-up after treatment completion

24 Transformative Science HIV/LTBI Co-Rx: A5372 Study Design Design Network(s) Duration Open Label, 2-arm, multicenter, DDI PK study ACTG Step 1: 4 weeks Step 2: 4 weeks Sample Size Arm 1 (DTG/TDF/FTC BID): 36 Arm 2 (DTG/TDF/FTC QD): 36 Population Regimens HIV+, LTBI+ DTG/TDF/FTC + daily RPT/INH (x28d)

25

26 Special populations, dire unmet medical need: IMAGINE-TBM A5384 Design: Randomized, open-label, multicenter Phase 2 trial Duration: 24 to 36 weeks on study treatment; total follow-up 72 weeks Population: Age 15 or older, with probable, definite, or possible TBM, with or without HIV co-infection Sample size: 150 per arm (300 total participants) (R=rifampicin, H=isoniazid, L=linezolid, Z=pyrazinamide, E=ethambutol)

27 TB TSG priorities: 2020 & beyond Evaluate new drugs & NCEs for shorter, less toxic DS TB, TB/HIV, MDR TB, Pan TB treatment A Working Group has been established to identify novel regimens using NCE for DS TB Evaluate therapeutic TB vaccines to reduce duration of treatment and or recurrence & TB vaccines that prevent progression to disease ACTG/HVTN TB vaccines and immunology WG established Evaluate long acting TB drugs for TB treatment and prevention Evaluate Host Directed Therapy regimens

28 Summary Notable successes include A5279 (1HP for TB prophylaxis) and completing enrolment into A5349 (RPT for DS-TB) A5312 (INH dosing) and A5343 (BDQ-DLM safety) with results that we hope will impact treatment of MDR-TB A number of bumps along the way-- particularly accessing study product & adapting to a rapidly changing field Recent advances in TB vaccines present an opportunity for the TB TSG to expand its research portfolio, but brings with it a number of challenges Developing novel regimens for Drug-susceptible TB using NCE is a priority

29 ACTG Non-US Sites* Africa FAM CRU, S. Africa Wits Helen Joseph CRS Department of Medicine, University of Witwatersrand, S. Africa Durban International Clinical Research Site, S. Africa South African Tuberculosis Vaccine Initiative (SATVI), S. Africa University of Cape Town Lung Institute (Pty) Ltd, S. Africa TASK Applied Science, S. Africa Soweto ACTG CRS, S. Africa Kisumu CRS, Kenya KEMRI Walter Reed Project, Kericho, Kenya Moi University Clinical Research Site, Kenya Blantyre CRS (Johns Hopkins Research Project, COM-JHP), Malawi UNC Project Tidziwe Centre, Malawi Joint Clinical Research Centre, Kampala, Uganda Parirenyatwa Clinical Research Site, Zimbabwe Asia The Thai Red Cross AIDS Research Centre, Thailand Thai-CTIU, CMU HIV Treatment CRS, Thailand BJ Medical College, India Chennai Antiviral Research and Treatment (CART) CRS, India Central America GHESKIO centers IMIS, Haiti Les Centre GHESKIO INLR, Haiti South America Asociacion Civil Impacta Salud y Educacion, Peru CRS San Miguel, Peru Insituto Nacional de Pesquisa Clínica Evandro Chagas, Brazil Hospital Nossa Senhora da Conceicao, Brazil *a few study-specific sites not listed

30 TB TSG membership Gavin Churchyard, The Aurum Institute, Chair Kelly Dooley, Johns Hopkins University, Vice Chair Anchalee Avihingsanon, Thai Red Cross AIDS Research Center Treatment CRS Constance Benson, University of California, San Diego Sara Browne, University of California, San Diego Richard Chaisson, Johns Hopkins University Salome Charalambous, The Aurum Institute Francesca Conradie, University of the Witwatersrand Helen Joseph CRS Kathleen Donahue, Data Management Center Jennifer Furin, Case Western Reserve University Neel Gandhi, The Ponce de Leon Center CRS Maria Tarcela Gler, De La Salle Health Science Institute Medical Research Center Amita Gupta, Johns Hopkins University Richard Hafner, DAIDS Mark Harrington, Treatment Action Group Mark Hatherill, SATVI CRS Chris Hikuam, SATVI CRS David Horne, University of Washington Moises Huaman, Cincinnati CRS Anne Kasmar, Bill & Melinda Gates Foundation Surakshya Karki, Network Coordinating Center Serena Koenig, Les Centres Gheskio CRS George Kukhala, Blantyre CRS Alan Landay, Rush University CRS Mamoudou Maiga, Northwestern University CRS Vidya Mave, BJ Medical College CRS Alberto Mendoza, San Miguel CRS John Metcalfe, University of California, San Francisco Laura Moran, Network Coordinating Center Sachiko Miyahara, SDAC Payam Nahid, University of California, San Francisco Eric Nuermberger, Johns Hopkins University Manoj Pardeshi, BJ Medical College CRS Patrick Phillips, University of California, San Francisco Ritesh Ramchandani, SDAC Roxana Rustomjee, DAIDS Natasha Rybak, The Miriam Hospital (TMH) CRS Wadzanai Samaneka, Parirenyatwa CRS Ian Sanne, Wits HIV CRS Rada Savic, University of California, San Francisco Kim Scarsi, University of Nebraska Medical Center Sarita Shah, Center for Disease Control Yuri van der Heijden, Vanderbilt Therapeutics (VT) CRS Susan Swindells, University of Nebraska Medical Center Gustavo Velasquez, Brigham & Women s Hospital Therapeutics CRS Nicholas Walter, University of Colorado Denver Karki, Surakshya

31 Thank you.