AIDS Clinical Trials Group A5349 Rifapentinecontaining treatment shortening regimens for pulmonary tuberculosis A randomized openlabel controlled phase 3 clinical trial Payam Nahid MD MPH ID: 731340
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Tuberculosis Trials Consortium Study 31AIDS Clinical Trials Group A5349Rifapentine-containing treatment shortening regimens for pulmonary tuberculosis: A randomized, open-label, controlled phase 3 clinical trial Payam Nahid, MD, MPHProfessor of MedicineUCSF – Department of MedicineDivision of Pulmonary and Critical Care
1Slide2
Rifapentine (RPT, P): BackgroundCyclopentyl ring-substituted rifamycinMIC90 = 0.06 g/ml (vs. 0.25 for RIF)Half-life = 14-18 h (vs. 2-4 for RIF)Less potent inducer of cytochrome P450 than rifampinPreclinical:
Daily rifapentine is highly active in the murine model of TB
1,2,3
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 adults4No evidence of dose-dependent increase in frequency of known rifamycin-associated toxicities. Maximum tolerated dose at least 20 mg/kg/d
3 Rosenthal et al; AAC 2012;56:43314 Dooley et al; Clin Pharmacol Ther 2012;91:881
1 Rosenthal et al;
PLoS
Med 2007;4:e344
2 Rosenthal et al; AJRCCM 2008;178:989Slide3
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 & safetyEstimate antimicrobial activity, using a surrogate endpoint for ‘cure’Dorman, et al. Am J Respir Crit Care Med. 2015Slide4
Stable culture conversion MITTSOLID MEDIA BY RIFAPENTINE AUC TERTILERPT 3rd AUC tertile
RPT 2nd
AUC
tertile
RPT 1st AUC tertileRifampinSlide5
Stable culture conversion MITTLIQUID MEDIA BY RIFAPENTINE AUC TERTILERPT 3rd AUC tertile
RPT 2nd
AUC
tertile
RPT 1st AUC tertileRifampinSlide6
Results: Tolerability Assigned treatment arm --->RIF 10
N=85RPT 10N=87
RPT 15
N=81
RPT 20N=81Regimen permanently discontinuedUpper bound of 90% one-sided CL*11 (12.9%)19.0
5 (5.7%)10.55 (6.2%)
11.3
9
(11.1%)
17.1
based
on microbiology
4
2
3
3
death
0
0
1
1
toxicity other than death3012 w/draw consent, refuse to continue2300 Other2003
*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%Slide7
Study 31 / A5349 Primary ObjectivesEvaluate 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 treatment2PHZE/2PHEvaluate 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)
2P
HZ
M
/2PHM7Slide8
Study 31/A5349 Phase 3 DesignOpen-labelNon-inferiority designN = 2500 – allowing for pre-specified analyses in subpopulationsSeveral secondary objectives and substudies, including PK/PD and biomarker studiesFDA registration level quality controlsDSMB review annually and as neededRegistration of ClinicalTrials.gov: NCT024107728Slide9
Study 31/A5349, Selected eligibility criteriaInclusionPositive sputum smear for AFB or positive Xpert MTB with medium or high resultAge >= 12If HIV (+), CD4 T cell count >= 100 cells/mm3Initially enrolling only “EFV1” group, stable on efavirenz-based ART, for drug interaction PK and viral load testingExclusion> 5 days TB treatment within previous 6 months> 5 days treatment with anti-TB drugs within previous 30 daysTB of CNS, bones or joints, miliary, pericardialWeight < 40 kgSlide10
Study 31/A5349 SchemaRegimen 1(control)2RHZE/4RH (26 wks)Regimen 2(investigational)2PHZE/2PH
(17 wks)
Screen for eligibility
Consent, enroll
Randomize 1:1:1
Evaluation for primary outcome at 12 months after randomization, secondary at 18 month
Regimen 3
(investigational)
2PHZM/2PHM
(17
wks
)
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
SECONDARY:
Evaluate safety and tolerability of the regimens, e
xtensive PK of ALL TB drugs and EFV,
biobankingSlide11
Currently S31/A5349 is enrolling in 13 countriesSlide12
Cumulative Enrollments by MonthFirst enrollment 25 January, 2016Monthly enrollment rate needed to finish by December, 2018: 100 Enrolled Last Month (February 2018): 109Enrolled in Last 30 Days: 1151809 enrollments (as of 09Mar2018) 72% of target enrollmentAnticipated completion December 2018Slide13
Enrollment of HIV-infection participantsDescriptionTotal
EFV 1 group
HIV+ test at enrollment
52
HIV+ test at enrollment & randomized to RPT regimen
52
HIV+ test at BL, randomized to RPT regimen, eligible &
submitted at least one EPK form
48
EFV 2 group
HIV+ test at enrollment
29
HIV+ test at enrollment & randomized to RPT regimen
29
HIV+ test at BL, randomized to RPT regimen, eligible &
submitted at least one EPK form
14Slide14
Study 31 / A5349 Safety MonitoringBy site teamsCentral (TBTC Data Center)Data Safety Monitoring BoardNo 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
2016
August 25, 2016
August 11, 2016
3
2017
May 12, 2017
March 31, 2017
4
2018
May 15, 2018
March 30, 2018Slide15
SummaryThe 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 studiesRPT 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 2019Slide16
16Marilyn Maroni (Sanofi)Cynthia MerrifieldJose M. MiroSachiko Miyahara*Nguyen Viet NhungApril PettitAnthony Podany*Kathleen Robergeau (Westat)Wadzanai Samaneka*Erin SizemoreSusan Swindells*, ACTG Chair
Andrew VernonMark WeinerLisa Wolf*
Suria Yesmin*
*ACTG
**ACTG and TBTCSusan Dorman, ChairPayam Nahid, ChairStefan Goldberg, Study OfficerJanet Anderson*Richard Chaisson**Kwok-Chiu Chang
Michael Chen, Study StatisticianMark CottonDalene von Delft (CRAG)Kelly Dooley**Melissa EnglePei-Jean Feng
Courtney Fletcher*
Phan
Ha
Chad
Heilig
Daniel Johnson*
John L. Johnson
Study 31 / A5349 Protocol Team
(v. 2.0, May 2015)