ACTG TB Transformative Science Group

Protocol updates, Union NAR Meeting

February 23, 2019

Gavin J. Churchyard, Chair

Kelly Dooley, Vice Chair

Overview

TB TSG scientific agenda

Protocol overview

New Directions

Conclusions

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

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)

Enrolling

A5312 (High-dose INH for MDR-TB)

A5302 (Biobank for Biomarkers)

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)

Studies completed

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, 100-250, and >250 cells/mm3) 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

6CROI 2017, Abstract LB37

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

Transformative Science: A5338 Depo-Provera with HIV &TB treatment

Study Group: 18-46 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 bloodsDMPA PKPregnancy testCD4 HIV-1 RNA

DMPA PK Progesterone Levels

Safety bloodsPregnancy test

Week 2

DMPA

Clinical assessments & adherence assessment every 2 weeksViral load at entry and week 12

Week 4

Week 6

Week 8

Week 10

Week 12

Enrolment completed

MDR-TB-- A5343, the DELIBERATE trialDESIGN: Randomized, open-label, three arm pharmacokinetic and safety trial

DURATION: 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 weeksArm 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)

Study Schema

Weeks 1-24: Study treatment Weeks 25+: Standard MDR-TB Treatment

BaselineECGs

Week 2 Week 8 Week 24

Multidrug Background Treatment

Bedaquiline + MBT

Bedaquiline + Delamanid + MBT

Delamanid + MBT Multidrug Background Treatment

ECG assessments, sparse PK sampling

= intensive PK

ECG and sparse PK every 2 weeksto 24 weeks, then once at 28 weeks

Look for results at CROI

TBTC S31/A5349: Rifapentine-containing tuberculosis treatment shortening regimens Version 2.0 14 May 2015

Protocol Summary

Schematic of Study Design:

Screen for eligibility

Enroll

Randomize 1:1:1

Regimen 1

(control regimen)

2RHZE/4RH

(26 weeks)

Regimen 2

(investigational)

2PHZE/2PH

(17 weeks)

Regimen 3

(investigational)

2PHZM/2PHM

(17 weeks)

Participant follow-up:

18 months after treatment assignment

Analysis of Outcome Measures

Primary at 12 months; secondary at 18 months

Drug-susceptible TB: TBTC 31/ACTG 5349:High-dose rifapentine

KeyP=rifapentineR=rifampin

M=moxifloxacinE=ethambutol

H=isoniazidZ=pyrazinamide

Total enrolled: 2,516 Timeline:First enrollment – 25 January 2016.Last enrollment – 30 October 2018. Completion of study treatment - May 2019. Primary efficacy and safety endpoints analysis (12-months) - Q1 2020.Completion of follow up - May 2020. Secondary analysis (18-months endpoints) –Q4 2020.

Enrolling

Isoniazid: What’s the right dose for patients with MDR-TB?Revised Design of A5312

INH-resistant TB

M. tuberculosis with inhA mutation

M. tuberculosis with katG mutation

Individual INH PK7-day EBA

MIC data (bug)

Apply treatmentINH 5, 10, or 15 mg/kg (drug)

Measure 7-day Early Bactericidal Activity

(EBA)

Individual INH PK

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.

Drug-sensitive TB

Apply treatmentINH 5mg/kg (drug)

Measure 7-day Early Bactericidal Activity

(EBA)

Group 2: Positive Control ArmStandard INH dosing

Group 1: Dose-ranging Group 3: Previously MIC only; now Rx arms

Apply treatmentINH 15 or 20 mg/kg

Treatment response

Look for top-line results Groups 1 & 2 at CROI

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.

To open

A5300B/IMPAACT2003B

Protecting Households On Exposure to Newly Diagnosed Index Multidrug-Resistant Tuberculosis Patients

(A5300B/I2003B/PHOENIx)

Protocol update

Washington

19th June 2018

Protocol Chairs

ACTG: GJ Churchyard, S Swindells

IMPAACT: AC Hesseling, A Gupta

TB Preventative Therapy

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

Study populationHigh 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

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

In Development

Study Description Status

A5362 –

CLO-Fast

Clofazimine- and Rifapentine-Containing Treatment

Shortening Regimens in Drug-Susceptible Tuberculosis

Projected to open

06.30.2019

Clofazimine approved for procurement under the Global Fund’s Expert Review Panel (ERP) while it undergoes WHO Prequalification. GDF finalizing the price and termsCurrent approved shelf-life is short (only 18 months).

Drug susceptible TB Treatment Studies

Screening/Randomization

INH-monoresistant TB: Fighting Isoniazid Resistant Strains of Tuberculosis (FIRST) A5373

Arm 1Daily HD-INH, RIF, PZA, EMB (plus pyridoxine) for 26 weeks

Arm 2Intensive phase:Daily LFX, RIF, PZA, EMB for 8 weeks

Arm 2Continuation phase:Daily RIF and LFX for 18 weeks

48 weeks follow-up after treatment completion

Transformative Science– HIV/LTBI Co-Rx: A5372 Study Design

Design Open Label, 2-arm, multicenter, DDI PK study

Network(s) ACTG

Duration Step 1: 4 weeks Step 2: 4 weeks

Sample Size Arm 1 (DTG/TDF/FTC BID): 36Arm 2 (DTG/TDF/FTC QD): 36

Population HIV+, LTBI+

Regimens DTG/TDF/FTC + daily RPT/INH (x28d)

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)

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

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

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

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

Thank you.