# Presentation: 845839

## 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**

## 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

- FDA Anti-Infective AC Meeting

- 08 JAN 03

## 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

- FDA Anti-Infective AC Meeting

- 08 JAN 03

## 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 |  |

- FDA Anti-Infective AC Meeting

- 08 JAN 03

## 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

- FDA Anti-Infective AC Meeting

- 08 JAN 03

**Notes:**
<number>

## Adverse Events:  Subgroups____________________________

|  | Subjects with AEs  n/N (%) |  |  |  |
| --- | --- | --- | --- | --- |
| Subgroups | TEL |  | AMC |  |
|   Total subjects with AEs | 2807/12159 | (23) | 2745/11978 | (23) |
|    65 years | 518/2273 | (23) | 526/2203 | (24) |
|   Hepatic impairment | 31/97 | (32) | 41/119 | (35) |
|   Severe Renal impairment  | 5/23 | (22) | 0/17 | (0) |
|   Cardiovascular disease | 793/2965 | (27) | 737/2915 | (25) |
|     History of CHF | 83/277 | (30) | 65/270 | (24) |
|   CYP3A4 substrates | 1499/5834 | (26) | 1542/5795 | (27) |
|   HMG Co-A inhibitors*             | 347/1420 | (24) | 305/1341 | (23) |
| *Simvastatin, Lovastatin, Atorvastatin |  |  |  |  |

- FDA Anti-Infective AC Meeting

- 08 JAN 03

## 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

- FDA Anti-Infective AC Meeting

- 08 JAN 03

**Notes:**
<number>

## Hepatic  AESI  Resolution____________________________

|  | Number of subjects (%) |  |  |
| --- | --- | --- | --- |
|  | N=12,159 | N=11,978 | N=24,137 |
| Hepatic AESIs | 111 (0.9) | 98 (0.8) | 209 (0.9) |
| Lab recovery | 101 (0.8) | 95 (0.8) | 196 (0.8) |
| Concurrent illness | 4 (0.03) | 2 (0.02) | 6 (0.02) |
| Partial follow-up  | 9 (0.06) | 1 (0.0) | 10 (0.07) |

- FDA Anti-Infective AC Meeting

- 08 JAN 03

## 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 |
|  ULN | 7158  | 7044  | 585  | 607  |
| >1 to  2 | 488  | 433  | 57 | 42 |
| >2 to  3 | 35  | 22 | 6 | 4 |
| > 3 to  5  | 12 | 8  | 4  | 3  |
| > 5 to  8  | 8  | 7  | 4  | 0  |
| > 8       | 7  | 2  | 8  | 3  |

- FDA Anti-Infective AC Meeting

- 08 JAN 03

## Changes in AST:  Normal Baseline____________________________

|  | Post-Therapy |  |
| --- | --- | --- |
| Changes in AST | TEL
(N=7570) | AMC
(N=7390) |
| >  5 to  8 x ULN | 5  | 1  |
| >  8 x ULN | 5  | 1  |

- FDA Anti-Infective AC Meeting

- 08 JAN 03

## Changes in Hepatic Analytes at any Post-Therapy Time Point____________________________________________________________________________________

|  | n/N (%) of Subjects |  |  |  |
| --- | --- | --- | --- | --- |
| Hepatic analytes | TEL |  | AMC |  |
| ALT > 3 x ULN | 110/11570 | (1.0)* | 96/11311 | (0.8) |
| ALT > 8 x ULN | 19/11570 | (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 |  |  |  |  |

- FDA Anti-Infective AC Meeting

- 08 JAN 03

## Combined ALT and Bilirubin Changes  at any Post-Therapy Time Point____________________________________________________________________________________

|  |
| --- |

| Analytes  (x ULN) | Number of Subjects
    TEL             AMC |  |
| --- | --- | --- |
| Total number of subjects treated | 12159 | 11978 |
| ALT  3   and T. Bili  1.5  | 3 | 6 |
| ALT  3   and T. Bili  1.5  without increase in Alk. Phos. | 1 | 4 |
| Transaminase elevation and  jaundice 
without increase in Alk. Phos.
 | 0 | 1 |

- FDA Anti-Infective AC Meeting

- 08 JAN 03

## 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  5  | 7  | 5  |
| >5 to  8  | 4  | 4  |
| >8   | 5  | 2  |

- FDA Anti-Infective AC Meeting

- 08 JAN 03

## 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)

- FDA Anti-Infective AC Meeting

- 08 JAN 03

**Notes:**
<number>

## Case # 0187-026___________________________________________________________________________________________________________________________________________________________________________________

- FDA Anti-Infective AC Meeting

- 08 JAN 03

## Case # 3440-001___________________________________________________________________________________________________________________________________________________________________________________

- FDA Anti-Infective AC Meeting

- 08 JAN 03

## Case 2004-002___________________________________________________________________________________________________________________________________________________________________________________

|  | 72 y/o M, CAP- TEL 7-10 days |
| --- | --- |
| PMH | DM, HTN, CHG, CAD, Pleural effusion (-) liver dz or ETOH |
| MEDS | Aceon, coumadin, glyburide, lasix, spironazide, Tylenol prn |
| Symptoms | Day 30: Jaundice (Treated with Levaquin) |
| Diagnostics | Day 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 |
| Outcome | Clinically resolved at Day 58; 
Adjudicated as possibly drug related, passage of stone cannot be ruled out |

- FDA Anti-Infective AC Meeting

- 08 JAN 03

## 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

- FDA Anti-Infective AC Meeting

- 08 JAN 03