HIRIF:A Randomized, Placebo-ControlledTrial of High-Dose Rifampin in Patientswith New, Smear-Positive TB
Carole Mitnick, ScD
21 October 2011
INTERTB Symposium
Summary HIRIF
Background, rationale
Design
Related studies
Challenges
Next steps
HIRIF
Phase II trial
Pharmacokinetic (PK), safety,bacteriologic endpoints
Provide proof of concept that dailydose of RIF could:
Shorten standard therapy
Add no additional toxicity
Rationale for high-dose RIF (1)
In vitro, animal, human evidence of dose-dependent activity of rifamycins
Low RIF blood levels associated with failure
Most potent sterilizing activity of 1st-line drugs
RIF & PZA critical to 6-month treatment
No plateau in activity detected at 600 mg
600 mg standard for cost & availability
Historical efforts to test shorter regimens inhumans were problematic: Too short
Weak companion drugs
Toxicity associated with intermittent dosing
Rationale for high-dose RIF (2)
Sirgel et al., AJRCCM, 2005
Rationale for high-dose RIF (3)
Higher doses used safely for other indications(leprosy, brucellosis, pneumococcuspneumonia)
Liver toxicity (2-5%), blood toxicities thoughtto be idiosyncratic
Flu-like syndrome associated withintermittency, not dose
Universally available, several genericproducers, inexpensive
Equipoise: do higher doses of RIF hold promiseto shorten treatment?
Design: Treatment arms
Extra RIF in intervention arms placebo controlled
Exclusion criteria
Smear < 2+ or culture-negative
Resistance; previous treatment
CNS or miliary TB; pericardial or pleural TB
HIV positive, CD4<350
61>Age<18 years
Pregnant, breastfeeding
Abnormal liver or renal function
Hgb<7.0 g/dL, platelet<75,000 mm3
Study methods
Rapid resistance test (HAIN)
Daily ambulatory, supervised therapy
Overnight serial sputum collection (6)
PK coordinated with 1 collection
DST, isolate storage for typing in case ofrecurrent disease
Clinical (& lab) monitoring for adverse events
Monthly smear & culture during continuation
Quarterly follow-up 6 months after treatment
Objectives
Across 3 treatment arms:
Evaluate Pharmacokinetic (PK) parameters: AUC0-24/MIC
Estimate efficacy: Decline in M. tb log colony forming units (CFU)
Time to culture conversion (solid & liquid)
Change in time to detection of M. tb (liquid)
Culture negativity at 8 weeks (solid)
Assess safety Time to AEs, Grade 2 and higher
Randomization
1. Block randomize to treatment arms(blinded)
2. Within arms, randomize to sputumcollection schedule (1:1)
1. Days 0, 1, 3, 8-10, 13-16 (PK), 47-51
2. Days 0, 2, 7, 9-11, 26-30 (PK), 54-58
3. Within arms, randomize to PKsampling scheme, sparse:intensive(2:1)
Sample Size & Power
180 patients enrolled
Expect 150 to be evaluated
PK: 90% power to detect expected difference:
14 mcg/ml*hr between lowest & highest dose
Efficacy: 80% power to detect expecteddifference: 0.025 log10 CFU/ml
Safety: 68% power to detect difference infrequency (10 vs. 20%) of Grade 2 or higher;greater power to detect continuous timeendpoint
Substudies
Three substudies will examine:
1) The value of lipid-body content in sputum samplesas a surrogate marker for clinical endpoints.
2) The effect of different processing (decontaminatedSSCC, SSCC without decontamination, MGIT withdecontamination) techniques on the agreementamong bacteriologic endpoints.
3) The frequency of mixed-strain infections detectablein pooled sputum collections & the effect of mixed-strain infections on interim and clinical outcomes.
TimelineStudy Period: 20 August 2011-31 July 2014
2011 2012 2013 2014
Study activities-HIRIF Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3
Approvals & staffing x x xFinalize CRFs and database x x
Training x x
Enrollment x x x x x
On Study Drug x x x x x x
Follow up x x x x x x x x
Interim, blinded PK analysis xFinal PK and efficacy analysis x
Final safety analysis x
Sites
National TB Program & Socios En Salud(Leo Lecca), Lima, Peru
Pending: Federal University of Espirito
Santo, Vitoria, Brazil (Reynaldo Dietze)
Other Collaborators
University of Liverpool: Gerry Davies
St. George’s Hospital, University ofLondon/INTERTB: Denis Mitchison,Amina Jindani, David Coleman
University of FL: Chuck Peloquin
Partners In Health, Brigham andWomen’s Hospital, Harvard School ofPublic Health
Other involved entities
Division of Microbiology & InfectiousDiseases, NIAID, NIH
Funder
Sanofi Aventis
RIF & placebo
FIND
HAIN, MGIT
US Food & Drug Administration
Being done under IND
Challenges
Foreign clearance for Brazil May not occur in time
Increased enrollment demand Peru
Lengthy approval process
Laboratory capacity in Peru Public-health labs overburdened, establishing
dedicated research lab
Expectations/competition for study sites Study site to be hospital
Deviations from program norms
IND
Other related studies
RIFAQUIN, TBTC
APRIORI: evaluation of HD-RIF in Africafor treatment shortening Similar Ph II study
Max. dose tolerability study
Larger Ph II/III study
RIFATOX
High-dose RIF West Africa?
Subsequent Steps
Pool results with Phase II study in TZ
Consider rifapentine results
Use results to inform next step:
Phase III study: multiple durations
Combined Phase II/III with higher dosein Phase II
Rifapentine arm?
…
Acknowledgements
Sid Atwood
Ellen Ball
Jaime Bayona
Mercedes Becerra
Vera Belitsky
Roger Calderon
Ted Cohen
David Coleman
Gerry Davies
Reynaldo Dietze
Lee Zagorski
Beth Groom
David Hadad
Amina Jindani
Deb Keaney
Leo Lecca
Juliana Lopes Favaro
Hannah Massoud
Danny Meltzer
Denis Mitchison
Elna Osso
Marcello Pagano
Charles Peloquin
Malena Ramos
Noah Schectman
KJ Seung
Dave Thomas
Eva Tomczyk
DMID