Large Comparative Safety Trial in an Usual Care Setting ____________________________________________

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Large Comparative Safety Trial in an Usual
Care Setting_____________________________________
__________________________________________________
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C. George Rochester, Ph.D. FDA Anti-Infective
Advisory Committee Meeting Mathematical
Statistician, Division of Biometrics III January
8, 2003 RochesterG_at_cder.fda.gov
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Study 3014Elements of Study Design
(1)______________________________________________
_________________________________________________

• Randomized, comparative, open-label
• Community-acquired respiratory tract infections
  CAP, AECB, or AS
• Approximately 12,000 subjects per arm
• Telithromycin (TEL) 800 mg qd orally x 5 days for
  AS 7-10 days for CAP or AECB
• Comparator Amoxicillin-clavulanic acid (AMC) 875
  mg/125 mg bid x 7-10 days for all indications

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Elements of Study Design (2)_____________________
__________________________________________________
________________________

• Usual care setting with relaxed inclusion and
  exclusion criteria and included subjects with
  CARTIs
• Indication distribution 10 CAP, 30 AECB, 60
  AS
• Target - ? 40 subjects with CAP/AECB,
  - ? 35 subjects ? 50 years
  of age
• Subjects with cardiovascular disease, renal or
  hepatic impairment, and concomitant drug use,
  such as, subjects taking that inhibit or are
  metabolized by CYP3A4 or CYP2D6

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Definition of Adverse Events of Special
Interest (AESIs) ________________________________
_________________________________________
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Overall Adverse Event Rates______________________
__________________________________________________
_______________________

• Phase 3 trials ? 50 of subjects had AEs
• Study 3014 had many subjects with
  co-morbidities - diabetes, renal or hepatic
  impairment, cardiovascular disease, many
  concomitant drugs ? 23 of subjects had AEs
• Subjects with CAP accounted for 10 of study
  population
• Usual care setting - population may be more
  heterogenous than those enrolled in previous
  phase 3 trials

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Adverse Events Subgroups_______________________
_____
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Hepatic AESI Investigation Process______________
__________________________________________________
_______________________________

• Hepatic laboratory testing was done at Pretherapy
  (Day 1) and Post-therapy (Day 17-22) clinic
  visits
• Alteration in hepatic laboratory values of
  increase in ALT gt 3xULN was used to flag
  potential hepatic AESIs
• Follow-up to return to baseline or sufficient
  decline was done for subjects with potential
  hepatic AESI - 6 months
• Management algorithms were not utilized could
  have guided investigators with minimum
  expectation for follow-up of AEs and minimize
  missing critical data and improve completeness of
  case documentation
• Adjudication by blinded CECs was planned at
  regular intervals but was largely done in batch
  at the end of the trial

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Hepatic AESI Resolution________________________
____
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Changes in ALT Normal Baseline
____________________________
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Changes in AST Normal Baseline_________________
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Changes in Hepatic Analytes at any Post-Therapy
Time Point_______________________________________
_____________________________________________
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Combined ALT and Bilirubin Changes at any
Post-Therapy Time Point__________________________
__________________________________________________
________
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Changes in ALT among Telithromycin-treated
Subjects By Duration____________________________
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Subjects who Met Hepatic Endpoint Definition
_________________________________________________
______________________________________________

• Subjects who met the definition of a possibly
  drug related hepatic event
• TEL 3/12,096 (95 C.I., 0.5 - 7.2/10,000)
• AMC 2/11,883 (95 C.I., 0.2 - 6.1/10,000)

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Case 0187-026__________________________________
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Case 3440-001__________________________________
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Case 2004-002____________________________________
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Summary _________________________________________
__________________________________________________
__________________________________________________
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• Hepatic AESIs were uncommon ( about 1) of
  subjects exposed to telithromycin
• Telithromycin appeared similar to AMC with
  elevations in hepatic analytes (specifically,
  ALT) up to 3 x ULN
• More extreme elevations in ALT (gt 8 x ULN) were
  slightly more common among telithromycin treated
  subjects
• A minority of subjects were symptomatic in both
  treatment arms
• There were no cases of liver failure or deaths
  among hepatic cases
• At the 6 month follow-up no subjects were
  reported with known sequelae, one
  telithromycin-treated subject had persistent RUQ
  tenderness on examination x 6 months