Tuberculosis Trials Consortium overview

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Tuberculosis Trials Consortium - overview

• Multicenter clinical trials group funded by the
  Division of TB Elimination at CDC
• Mission To conduct programmatically-relevant
  studies to improve the treatment of latent and
  active TB
• History
• 1994 constituted to conduct one trial
• 1997 re-organized to be an ongoing clinical
  trials group
• 1999 sites re-competed for 10-year contract

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Current TBTC sites
28 clinical sites worldwide CDC
Administrative, Statistical, and Data Management
Center
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Other TBTC activities

• Data and coordination center - CDC
• Central microbiology lab - CDC
• confirmatory drug-susceptibility testing
• genotypic resistance testing
• DNA fingerprinting
• CRO for training and site-monitoring (Westat)
• PK working group
• Biomarkers working group
• MDR-TB working group

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Major studies

• Study 22 once-weekly rifapentine during
  continuation phase of TB treatment (large
  randomized trial)
• Study 23 rifabutin-based regimen for HIV-TB (to
  foster use of ART)
• Study 24 treatment of INH-resistant TB
• Study 25 higher doses of rifapentine
• Study 26 phase 3 trial of weekly INH/RPT x 12
  doses vs. 9 mos of INH for latent TB (includes
  enrollment of children, HIV-positives)
• Studies 27, 28 role of moxifloxacin in
  treatment of active TB

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TBTC current capabilities

• Trials of treatment of active TB
• Enrollment of 400 patients per year
• Pilot studies of MDR-TB treatment enrollment of
  25-50 patients per year
• Latent TB
• Enrollment of 1350 patients per year
• Enrollment of children (gt 2 years)

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Needs and opportunities in TB therapeutics
research

• Latent TB treatment
• Children
• HIV-infected persons
• Patients with intolerance/interactions
• Active TB drug-susceptible
• Treatment-shortening
• Intermittency
• Improving tolerability
• PK/PD possible contribution

• Active TB drug-resistant
• Duration of treatment
• Use of new drugs
• Special populations
• Pediatric TB
• HIV co-infection
• Extrapulmonary TB
• Biomarkers
• Decision-analysis / modeling impact

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Summary priorities for research on latent TB
treatment

• Highest priority ensure enrollment of a
  sufficient number of children to evaluate the
  tolerability of weekly INH/RPT and the adequacy
  of dosing for young children (completion of 26 PK
  sub-study)
• Lower priority Phase 2 studies (assessment of
  tolerability) of alternatives to weekly INH/RPT
  for patients with toxicity from first-line
  treatment regimens
• Further in the future evaluation of new drugs
  for treatment of latent infection

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The challenges of research on treatment of active
disease

• Success of drug development 5-10 new drugs in
  the next decade
• Multidrug therapy need to investigate
• Dose
• Place in the regimen (companion drugs)
• Dosing frequency
• Success of our current therapy - low endpoint
  rate for clinical outcomes
• Funding

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Lessons from the history of TB clinical trials

• Dose x role in regimen x dosing frequency Need
  to evaluate many regimens to find the optimal
  form of treatment
• BMRC evaluated gt 100 regimens to come up with
  DOTS

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Phase 3 trials in TB treatment

• need to be large to detect clinically-relevant
  differences in failure/relapse and rates of
  serious toxicity
• 2 vs. 5, 80 power 1308 patients
• 2 vs. 5, 90 power 1706 patients
• need to include key subgroups (HIV-infected)
• need to evaluate regimens in a very diverse
  patient populations TB regimens for the world
  should be evaluated around the world

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The problems of getting from 6 to 2

• Need to evaluate a number of doses, combinations,
  and dosing frequencies to identify the optimal
  new regimen for ultrashort course therapy
  liberal use of Phase 2 trials, more efficient
  Phase 2 trial designs, shorter turn time
• Need for large trials to fully evaluate the
  efficacy and toxicity of new regimens few large
  Phase 3 trials

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Summary priorities for treatment of active,
drug-susceptible TB

• Goal treatment-shortening
• Continue to work on the evaluation of Moxi and
  RPT
• Other new drugs, as they become available
• Sub-studies, sample collection to evaluate
  possibility of decreasing sample size
• Possible biomarkers
• PK sampling

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Drug-resistant TB and TBTC

• Time is right
• Clear problem
• Treatment programs for MDR-TB
• Development of trial methodologies for
  drug-resistant pathogens
• Opportunities for trials - old questions, new
  drugs
• Pilot study of the tolerability and activity of
  reduced-dose linezolid for MDR-TB

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Special populations - children

• Need for (requirement for) involvement in
  research on new drugs
• Timing of evaluation in children
• Ways to involve children
• Independent studies
• Enroll into common protocol with adults
• Endpoints tolerability, PK

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Special populations HIV co-infection

• Questions about ART during TB treatment being
  evaluated by HIV trials groups
• Issues of PK of TB drugs, drug interactions
  need to collaborate to be able to evaluate the
  many questions
• TB-specific questions not being evaluated
• Duration of therapy
• Intermittency

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Prioritizing HIV-specific studies

• Include HIV-infected patients in all TBTC trials
• Assess the effect of HIV-serostatus on key
  outcomes
• HIV-specific questions (e.g., optimal treatment
  duration)
• Insufficient capacity at present

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Summary of current goals of TBTC

• Latent TB complete the evaluation of a 3-month,
  12-dose regimen
• Adequate evaluation among children (including PK)
  and HIV-infected patients
• Active TB identify and definitively evaluate a
  3-month regimen
• MDR-TB develop the capacity for MDR trials