# Presentation: 828482

## COX-2 CV Safety celecoxib

- James Witter MD, PhD
- DAAODP/ODE V
- February 16, 2005

## Reasons for Drug Exposure

- Acute or chronic pain
*Patients*
- Placebo-control
- Short-term - acceptable (rescue)
- Long-term - not realistic, ? difficult
- Prevention of disease progression (Alzheimer’s, polyps)
*Subjects*
- Placebo-control - acceptable

## NSAIDs: Rx and OTC

- Concomitant medications during trials
- Ibuprofen (approved OTC May 1984)
- Naproxen (approved OTC January 1994)
- Robustness of prior approvals (324 pt yrs)
- Diclofenac (approved in 1988) with safety data that included:
- OA (pivotal trials): 97 pts (6 weeks)
- RA (pivotal trials): 344 pts (6-10-12 weeks)
- Phase 1-2 trials: 950 pts/volunteers (most 14 day)
- Supportive trials: 111 pts (12 week)
- Long-term, open-label trials: 252 pts (38 weeks)
- 2 MI, one in double-blind, one in open-label trials

## W.H.O. Adverse Reaction Terminology (cardiovascular)

- Myocardial infarction
- Myocardial ischemia
- Cerebrovascular disorder
- Embolism pulmonary
- (continued)

## W.H.O. Adverse Reaction Terminology (cardiovascular)

- Thrombophlebitis (arm, deep, leg deep, superficial)
- Unstable angina
- Angina pectoris
- Coronary artery disorder

## Adverse Event Recording

- Adverse Events
- Serious
- 21 CFR 312.32
- Deaths
- “hard endpoint”
- Celebrex NDA
- Spontaneous investigator reporting
- Not pre-specified or adjudicated
- CLASS
- GI endpoints: pre-specified and adjudicated
- CV: not pre-specified and non-adjudicated spontaneous investigator reports

##  Cardiovascular EndpointVIGOR study

**Anti-platelet Trialist Collaboration (APTC) composite endpoint:**
**CV death, non-fatal myocardial infarction & stroke**

- 2.2

- 2.0

- 2.4

- 1.9

## Celebrex (celecoxib)www.cder.fda.gov

- Original NDA (submitted June 29, 1998)
- 51 studies
- Phase 1 (PK, drug interaction, etc.): 29 studies
- Arthritis (OA/RA): 14 studies
- Post-surgical analgesia: 7 studies
- Long-term (2 year) safety: 1 open-label study (024)
- Patients allowed to increase drug (dose creep)
- No control arm, concomitant (OTC) medication use
- (continued)

## Celebrex (celecoxib)www.cder.fda.gov

- CLASS trial
- -2x safety
- SUCCESS-1
- Alzheimer’s
- -IQ5-97-02-001 (Alzheimer’s IND)
- -ADAPT
- Polyp prevention
- -preSAP
- -APC

## Celebrex NDA Clinical Review Team

- Primary Medical Officer (overall efficacy/safety)
- Renal/cardiovascular Consultant Medical Officer
- General Safety Medical Officer (including CV)
- GI Consultant/Secondary Medical Reviewer
- Analgesic Trials Medical Officer
- Platelet Safety Medical Officer

## CelebrexOA and RA Exposure (pt-yrs)

|  | 25-100 mg | 200 mg | 300 mg  | 400 mg | Total |
| --- | --- | --- | --- | --- | --- |
| Controlled trial
 < 180 days
 > 180 days | 
3067
0 | 
2654
39 | 
0
0 | 
615
0 | 
6337
39 |
| Open-label trials
 < 180 days
 > 180 days | 
3079
236 | 
3036
941 | 
1209
222 | 
689
410 | 
8023
1809 |
| TOTAL | 6383 | 6670 | 1441 | 1714 | 16208 |

**Table 3.1.3.2  (12/10/98 Consult)**

## CelebrexCV Mortality

| Population | # Deaths |  | Pt-yrs Exposure | Mortality Rate |
| --- | --- | --- | --- | --- |
| Controlled Arthritis Trials |  |  |  |  |
| Cardiac Deaths during trial

Placebo
Celebrex
NSAID | 

0
1
2 |  | 

208
1020
535 | 

0.00%
0.10%
0.37% |
| All Known Cardiac Deaths

Placebo
Celebrex
NSAID | 

0
2
2 |  | 

208
1020
535 | 

0.00%
0.20%
0.37% |
| Long-term, Open-label Arthritis Trial  |  |  |  |  |
| All Known Cardiac Deaths |  | 15 | 4274 | 0.35% |

- Table 5.1.1.2.4  (12/10/98 Consult)

## Celebrex Serious Adverse Events Cardiac & Renal 

| Event | Placebo
(n=1864) | Celecoxib (25-400 mg)
(n=5083) | NSAID
(n=2098) |
| --- | --- | --- | --- |
| Total | 30  (1.6%) | 75  (1.5%) | 39  (1.9%) |
| Sudden death
Chest pain
Unstable angina
Heart failure
Myocardial infarction
Rhythm disturbances
Hypertension
Renal failure | 0  (0%)
0  (0%)
0  (0%)
1  (<0.1%)
2  (0.1%)
1  (<0.1%)
0  (0%)
0  (0%) | 0  (0%)
3  (<0.1%)
1  (<0.1%)
3  (<0.1%)
8  (0.1%)
5  (0.1%)
3  (<0.1%)
0  (0%) | 1  (<0.1%)
0  (0%)
1  (<0.1%)
0  (0%)
2  (0.1%)
2  (0.1%)
0  (0%)
0  (0%) |

- Table 5.1.2.1  (12/10/98 Consult)

## Celebrex CV mortality 

| Celecoxib 
Dose  | Number of Deaths | Patient-years of Exposure | Crude Mortality Rate |
| --- | --- | --- | --- |
| 100 mg | 0 | 519 | 0% |
| 200 mg | 4 | 1271 | 0.31% |
| 300 mg | 2 (1) | 340 | 0.59% (0.29) |
| 400 mg | 3 (2) | 465 | 0.64% (0.43) |

- Celebrex CV mortality
- Long-term, Open-label Safety (024)

- Table 2.1a.1  (12/10/98 and 1/5/01 Consult)

## SUCCESS-1Successive Celecoxib Efficacy & Safety StudyStudy I49-98-02-096

- 12 Week Study in Patients with OA
- - Celebrex 100 mg BID
- - Celebrex 200 mg BID
- - Naproxen 500 mg BID
- - Diclofenac 50 mg BID
- 1142 Centers in 39 Countries
- - Intended to evaluate “homogeneity” of efficacy and safety around world

## SUCCESS-1 Summary Results

| 
Event | Celecoxib 
100-200 mg BID
(n=8800) | Diclofenac 
50 mg BID
(n=3489) | Naproxen 
500 mg BID
(n=905) |
| --- | --- | --- | --- |
| Deaths
  CV | 5 (< 0.1)
2 (< 0.1) | 5 (0.1)
4 (0.1) | 0
0 |
| SAE | 265 (3.0) | 95 (2.7) | 48 (5.3) |
| Withdrawal-AE | 809 (9.1) | 274 (7.9) | 177 (19.6) |
| CV | 59 (0.7) | 14 (0.4) | 4 (0.4) |
| HTN | 119 (1.4) | 44 (1.3) | 13 (1.4) |
| Edema | 171 (1.9) | 34 (1.0) | 43 (4.8) |

- Data presented to AAC, Dec. 7, 2001
- Updated 1/12/05:  MI 8 (0.2%) for Celebrex 100 mg; 2 (< 0.1) for Celebrex 200 mg; 1 (< 0.1) for NSAIDs

## CLASS

- Celecoxib
- Long-term
- Arthritis
- Safety
- Study

## CLASS 

- Unique Trial
- Intended to mimic “real world” setting
- ASA Use if Indicated
- Patients with OA or RA
- RA doubles risk of heart failure
- Arthritis Rheum: Feb. 2005
- Designed as GI Safety Study
- Intended to change NSAID template regarding GI
- Not powered or designed as CV study

## COX-2 & 2x Improved Safety?

- CLASS/VIGOR-AAC
-  February 7-8, 2001

## “Clinically Relevant Events”

- “It has been demonstrated that upper GI ulcers, gross bleeding or perforation, caused by NSAIDs, appear in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year”
- 						(FDA, GI template warning label)
- NSAID-induced gastropathy may result in 107,000 hospitalizations and 16,500 deaths 								(ARAMIS 1998)

## CLASS - Baseline demographics

- Mean/median age ~60 years
- about 11%  age 75 years or older
- Most white females
- Approximately:
-  27% with RA
- 10% with history of GI bleed or GD ulcer
- 21% taking ASA

## CLASS - Patients

- Inclusion
- Age to give written informed consent
- OA or RA for 3 months requiring NSAIDs
- Not pregnant
- Exclusion
- Active malignancy, GI disease/ulceration
- Significant renal, hepatic or coagulation defect
- AST/ALT > 1.5x ULN

## Aspirin Use - CLASS

- Allowed at  325 mg daily
- - patients at risk for CV events
- Use was not stratified in the CLASS study
- Dose and duration of use may have varied
- No conclusions regarding ASA co-use can be drawn from CLASS, only observations and possible directions for future studies

## CLASS - Exposure

| Treatment Group | Patients Exposed | Patient-Years
of Exposure |
| --- | --- | --- |
| Celecoxib 400 mg BID | 3987 | 2340 |
| Diclofenac 75 mg BID | 1996 | 1080 |
| Ibuprofen 800 mg TID | 1985 | 1122 |

- Table 2.0a.1  (1/5/01Consult)

## CLASS - Exposure

| Interval on Drug | Celecoxib  | Diclofenac | Ibuprofen |
| --- | --- | --- | --- |
| 3 months | 1202 (30%) | 621 (31%) | 715 (36%) |
| 3-6 months | 467 (12%) | 262 (13%) | 246 (12%) |
| 6-9 months | 291 (7%) | 136 (7%) | 130 (7%) |
| 9-12 months | 1442 (36%) | 913 (46%) | 415 (21%) |
| 12-15 months | 585 (15%) | 64 (3%) | 477 (24%) |
| >15 months | 0 (0%) | 0 (0%) | 2 (<1%) |

- Table 2.0a.2  (1/05/01 Consult)

## Deaths (pt-yrs)

- Overall, 36 deaths for all causes
- Celecoxib 19 (0.8 %)
- Diclofenac 9 (0.8%)
- Ibuprofen  8 (0.7 %)
- Most (69%) in patients  65 years
- Most cardiovascular in nature
- Celecoxib (11 /19 = 58 %)
- Diclofenac (5/9 = 56 %)
- Ibuprofen (5/8 = 63 %)

## CLASS: Mortality-ASA Use (pt-yrs)

|  | Celecoxib
n=3987 (2320) | Diclofenac
n=1996 (1080) | Ibuprofen
n=1985(1122) |
| --- | --- | --- | --- |
| Deaths (All Causes) |  |  |  |
| All | 19 (0.8) | 9 (0.8) | 8 (0.7) |
| ASA Users  | 6 (1.2%) | 1 (0.4%) | 4 (1.6%) |
| Non-ASA Users  | 13 (0.7%) | 8 (1.0%) | 4 (0.5%) |
| Cardiac Deaths (Entire Study) |  |  |  |
| All | 11 (0.5) | 5 (0.5) | 5 (0.4) |
| ASA Users | 5 (1.0%) | 0 (0%) | 3 (1.2%) |
| Non-ASA Users | 6 (0.3%) | 5 (0.6%) | 2 (0.2%) |

## CLASS - Serious CV Events (pt-yrs)

| Serious Adverse Event | Celecoxib  | Diclofenac  | Ibuprofen  |
| --- | --- | --- | --- |
| ASA Users | n=882
(517) | n=445
(239) | n=412
(249) |
| Myocardial infarction | 13 (2.5%) | 2 (0.8%) | 7 (2.8%) |
| Combined  Atrial  | 7 (1.4%) | 1 (0.4%) | 4 (1.6%) |
| Combined Anginal Disorders
 | 20 (3.9%) | 11 (4.6%) | 8 (3.2%) |
| Non-ASA Users | n=3105
(1804) | n=1551
(841) | n=1573
(874) |
| Myocardial infarction | 6 (0.3%) | 2 (0.2%) | 2 (0.2%) |
| Combined  Atrial  | 6 (0.3%) | 1 (0.1%) | 0 (0%) |
| Combined Anginal Disorders | 10 (0.6%) | 3 (0.4%) | 2 (0.2%) |

- Table 2.1b.2  (1/5/01 Consult)

## CLASS - APTC-like Events

| Event | Celebrex
(n=3987) | Diclofenac
(n=1996) | Ibuprofen
(n=1985) |
| --- | --- | --- | --- |
| CV death | 11 | 5 | 5 |
| MI | 19 | 4 | 9 |
| Stroke | 4 | 6 | 6 |
| TOTAL | 34 (0.9%) | 15 (0.8%) | 20 (1.0%) |

## CLASS: Non-Aspirin Users

**●**

**●**

- Days

- Cumulative Incidence (%)

**0**

**40**

**80**

**120**

**160**

**200**

**240**

**280**

**320**

**360**

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- KM: Serious Thromboembolic CV Events** **

- Diclofenac 75 mg BID
- (n=1551)

- Celecoxib 400 mg BID
- (n=3105)

- Ibuprofen 800 mg TID
- (n=1573)

- 	    Rates
-                    _Crude    Pt-yr_
- Diclofenac  0.97%   1.78%
- Celebrex    0.77%   1.33%
- Ibuprofen	0.45%   0.80%

- Fitzgerald: Nature Reviews/Drugs Discovery (2) 2003
- Strand & Hochberg: Arthritis Rheum 47, 349-355 (2002)

## Alzheimer’s (IND)Division of Neuropharmacological Drug Products

- Study IQ5-97-02-001 (April 1997)
- DB, PC, 52-week comparative study of Celecoxib for the Inhibition of Alzheimer’s Disease
- Celecoxib 200 mg BID did not limit progression
- Study IQ5-01-06-004
- OL for long-term safety
- Terminated due to 001
- (continued)

## Alzheimer’s (IND)Division of Neuropharmacological Drug Products

- Study EQ5-00-06-002
- PC, long-term with vitamin E to evaluate MRI (brain size) and Alzheimer’s disease-associated proteins and inflammatory mediators
- Terminated due to 001
- IND inactivated July 2001

## Alzheimer’s 001 - DSMB LetterDecember 24, 2004

- Trial conducted 1997-1999 with DSMB
- No adverse events to support stopping trial
- Final review: excess of CV-related and other risk but difficult to interpret due to:
- Small sample size (relative risks and odds ratios unreliable)
- Frail, fragile population
- Substantial co-morbidity and concomitant medications
- Indications of failure of randomization in baseline CV disease and CV medications
- Celecoxib more than placebo      (continued)

## Alzheimer’s 001 - DSMB LetterDecember 24, 2004  (continued)

- Concerned that this data only presented in abstract
- May be only medically ill elderly population with placebo control

## Alzheimer’s - CV Events (IQ5-97-02-001)# patients (crude rates)

| Event | Celebrex 200 mg BID
(n=285) | Placebo
(n=140) |
| --- | --- | --- |
| Deaths
cardiac | 13 (4.6)
8 (2.8) | 4 (2.0)
2 (1.4) |
| Serious Adverse Events
MI
CHF
Atrial fibrillation
Angina pectoris
Cerebrovascular hemorrhage
Cerebrovascular disorder
PE/DVT
HTN
Edema
APTC like | 24 (8.4)
 2 (0.7)
 5 (1.8)
 3 (1.1)
 4 (1.4)
 1 (0.4)
 6 (2.1)
 1 (0.4)
 1 (0.4)
 1 (0.4)
11 (3.9) | 3 (2.1)
0
0
0
0
0
3 (2.1)
0
0
0
2 (1.4) |

- From Table T5 and Table 1  (12/22/04 submission, SN 1149)

## Study 001 – CV Randomization

|  | Placebo
N = 140 | Celecoxib
200 mg BID |
| --- | --- | --- |
| Medical History Term
Hypertension
Diabetes
Aortocoronary Bypass Surgery
Transcerebral Ischemia
Coronary Artery Disease | 
31 (22.1%)
10 (7.1%)
1 (0.7%)
4 (2.9%)
1 (0.7%) | 
91 (31.9%)
28 (9.8%)
9 (3.2%)
15 (5.3%)
8 (2.81%) |

- Table 9: Cardiovascular-related medical history terms that differ by > 2%  (Dec. 22, 2004 submission)