1. Tuberculosis Trials Consortium Study 31 AIDS Clinical Trials Group A5349 Rifapentine-containing treatment shortening regimens for pulmonary tuberculosis: A randomized, open-label, controlled phase 3 clinical trial Payam Nahid, MD, MPH Professor of Medicine UCSF – Department of Medicine Division of Pulmonary and Critical Care

2. Rifapentine (RPT, P): Background
Cyclopentyl ring-substituted rifamycin
MIC90 = 0.06 g/ml (vs for RIF)
Half-life = h (vs. 2-4 for RIF)
Less potent inducer of cytochrome P450 than rifampin
Preclinical: Daily rifapentine is highly active in the murine model of TB1,2,3
Replacing RIF 10 mg/kg/d with RPT 10 mg/kg/d increases bactericidal and sterilizing activity, and halves the time needed for cure
Phase 1: Daily rifapentine doses of up to 20 mg/kg/d are safe and tolerated in healthy adults4
No evidence of dose-dependent increase in frequency of known rifamycin- associated toxicities. Maximum tolerated dose at least 20 mg/kg/d
Reluctance to increase RIF dose. We have recently become quite interested in the potential of the long-acting rifamycin rifapentine. This drug has an MIC that is consistently 1 to 2 dilutions lower than that of RIF and a half-life that is 5 times longer. The 600 mg or 10 mg/kg dose has been approved for twice-weekly therapy during the initial 2-mo intensive phase and once-weekly therapy during the continuation phase, but the most influential clinical studies have only looked at once-weekly continuation phase therapy with disappointing results in patients at high risk for treatment failure. We believe RPT could be resurrected as a potent new TB drug if it was administered at higher doses, twice weekly, throughout the course of therapy. Based on the data we have to date, 15 and perhaps even 20 mg/kg administered twice-weekly throughout the course of treatment, regimens that would at least triple the drug exposure obtained with the 10 mg/kg dose once-weekly.
1 Rosenthal et al; PLoS Med 2007;4:e344
2 Rosenthal et al; AJRCCM 2008;178:989
3 Rosenthal et al; AAC 2012;56:4331
4 Dooley et al; Clin Pharmacol Ther 2012;91:881

3. Determine tolerability & safety
For regimens that include daily RPT at a dose higher than 10 mg/kg/d (in addition to H+Z+E) administered during intensive phase treatment of smear positive, drug susceptible pulmonary TB:
Determine tolerability & safety
Estimate antimicrobial activity, using a surrogate endpoint for ‘cure’
Dorman, et al. Am J Respir Crit Care Med. 2015

4. Stable culture conversion BY RIFAPENTINE AUC TERTILE
RPT 3rd AUC tertile
RPT 2nd AUC tertile
RPT 1st AUC tertile
Rifampin
Stable culture conversion
MITT
SOLID MEDIA
BY RIFAPENTINE AUC TERTILE

5. Stable culture conversion BY RIFAPENTINE AUC TERTILE
RPT 3rd AUC tertile
RPT 2nd AUC tertile
RPT 1st AUC tertile
Rifampin
Stable culture conversion
MITT
LIQUID MEDIA
BY RIFAPENTINE AUC TERTILE

6. Results: Tolerability
*A well-tolerated regimen was pre-defined as one for which the 90% one-sided confidence limit of the % of participants who permanently discontinued that regimen was < 30%
Assigned treatment arm --->
RIF 10
N=85
RPT 10
N=87
RPT 15
N=81
RPT 20
Regimen permanently discontinued
Upper bound of 90% one-sided CL* 11
(12.9%)
19.0 5
(5.7%)
10.5
(6.2%)
11.3 9
(11.1%)
17.1
based on microbiology 4 2 3
death 1
toxicity other than death
w/draw consent, refuse to continue
Other

7. Study 31 / A5349 Primary Objectives
Evaluate efficacy of a high dose rifapentine-containing regimen to determine whether the single substitution of RPT for RIF makes it possible to reduce to 4 months (17 weeks) the duration of treatment
2PHZE/2PH
Evaluate efficacy of a 4 month (17 weeks) regimen that substitutes a) high dose RPT for RIF and b) MOX for EMB to determine whether reduction to 4 months (17 weeks) duration is possible (optimized regimen using existing drugs)
2PHZM/2PHM

8. Study 31/A5349 Phase 3 Design Open-label Non-inferiority design
N = 2500 – allowing for pre-specified analyses in subpopulations
Several secondary objectives and substudies, including PK/PD and biomarker studies
FDA registration level quality controls
DSMB review annually and as needed
Registration of ClinicalTrials.gov: NCT

9. Study 31/A5349, Selected eligibility criteria
Inclusion
Positive sputum smear for AFB or positive Xpert MTB with medium or high result
Age >= 12
If HIV (+), CD4 T cell count >= 100 cells/mm3
Initially enrolling only “EFV1” group, stable on efavirenz-based ART, for drug interaction PK and viral load testing
Exclusion
> 5 days TB treatment within previous 6 months
> 5 days treatment with anti-TB drugs within previous 30 days
TB of CNS, bones or joints, miliary, pericardial
Weight < 40 kg

10. Study 31/A5349 Schema Regimen 1 (control) 2RHZE/4RH (26 wks) Regimen 2
Screen for eligibility
Key Notes:
All treatment: daily 7/7
Flat P dose of 1200 mg
M dose of 400 mg
Food guidance: food with RPT, no food with RIF
Consent, enroll
Randomize 1:1:1
Regimen 1
(control)
2RHZE/4RH
(26 wks)
Regimen 2
(investigational)
2PHZE/2PH
(17 wks)
Regimen 3
(investigational)
2PHZM/2PHM
(17 wks)
Evaluation for primary outcome at 12 months after randomization, secondary at 18 month
SECONDARY: Evaluate safety and tolerability of the regimens, extensive PK of ALL TB drugs and EFV, biobanking

11. Currently S31/A5349 is enrolling in 13 countries

12. Cumulative Enrollments by Month
First enrollment 25 January, 2016
Monthly enrollment rate needed to finish by December, 2018: 100
Enrolled Last Month (February 2018): 109
Enrolled in Last 30 Days: 115
1809 enrollments (as of 09Mar2018)
72% of target enrollment
Anticipated completion December 2018

13. Enrollment of HIV-infection participants
Description
Total
EFV 1 group
HIV+ test at enrollment 52
HIV+ test at enrollment & randomized to RPT regimen
HIV+ test at BL, randomized to RPT regimen, eligible &
submitted at least one EPK form 48
EFV 2 group 29 14

14. Study 31 / A5349 Safety Monitoring
By site teams
Central (TBTC Data Center)
Data Safety Monitoring Board
No safety concerns raised in 3 DSMB meetings
DSMB Meeting History for TBTC S31/ACTG A5349
The following DSMB meetings have been held, for this study, since enrollment started. #
Year
Meeting Date
Data Cut-Off Date 1
2016
May 3, 2016
April 30, 2016 2
August 25, 2016
August 11, 2016 3
2017
May 12, 2017
March 31, 2017 4
2018
May 15, 2018
March 30, 2018

15. Summary
The long-acting rifamycin, rifapentine, has an MIC that is 1 to 2 dilutions lower than that of rifampin and a half-life that is 5 times longer.
Daily high-dose RPT based regimens appears to be highly efficacious and tolerated up to 20mg/kg/day or flat dosing of 1200mg in Phase 2 studies
RPT at 1200mg daily, as part of 4 drug regimen, appears to have promise for shortening duration of TB treatment.
TBTC Study 31 / A5349 results to be reported in 2019

16. Study 31 / A5349 Protocol Team (v. 2.0, May 2015)
Susan Dorman, Chair Payam Nahid, Chair Stefan Goldberg, Study Officer Janet Anderson* Richard Chaisson** Kwok-Chiu Chang Michael Chen, Study Statistician Mark Cotton Dalene von Delft (CRAG) Kelly Dooley** Melissa Engle Pei-Jean Feng Courtney Fletcher* Phan Ha Chad Heilig Daniel Johnson* John L. Johnson
Marilyn Maroni (Sanofi) Cynthia Merrifield Jose M. Miro Sachiko Miyahara* Nguyen Viet Nhung April Pettit Anthony Podany* Kathleen Robergeau (Westat) Wadzanai Samaneka* Erin Sizemore Susan Swindells*, ACTG Chair Andrew Vernon Mark Weiner Lisa Wolf* Suria Yesmin* *ACTG **ACTG and TBTC