Lisa Eisenbeis RN, BScN, BSc -- Starting the Circle (asking good questions) Research at the Edmonton TB Clinic

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Starting the circle(asking good questions)
Research at the Edmonton Tuberculosis Clinic

• Lisa Eisenbeis RN, BScN, BSc
• 22March2012
• 2012 TB Symposium - Edmonton

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(No Transcript)
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• My mother made me a scientist without ever
  intending to.  Every other Jewish mother in
  Brooklyn would ask her child after school, "So? 
  Did you learn anything today?" 
• But not my mother.  "Izzy," she would say,
• "did you ask a good question today?" 
• That difference - asking good questions -
  made me become a scientist. 
• Isidor Isaac Rabi

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Currently under way (or soon to be)

1. 4 months Rifampin vs 9 months Isoniazid for LTBI
   in adults phase 3 effectiveness (4R9H)
2. Biomarker component amendment to above study
3. 4 months Rifampin vs 9 months Isoniazid treating
   LTBI in children - comparing safety and
   tolerability (P4R9H)
4. Drug Induced Liver Injury (international
   consortium)

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The international team of principle investigators
and study coordinators

• The Principal Investigator for the Edmonton site
  is Dr. Richard Long

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Participating Countries
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1. 4 months Rifampin vs 9 months Isoniazid for
treatment of latent TB infection in adults
Phase III - effectiveness

• 4RIF9INH

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Objectives

• Primary Objective
• To compare the cumulative incidence during 28
  months after randomization, of confirmed active
  tuberculosis among all persons randomized
  (effectiveness, using intention to treat
  analysis) to 4Rif and 9INH

Is Rif just as good as INH?
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In a nutshell

• Pragmatic trial
• Phase 2 demonstrated increased compliance, fewer
  side effects and better cost analysis with
  Rifampin
• Open label trial
• Non-inferiority
• Recruiting adults with risk factor for
  reactivation
• 28 months follow up after randomization
  (q3months)
• Goal of 6000 participants

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Eligibility Criteria
TST 5-9 or QFT TST 10-14 or QFT TST gt15
HIV Converter (within 2 yrs, gt6mm ?) 1 of -recent arrival from high risk country (within 2 years) -underweight (lt90 ideal) -CXR past disease -smoker gt1/2 ppd
Close contact (C case) Casual Contact (S case) 1 of -recent arrival from high risk country (within 2 years) -underweight (lt90 ideal) -CXR past disease -smoker gt1/2 ppd
Apical fibronodular disease gt2cm² Conversion (2-5 yrs, gt10mm?) 1 of -recent arrival from high risk country (within 2 years) -underweight (lt90 ideal) -CXR past disease -smoker gt1/2 ppd
Immunocompromised (medical condition or therapy chemo, Tx) 2 of -recent arrival from high risk country(within 2 years) -underweight (BMIlt19) -CXR past disease -smoker gt1/2 ppd 1 of -recent arrival from high risk country (within 2 years) -underweight (lt90 ideal) -CXR past disease -smoker gt1/2 ppd
Immunocompromised (medical condition or therapy chemo, Tx) Other immunocompromised (Renal, Diabetes) 1 of -recent arrival from high risk country (within 2 years) -underweight (lt90 ideal) -CXR past disease -smoker gt1/2 ppd
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So far

• Halfway through recruitment (Dec 2013)
• Approaching 3000 enrollees
• First interim safety review demonstrated even
  less AE associated with rifampin than reported in
  phase 2

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Research serves to make building stones out of
stumbling blocks. -Arthur D. Little
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2.Biomarker amendment
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Objectives

• To compare the change in T-cell cytokine response
  to TB specific antigens from therapy initiation
  to four months later between compliant subjects
  allocated to 4RIF vs. 9INH. Compliant subjects
  are those taking at least 80 of the allocated
  study drug up to that time.
• Among participants in this trial, to compare the
  change in T-cell cytokine response to TB specific
  antigens from initiation of therapy to 9 months
  later (i.e. after treatment completion), by level
  of compliance as estimated by the percentage of
  recommended doses taken of 9INH or 4RIF.

What does the IGRA do after treatment?
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In a nutshell

• Incorporated as part of the adult 4RIF9INH trial
  and thus same eligiblity
• IGRAs to be done at baseline, 4 months and 9
  months post randomization
• Opt out consent
• A Biobank will also be constructed for future use
  i.e. test new diagnostic technologies
• The IGRAs will be performed here in the lab of
  Dr. Dennis Kunimoto

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What is research, but a blind date with
knowledge. -William Henry
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3.4 months Rifampin vs 9 months Isoniazid for
latent TB infection in Children Safety and
tolerability

• P4R9H

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Objectives

• Primary Objective

To compare the rates of premature discontinuation
of study therapy because of adverse events of all
grades judged probably related to 4RIF or 9INH,
by the majority of an independent panel of 3
reviewers, blinded to study drug.
How do kids do on Rif INH?
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In a nutshell

• Close attention to adverse events
• Period of follow up is 16 months
• Will be using predetermined dosing at all sites
• Goal of 900 enrollees
• Challenges
• counting doses with liquid formulations
• Large age range, differences in ability to take
  medications

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Eligibility Criteria
Patient lt18 yrs and being recommended prophylaxis

TST 5-9 or QFT TST 10-14 or QFT TST gt15
HIV Casual Contact (S case) 1 of -recent arrival from high risk country (within 2 years) -underweight (lt90 ideal)
Contact with adult or adolescent (gt14 yrs) with S pulmonary TB 2 of -recent arrival from high risk country(within 2 years) -underweight (BMIlt10th percentile) 1 of -recent arrival from high risk country (within 2 years) -underweight (lt90 ideal)
Age 5 yrs or less Other immunocompromised (Renal, Diabetes) 1 of -recent arrival from high risk country (within 2 years) -underweight (lt90 ideal)
Immunocompromised (medical condition or therapy chemo, Tx) Other immunocompromised (Renal, Diabetes) 1 of -recent arrival from high risk country (within 2 years) -underweight (lt90 ideal)
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So far

• Recruitment is underway but not in all sites as
  of yet
• Edmonton awaiting first enrolment started March
  12, 2012
• ..wishing for our first soon

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Science is simply common sense at its best. 
-Thomas Huxley
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4.Drug Induced Liver Injury

• iDilic
• International Drug-Induced Liver Injury Consortium

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Background
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Under the 4R9H RCT

• Primary Objective
• identify and validate DNA variants useful in
  predicting the risk of drug induced serious
  adverse events, specifically liver
  injury/hepatitis
• Under the 4RIF9INH RCT, will look at Rifampin and
  Isoniazid (other partners looking at other drugs)

Who is going to have liver problems during
treatment?
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Eligibility Criteria

• Patients who are enrolled in the RCT Phase 3.
• 18 years of age or over
• Diagnosed with drug-induced liver injury
• Grade 3 or 4 severity
• gt3ULN ALT/AST symptoms
• gt5ULN ALT/AST
• gt10ULN ALT/AST
• Likely related to study drug

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In Appreciation
Dr. Dennis Kunimoto Medical Director, ETBC
Edmonton TB Clinic Staff
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Questions??

• He who does not research has nothing to teach.
• -Proverb