1. Large Comparative Safety Trial in an Usual Care Setting ________________________________________________________________________________________________ C. George Rochester, Ph.D. FDA Anti-Infective Advisory Committee Meeting Mathematical Statistician, Division of Biometrics III January 8, 2003 RochesterG@cder.fda.gov

2. 08 JAN 03FDA Anti-Infective AC Meeting2 Study 3014: Elements 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

3. 08 JAN 03FDA Anti-Infective AC Meeting3 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

4. 08 JAN 03FDA Anti-Infective AC Meeting4 Definition of Adverse Events of Special Interest (AESIs) _________________________________________________________________________ Hepatic: Clinically overt presentation of significant hepatic injury, alanine aminotranferase (ALT) > 3x ULN a, total bilirubin > 1.5 x ULN, worsening of a pre- existing hepatic condition Cardiac:Torsades de Pointes, ventricular arrythmias, syncope, cardiac arrest, unwitnessed or unexplained deaths Visual:visual disturbances (blurred vision) Vasculitis:purpura or other signs of vasculitis a ULN=Upper limit of normal

5. 08 JAN 03FDA Anti-Infective AC Meeting5 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

6. 08 JAN 03FDA Anti-Infective AC Meeting6 Adverse Events: Subgroups ____________________________ Subjects with AEs n/N (%) Subgroups TELAMC Total subjects with AEs2807/12159(23)2745/11978(23)  65 years 518/2273(23)526/2203(24) Hepatic impairment31/97(32)41/119(35) Severe Renal impairment5/23(22)0/17(0) Cardiovascular disease793/2965(27)737/2915(25) History of CHF83/277(30)65/270(24) CYP3A4 substrates1499/5834(26)1542/5795(27) HMG Co-A inhibitors*347/1420(24)305/1341(23) *Simvastatin, Lovastatin, Atorvastatin

7. 08 JAN 03FDA Anti-Infective AC Meeting7 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 > 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

8. 08 JAN 03FDA Anti-Infective AC Meeting8 Hepatic AESI Resolution ____________________________ Number of subjects (%) N=12,159N=11,978N=24,137 Hepatic AESIs111 (0.9)98 (0.8)209 (0.9) Lab recovery101 (0.8)95 (0.8)196 (0.8) Concurrent illness4 (0.03)2 (0.02)6 (0.02) Partial follow-up9 (0.06)1 (0.0)10 (0.07)

9. 08 JAN 03FDA Anti-Infective AC Meeting9 Changes in ALT: Normal Baseline ____________________________ Post-Therapy Late Post-Therapy Changes in ALT ( X ULN) TEL N=7708 AMC N=7516 TEL N=664 AMC N=659  ULN71587044585607 >1 to  24884335742 >2 to  3352264 > 3 to  512843 > 5 to  88740 > 87283

10. 08 JAN 03FDA Anti-Infective AC Meeting10 Changes in AST: Normal Baseline ____________________________ Post-Therapy Changes in AST TEL (N=7570) AMC (N=7390) > 5 to  8 x ULN 51 > 8 x ULN 51

11. 08 JAN 03FDA Anti-Infective AC Meeting11 Changes in Hepatic Analytes at any Post-Therapy Time Point ____________________________________________________________________________________ n/N (%) of Subjects Hepatic analytesTELAMC ALT > 3 x ULN110/11570 (1.0 ) * 96/11311(0.8) ALT > 8 x ULN19/11570(0.2)10/11311(0.1) Alt > 3 x ULN and Total bilirubin > 1.5 x ULN 3/10864(0.03)6/10600(0.06) *Denominator reflects subjects with simultaneous assay values

12. 08 JAN 03FDA Anti-Infective AC Meeting12 Combined ALT and Bilirubin Changes at any Post-Therapy Time Point ____________________________________________________________________________________ Analytes (x ULN) Number of Subjects TEL AMC Total number of subjects treated1215911978 ALT  3 and T. Bili  1.5 36 ALT  3 and T. Bili  1.5 without increase in Alk. Phos. 14 Transaminase elevation and jaundice without increase in Alk. Phos.01

13. 08 JAN 03FDA Anti-Infective AC Meeting13 Changes in ALT among Telithromycin- treated Subjects: By Duration ____________________________ Post - Therapy Changes in ALT (x ULN) TEL 7-10 days (N=3024) TEL 5 days (N=4684) >3 to  575 >5 to  844 >852

14. 08 JAN 03FDA Anti-Infective AC Meeting14 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)

15. 08 JAN 03FDA Anti-Infective AC Meeting15 Case # 0187-026 ___________________________________________________________________________________________________________________________________________________________________________________

16. 08 JAN 03FDA Anti-Infective AC Meeting16 Case # 3440-001 ___________________________________________________________________________________________________________________________________________________________________________________

17. 08 JAN 03FDA Anti-Infective AC Meeting17 Case 2004-002 ___________________________________________________________________________________________________________________________________________________________________________________ 72 y/o M, CAP- TEL 7-10 days PMHDM, HTN, CHG, CAD, Pleural effusion (-) liver dz or ETOH MEDSAceon, coumadin, glyburide, lasix, spironazide, Tylenol prn SymptomsDay 30: Jaundice (Treated with Levaquin) DiagnosticsDay 1: Normal baseline LFTs Day 23: ALT 8xU, AST 5xU, Alk Phos 3xU T.bili 5x ULN Day 29: ALT 5xU, AST 3xU, Alk Phos 4xU T.bili 4x ULN, Direct Bili 6.5xU; Eosinophils 1 xU. Serologies (-) CT: Gallbladder with low density calculi, sludge Intervention Day 35: Cholecystectomy and liver biopsy OutcomeClinically resolved at Day 58; Adjudicated as possibly drug related, passage of stone cannot be ruled out

18. 08 JAN 03FDA Anti-Infective AC Meeting18 Summary ________________________________________________________________________________________________________________________________________________ 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 (> 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