hirif:a randomized, placebo-controlled trial of high-dose...

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