# Presentation: 688020

## FDA Advisory Committee Meeting

**29 November 2006**

**FDA Advisory Committee Meeting**

**Celecoxib in the Treatment of the Signs and Symptoms of Juvenile Rheumatoid Arthritis (JRA)**

## Delegation

| Dr Edward Giannini | EpidemiologyCincinnati Children’s Hospital Medical Center |
| --- | --- |
| Dr Benjamin Gold | Pediatric gastroenterologyEmory University School of Medicine |
| Dr Gary Koch | StatisticianUniversity of North Carolina at Chapel Hill |
| Dr Daniel Lovell | Pediatric rheumatologyCincinnati Children’s Hospital Medical Center |
| Dr Robert Stern | DermatologyHarvard Medical School |

## Objectives

**To present for Committee discussion the available data regarding celecoxib in the treatment of children with JRA**

**To demonstrate that, based on current data, celecoxib is efficacious without evidence for unique safety concerns compared to other NSAIDs in JRA**

**To highlight the concern of rare events and uncertain long-term risks of NSAID therapies  **

**To highlight the medical need for NSAIDs in the treatment of children with JRA**

## Objectives and Agenda

**Overview of celecoxib**
**Clinical characteristics and current treatments for children with JRA**
**Regulatory history, rationale for study of celecoxib in children, and clinical data for celecoxib in JRA**
**Overall conclusions**

**Dr S Lowry**

**Dr D Lovell**

**Dr S Lowry**

## Celecoxib Overview

**Selective inhibitor of COX-2 **
**Spares COX-1 at therapeutic doses**
**Approved indications:**
**1998:  OA and RA in adults**
**1999:  FAP**
**2001:  Acute pain and primary dysmenorrhea**
**2005:  Ankylosing spondylitis**
**Studied in over 25,000 adult patients**
**Epidemiologic data from ~200,000 patients**
**Experience in over 70 million patients worldwide since approval**

## Emerging Data in 2004:  CV Safety 

**September 30, 2004:** Rofecoxib withdrawn due to increased CV risk vs placebo in the APPROVe trial1,2
**December 2004:** Preliminary data from 1 out of 3 long-term trials with celecoxib showed increased CV risk vs placebo3,4

- 1. Merck press release. September 30, 2004; 2. Freudenheim. *The New York Times*. October 1, 2004; 3. NCI Press Release. December 17, 2004; 4. NIH News Press Release. December 20, 2004.

## FDA Actions Taken in 2005

**Convened a joint meeting of the AAC and the DSaRM **
**Outcome: Advisory Committee voted 31-1 that the ****overall risk:benefit profile of Celebrex supports ****continued marketing in the US**
**FDA memorandum **
**Questions still remain regarding the CV risks associated with all NSAIDs**
**Manufacturers of all prescription NSAIDs were requested ****to implement label changes**
**Class-labeling template on CV / GI risk issued**

- Joint Meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee Joint Meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee _[http://www.fda.gov/oc/advisory/accalendar/2005/cder12532ddd0216171805.html](http://www.fda.gov/oc/advisory/accalendar/2005/cder12532ddd0216171805.html)_
- Jenkins and Seligman.  Analysis and recommendations for Agency action regarding NSAIDs and cardiovascular risk.  US Food and Drug Administration Memorandum 6 April 2005

## US FDA Decision Memorandum

**Analysis and recommendations for Agency action regarding NSAIDs and cardiovascular risk **
**“****It is not possible to conclude at this point that the COX-2 selective drugs confer an increased risk over non-selective NSAIDs in chronic use.”**
**“****We believe that it is reasonable to conclude that there is a “class effect” for increased CV risk for all NSAIDs pending the availability of data from long-term controlled clinical trials that more clearly delineate the true relationships*****.*****”**

- Jenkins and Seligman. Analysis and recommendations for Agency action regarding NSAIDs and cardiovascular risk. US Food and Drug Administration Memorandum 6 April 2005.

## Boxed Warning for All Prescription NSAIDs

**Cardiovascular Risk**
**“****xxxx” may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs may have a similar risk. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk**
**“****xxxx” is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery**
**Gastrointestinal Risk**
**NSAIDs, including “xxxx”, cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events**

## ADAPT:  Composite CV Events

**Favors NSAID**

**Favors placebo**

**Hazard Ratio (95% CI)**

**ADAPT:  Composite CV Events**

**APTC**

**APTC/CHF**

**APTC/CHF/TIA**

**1.14 (0.61, 2.15)**

**1.57 (0.87, 2.81)**

**1.06 (0.60, 1.88)**

**1.66 (1.00, 2.77)**

**1.10 (0.67, 1.79)**

**1.63 (1.04, 2.55)**

**Celecoxib**

**Naproxen**

**Celecoxib**

**Naproxen**

**Celecoxib**

**Naproxen**

**APTC events = CV death, nonfatal MI, nonfatal stroke**
**ADAPT Research Group.  PLoS Clin Trials; 2006: 1:e33. doi:10.1371/journal.pctr.0010033 **

## CV Risk of NSAIDs

**Better than Non-use/Remote Exposure**

**Worse than Non-use/Remote Exposure**

**Relative CV Risk (95% CI)**

**CV Risk of NSAIDs**

**Naproxen**

**Ibuprofen**

**Celecoxib**

**Piroxicam**

**Meloxicam**

**Indomethacin**

**Rofecoxib**

**Diclofenac**

**0.97 (0.87, 1.07)**

**1.07 (0.97, 1.18)**

**1.06 (0.91, 1.23)**

**1.06 (0.70, 1.59)**

**1.25 (1.00, 1.55)**

**1.30 (1.07, 1.60)**

**1.35 (1.15, 1.59)**

**1.40 (1.16, 1.70)**

**McGettigan and Henry.  JAMA 2006; 296(13):1633-1644. **

## Events in 2006PRECISION Trial Initiated

_**P**_**rospective **_**R**_**andomized **_**E**_**valuation of **_**C**_**elecoxib **_**I**_**ntegrated **_**S**_**afety vs **_**I**_**buprofen **_**O**_**r **_**N**_**aproxen**
**~ 20,000 OA and RA patients with CV disease or at high-risk ****for developing CV disease**
**Primary endpoint: APTC composite endpoint (762)**
**Secondary endpoints: GI events, renal events, efficacy**
**Treatments**
**Celecoxib (100-200 mg BID)**
**Naproxen (375-500 mg BID)**
**Ibuprofen (600-800 mg TID)**
**Study will continue to allow all patients the opportunity for ****18 months of follow-up**
**Upper bound of 95% CI ****≤**** 1.33 and the point estimate of the hazard ratio is not >1.12 **

## Objectives and Agenda

**Overview of celecoxib**
**Clinical characteristics and current treatments for children with JRA**
**Regulatory history, rationale for study of celecoxib in children, and clinical data for celecoxib in JRA**
**Overall conclusions**

**Dr S Lowry**

**Dr D Lovell**

**Dr S Lowry**

## Slide 14

## Objectives and Agenda

**Overview of celecoxib**
**Clinical characteristics and current treatments for children with JRA**
**Regulatory history, rationale for study of celecoxib in children, and clinical data for celecoxib in JRA**
**Overall conclusions**

**Dr S Lowry**

**Dr D Lovell**

**Dr S Lowry**

## Context for Studying NSAIDs in JRA

**JRA is a relatively rare condition in a pediatric population**
**Studies for approval range from 59 patients to ****432 patients**
**8 weeks to 64 weeks in duration**
**Similar size / duration to DMARD / biologic trials ****for approval**
**Etanercept (69 patients)**
**Sulfasalazine (69 patients)**
**Methotrexate (127 patients)**

## Celecoxib Pediatric Written Request Key Elements

**FDA issued PWR in January 2002**
**Study Type/Objective:**
**Efficacy & safety of two doses celecoxib vs. standard ****active control**
**PK of celecoxib in children with JRA**
**Design:**
**Single study: 12-week double-blind, 3-arm study with ****12-week open-label, single-arm phase**
**PK – multi-dose assessment**
**Age Group/Population:**
**JRA patients aged 2-16; 10% < 5 years old**
**Polyarticular & pauciarticular allowed**
**Approximately 10% with systemic onset encouraged**

## Drug-Specific Safety Issues: 
General safety and laboratory testing
Development to be assessed and developmental adverse events targeted
Close monitoring of systemic JRA patients 
Drug Information:
Oral; appropriate formulation for pediatric population 
Labeling:
Information collected should provide for appropriate labeling

**General safety and laboratory testing**
**Development to be assessed and developmental ****adverse events targeted**
**Close monitoring of systemic JRA patients **
**Drug Information:**
**Oral; appropriate formulation for pediatric population **
**Labeling:**
**Information collected should provide for appropriate labeling**

**Celecoxib ****Pediatric Written Request**** ****Key Elements**

## Recent Regulatory History of NSAIDs in JRA

| Timeframe |  |
| --- | --- |
| 2002 | FDA issues final PWR
Celecoxib JRA Study initiated |

**Recent Regulatory History of NSAIDs in JRA**

## Recent Regulatory History of NSAIDs in JRA

| Timeframe |  |
| --- | --- |
| 2002 | FDA issues final PWR
Celecoxib JRA Study initiated |
| 2004 | Rofecoxib approved for use in JRA
APPROVe, APC, PreSAP, ADAPT preliminary data
Rofecoxib withdrawn |

**Recent Regulatory History of NSAIDs in JRA**

## Recent Regulatory History of NSAIDs in JRA

| Timeframe |  |
| --- | --- |
| 2002 | FDA issues final PWR
Celecoxib JRA Study initiated |
| 2004 | Rofecoxib approved for use in JRA
APPROVe, APC, PreSAP, ADAPT preliminary data
Rofecoxib withdrawn |
| 2005 | Celecoxib JRA Study completed
Class CV warnings for all NSAIDs
Meloxicam approved for use in JRA |

**Recent Regulatory History of NSAIDs in JRA**

## Recent Regulatory History of NSAIDs in JRA

| Timeframe |  |
| --- | --- |
| 2002 | FDA issues final PWR
Celecoxib JRA Study initiated |
| 2004 | Rofecoxib approved for use in JRA
APPROVe, APC, PreSAP, ADAPT preliminary data
Rofecoxib withdrawn |
| 2005 | Celecoxib JRA Study completed
Class CV warnings for all NSAIDs
Meloxicam approved for use in JRA |
| 2006 | Pfizer meets with FDA to agree on proposal for sNDA in JRA
sNDA filed
Advisory Committee convened |

**Recent Regulatory History of NSAIDs in JRA**

## Study 195Celecoxib vs Naproxen in JRA

## Study 195:  Study Objectives

**Primary**
**To evaluate the efficacy and safety of celecoxib suspension for the treatment of the signs and symptoms of JRA compared with naproxen suspension **
**Secondary**
**Obtain pharmacokinetic information to guide ****the dosing of celecoxib in pediatric patients**

## Study 195:  Inclusion Criteria

**Age 2 - 16 years of age and ****≥9 kg**
**Pauciarticular or polyarticular course **
**≥****1 swollen joint and ≥ 1 joint with limitation of motion**
**Systemic-onset eligible**
**Candidates for NSAID therapy **
**Score of ≥10 mm at Screening visit**
**Physician’s Global Assessment of Disease Activity**
**Parent’s Global Assessment of Overall Well-Being**

## Study 195:  Exclusion Criteria

| Presence of active systemic manifestations of JRA
Initiation of or changing the dose of medications:  |  |  |  |  |
| --- | --- | --- | --- | --- |
|  | Drug | Stabilization Period | Allowable Dose Range |  |
|  | Methotrexate | 8 weeks |  1 mg/kg/week or 40 mg maximum weekly dosage |  |
|  | Other DMARDs | 12 weeks | Sulfasalazine  3 grams/day |  |
|  | Biologics | 12 weeks |  |  |
|  | Gold Salts | 16 weeks |  |  |
|  | Corticosteroids | 4 weeks | Oral  0.2 mg/kg/day or  10 mg prednisone/day |  |

## Study 195:  Study Design

**Celecoxib  3 mg/kg BID (N= 77)**

**Celecoxib 6 mg/kg BID  (N= 82)**

**0**

**4**

**12**

**8**

**Visits (Week)**

**Screening**

**2**

**Naproxen 7.5 mg/kg BID (N= 83)**

**16**

**24**

**Celecoxib 6 mg/kg BID (N= 202)**

**Double-blind**

**Open-label**

**NSAIDs were to be discontinued >5 half-lives prior to baseline visit.**

## Study 195:  Primary Endpoint

**Percent of patients improved as defined by the ACR Pediatric ****30 Response Criterion at Week 12**
**≥****30% improvement in any 3 of 6 core set measures with no more than 1 of the remaining measures worsening by >30%**** **

| Core Set Measures |
| --- |
| Physician’s Global Assessment of Disease Activity |
| Parent’s Global Assessment of Overall Well Being   (CHAQ subsection) |
| Parent’s Assessment of Physical Function                (CHAQ Disability Index) |
| Number of joints with active arthritis |
| Number of joints with limited range of motion |
| Laboratory measure of inflammation (CRP) |

## Study 195:  Secondary Measures

**Change from baseline to each post-baseline assessment for:**
**Each ACR Pediatric 30 core set measure**
**Parent’s Assessment of Child’s Arthritis Pain (VAS) [CHAQ Subsection]**
**Celecoxib pharmacokinetics in pediatric patients**
**Safety**
**Adverse events**
**Clinical laboratory values**
**Vital signs**

## Study 195:  Statistical Methods

**Non-inferiority margin of 25% for ACR Pediatric 30 Response **
**Hypothesis testing was one-sided at the 2.5% level of significance**
**Non-inferiority claimed if lower limit of 2-sided 95% confidence interval for percent responders (celecoxib – naproxen) was above -25%**
**Sample size = 75 patients / treatment group**
**At least 80% power to conclude non-inferiority**
**Last observation carried forward, intent-to-treat population**

## Study 195:  Rationale for Non-inferiority Margin

**Prospectively specified in discussions with FDA**
**Surveyed practicing pediatric rheumatologists to assess clinically meaningful difference**
**Assumption that response rate for naproxen would be 60-80%**
**Meta-analysis of placebo-controlled studies in JRA**
**Range for placebo response = 9%-36%**

- Ruperto et al. Arthritis Rheum 2003;48 Suppl:S90

## Study 195:  Demographic Characteristics

|  | Celecoxib 3 mg/kg BID
N = 77 | Celecoxib 6 mg/kg BID
N = 82 | Naproxen 7.5 mg/kg BID
N = 83 |
| --- | --- | --- | --- |
| Age, n (%) |  |  |  |
|     2 – 4 years | 13 (16.9) | 16 (19.5) | 10 (12.0) |
|     5 – 7 years | 9 (11.7) | 9 (11.0) | 11 (13.3) |
|     8 – 12 years | 31 (40.3) | 35 (42.7) | 35 (42.2) |
|     13 – 16 years | 24 (31.2) | 22 (26.8) | 27 (32.5) |
| Gender, n (%) |  |  |  |
|     Female | 59 (76.6) | 53 (64.6) | 59 (71.1) |
| Race, n (%) |  |  |  |
|     White | 41 (53.2) | 47 (57.3) | 52 (62.7) |
|     Black     | 9 (11.7) | 7 (8.5) | 4 (4.8) |
|     Asian | 1 (1.3) | 3 (3.7) | 1 (1.2) |
|     Not listed | 26 (33.8) | 25 (30.5) | 26 (31.3) |

## Study 195:  Baseline Characteristics

|  | Celecoxib 3 mg/kg BID
N = 77 | Celecoxib 6 mg/kg BID
N = 82 | Naproxen 7.5 mg/kg BID
N = 83 |
| --- | --- | --- | --- |
| Duration of JRA (yr ± SD) | 2.7 ± 2.8 | 3.8 ± 3.4 | 3.4 ± 3.2 |
| JRA disease subtype, n (%) |  |  |  |
|     Pauciarticular course | 37 (48.1) | 45 (54.9) | 46 (55.4) |
|     Polyarticular course | 40 (51.9) | 37 (45.1) | 37 (44.6) |
| Systemic onset, n (%) | 4 (5.2) | 10 (12.2) | 8 (9.6) |

## Study 195:  Baseline Characteristics

|  | Celecoxib 3 mg/kg BID
N = 77 | Celecoxib 6 mg/kg BID
N = 82 | Naproxen 7.5 mg/kg BID
N = 83 |
| --- | --- | --- | --- |
| Duration of JRA (yr ± SD) | 2.7 ± 2.8 | 3.8 ± 3.4 | 3.4 ± 3.2 |
| JRA disease subtype, n (%) |  |  |  |
|     Pauciarticular course | 37 (48.1) | 45 (54.9) | 46 (55.4) |
|     Polyarticular course | 40 (51.9) | 37 (45.1) | 37 (44.6) |
| Systemic onset, n (%) | 4 (5.2) | 10 (12.2) | 8 (9.6) |
| DMARD/biologic use, n (%) | 39 (50.6) | 40 (48.8) | 43 (51.8) |
|     Any methotrexate use | 35 (45.5) | 33 (40.2) | 34 (40.9) |
|     Any biologic use | 2 (2.6) | 3 (3.7) | 3 (3.6) |
| Corticosteroid use, n (%) | 13 (16.9) | 16 (19.5) | 22 (26.5) |

- DMARDs/biologics used: azathioprine, hydroxychloroquine sulfate, methotrexate, sulfasalazine, etanercept
-                                           infliximab

## Study 195:  Baseline Disease Characteristics

|  | Celecoxib 3 mg/kg BID
N = 77 | Celecoxib 6 mg/kg BID
N = 82 | Naproxen 7.5 mg/kg BID
N = 83 |
| --- | --- | --- | --- |
| Physician’s Global Assessment of Disease Activity (0-100 mm) | 42.4 ± 2.3 | 41.1 ± 1.9 | 41.2 ± 1.8 |
| Parent’s Global Assessment of Overall Well Being (0-100 mm) | 38.4 ± 2.5 | 42.7 ± 2.2 | 45.0 ± 2.5 |
| Parent’s Assessment of Physical Function (0-3 scale) | 0.9 ± 0.1 | 0.9 ± 0.1 | 0.9 ± 0.1 |
| Parent’s Assessment of Child’s Arthritis Pain (0-100 mm) | 41.3 ± 2.8 | 41.5 ± 2.4 | 42.7 ± 2.3 |

**Mean ****± SE**

## Study 195 Patient DispositionDouble-Blind Phase 

**Patients Randomized**** **
**N = 242**

**Celecoxib 3 mg/kg BID**
**N = 77**

**Celecoxib 6 mg/kg BID**
**N = 82**

**Naproxen 7.5 mg/kg BID ****N = 83**

| Patients Withdrawn
n = 10 (13.0%)  |  |
| --- | --- |
| Adverse event | 3 (3.9%)  |
| Lack of efficacy | 2 (2.6%) |
| Consent withdrawn | 4 (5.2%) |
| Lost to follow-up | 1 (1.3%) |
| Protocol violation | 0 (0.0%) |

| Patients Withdrawn
n = 11 (13.4%)  |  |
| --- | --- |
| Adverse event | 7 (8.5%)  |
| Lack of efficacy | 1 (1.2%) |
| Consent withdrawn | 2 (2.4%) |
| Lost to follow-up | 0 (0.0%) |
| Protocol violation | 1 (1.2%) |

**Patients Completed**
**n = 67 (87.0%)**

**Patients Completed**
**n = 71 (86.6%)**** **

**Patients Completed**
**n = 74 (89.2%)**** **

| Patients Withdrawn
n = 9 (10.8%)  |  |
| --- | --- |
| Adverse event | 3 (3.6%)  |
| Lack of efficacy | 4 (4.8%) |
| Consent withdrawn | 1 (1.2%) |
| Lost to follow-up | 0 (0.0%) |
| Protocol violation | 1 (1.2%) |

## Study 195 Efficacy

## Study 195 ACR Pediatric 30 ResponsePercentage of Responders

**Responder: ********30% improvement in ********3 core set variables and no more than 1 variable worsening by >30%. **

**Celecoxib 3 mg/kg BID**

**Celecoxib 6 mg/kg BID**

**Naproxen 7.5 mg/kg BID**

**Week**

**Percentage of Patients (95% CI)**

## Study 195:  ACR Pediatric 30 ResponseDifference in Percent Responders at Week 12

**Celecoxib **
**3 mg/kg BID**

**Week 12 Responder Analysis:  Celecoxib - Naproxen (95% CI)**

**Celecoxib **
**6 mg/kg BID**

**1.36%, (-13. 1%, 15.8%)**

**13.0%, (-0.2%, 26.3%)**

**Non-inferiority margin = 25%;**** non-inferiority claimed if the LL of the 95% CI for the difference in percent improved (celecoxib – naproxen) was above -25%.**

**Favors naproxen**

**Favors celecoxib**

**Treatment Difference**

## Study 195: ACR Pediatric 30, 50, and 70 ResponsePercentage of Responders at Week 12

**Study 195: ACR Pediatric 30, 50, and 70 Response****Percentage of Responders at Week 12**

**Celecoxib 3 mg/kg BID**

**Celecoxib 6 mg/kg BID**

**Naproxen 7.5 mg/kg BID**

**Percentage of Patients (95% CI)**

## Study 195:  Percentage of Responders Core Set Measures at Week 12 (30% improvement)

- *

**p < 0.05 vs celecoxib 3 mg/kg BID**

**Celecoxib 3 mg/kg BID**

**Celecoxib 6 mg/kg BID**

**Naproxen 7.5 mg/kg BID**

## Study 195:  Global Assessments

**Study 195:  Global Assessments**

**Parent’s Global Assessment**
**of Overall Well Being**

**Physician’s Global Assessment**
**of Disease Activity**

***p < 0.05, celecoxib 3 mg/kg BID vs naproxen**
**Scales range from 0-100 mm**

- *

**Week**

## Study 195:  Joint CountsActive Arthritis and Limited Range of Motion

**Study 195:  Joint Counts****Active Arthritis and Limited Range of Motion**

**Number of Joints with Limited Range of Motion**

**Number of Joints with Active Arthritis**

***p < 0.05, celecoxib 3 mg/kg BID vs celecoxib 6 mg/kg BID**
**Total joints = 73**

**Total joints = 67**

**Week**

- *

- *

- *

## Study 195:  Functional Ability and CRP 

**Study 195:  Functional Ability and CRP **

**Scale ranges from 0-3  **

**CRP**

**Functional Ability**

**Week**

## Study 195:  Parent’s Assessment of Child’s Arthritis Pain (VAS)

**Study 195:  Parent’s Assessment of ****Child’s Arthritis Pain (VAS)**

**Scale ranges from 0-100 mm**

**Week**

## Study 195:  ACR Pediatric 30 Response JRA Course

**Study 195:  ACR Pediatric 30 Response ****JRA Course**

- *

**p < 0.05 vs. celecoxib 3 mg/kg BID and naproxen**

**N =       37        45         46                           40        37        37**

**Week 12**

**Percentage of Patients (95% CI)**

**Celecoxib 3 mg/kg BID**

**Celecoxib 6 mg/kg BID**

**Naproxen 7.5 mg/kg BID**

## Study 195:  ACR Pediatric 30 ResponseDMARD/Biologic Use

**Study 195:  ACR Pediatric 30 Response****DMARD/Biologic Use**

**N =      38          42         40                           39        40         43**

*** p < 0.05 vs. celecoxib 3 mg/kg BID**

- *

**Percentage of Patients (95% CI)**

**Celecoxib 3 mg/kg BID**

**Celecoxib 6 mg/kg BID**

**Naproxen 7.5 mg/kg BID**

**Week 12**

## Study 195:  Summary of EfficacyDouble-Blind Phase

**Both doses of celecoxib demonstrated non-inferiority to naproxen for the ACR Pediatric 30 Response at Week 12**
**Secondary efficacy endpoints supportive of the primary analysis**
**Subgroup analyses by disease type and baseline DMARD/biologic use consistent with results for overall population**

## Study 195 Safety

## Study 195:  Safety Results

**Adverse events**
**Body weight**
**Cardiorenal**
**Hematology and biochemistry**

## Safety Analyses – Double-Blind Phase

## Study 195:  Adverse Events By System Organ Class—Double-Blind Phase

|  | Celecoxib 3 mg/kg BID
N=77 | Celecoxib 6 mg/kg BID
N=82 | Naproxen 7.5 mg/kg BID
N=83 |
| --- | --- | --- | --- |
| Any event | 49 (63.6) | 57 (69.5) | 60 (72.3) |
| Eye disorders | 4 (5.2) | 4 (4.9) | 4 (4.8) |
| Gastrointestinal disorders | 20 (26.0) | 20 (24.4) | 30 (36.1) |
|    Abdominal pain | 3 (3.9) | 6 (7.3) | 6 (7.2) |
|    Abdominal pain upper | 6 (7.8) | 5 (6.1) | 8 (9.6) |
|    Vomiting | 2 (2.6) | 5 (6.1) | 9 (10.8) |
|    Diarrhea | 4 (5.2) | 3 (3.7) | 7 (8.4) |
|    Nausea | 5 (6.5) | 3 (3.7) | 9 (10.8) |
| General disorders | 10 (13.0) | 9 (11.0) | 15 (18.1) |
|    Pyrexia | 6 (7.8) | 7 (8.5) | 9 (10.8) |

**Incidence ≥ 5% in any treatment group**
**n (% of patients)**

**Study 195:  Adverse Events ****By System Organ Class—Double-Blind Phase**

## Study 195:  Adverse Events By System Organ Class—Double-Blind Phase

|  | Celecoxib 3 mg/kg BID
N=77 | Celecoxib 6 mg/kg BID
N=82 | Naproxen 7.5 mg/kg BID
N=83 |
| --- | --- | --- | --- |
| Infections | 19 (24.7) | 16 (19.5) | 22 (26.5) |
|    Nasopharyngitis | 4 (5.2) | 5 (6.1) | 4 (4.8) |
| Injury and poisoning | 3 (3.9) | 5 (6.1) | 4 (4.8) |
| Investigations | 2 (2.6) | 9 (11.0) | 6 (7.2) |
| Musculoskeletal disorders | 6 (7.8) | 8 (9.8) | 14 (16.9) |
|    Arthralgia | 2 (2.6) | 6 (7.3) | 3 (3.6) |
| Nervous system disorders | 13 (16.9) | 9 (11.0) | 17 (20.5) |
|    Headache | 10 (13.0) | 8 (9.8) | 13 (15.7) |
|    Dizziness | 1 (1.3) | 1 (1.2) | 6 (7.2) |
|  |  |  |  |

**Study 195:  Adverse Events ****By System Organ Class—Double-Blind Phase**

**Incidence ≥ 5% in any treatment group**
**n (% of patients)**

## Study 195:  Adverse Events By System Organ Class—Double-Blind Phase

|  | Celecoxib 3 mg/kg BID
N=77 | Celecoxib 6 mg/kg BID
N=82 | Naproxen 7.5 mg/kg BID
N=83 |
| --- | --- | --- | --- |
| Respiratory disorders | 6 (7.8) | 12 (14.6) | 12 (14.5) |
|    Cough | 5 (6.5) | 6 (7.3) | 7 (8.4) |
| Skin disorders | 8 (10.4) | 6 (7.3) | 15 (18.1) |

**Incidence ≥ 5% in any treatment group**
**n (% of patients)**

## Study 195:  Serious Adverse EventsDouble-Blind Phase

|  | Celecoxib 3 mg/kg BID
N=77 | Celecoxib 6 mg/kg BID
N=82 | Naproxen
7.5 mg/kg BID
N=83 |
| --- | --- | --- | --- |
| Any Event | 3 (3.9) | 2 (2.4) | 0 (0.0) |
|  | Abdominal Pain* | JRA aggravated* |  |
|  | Cytomegalovirus hepatitis* | Asthma* |  |
|  | Viral Infection |  |  |
|  |  |  |  |
|  |  |  |  |

*** Led to withdrawal from study**
**n (%of patients)**

## Study 195:  Withdrawals due to Adverse Events Double-Blind Phase

|  | Celecoxib 3 mg/kg BID
N=77 | Celecoxib 6 mg/kg BID
N=82 | Naproxen 7.5 mg/kg BID
N=83 |
| --- | --- | --- | --- |
| Any Event | 3 (3.9) | 7 (8.5) | 3 (3.6) |
|  | Dysphagia | Hypersensitivity | Upper abdominal pain  |
|  | Cytomegalovirus hepatitis | Hematuria present  | Abdominal pain, nausea, vomiting |
|  | Abdominal pain and esophageal pain | LFTs abnormal | JRA, aggravated |
|  |  | Transaminase  increased |  |
|  |  | Rash generalized |  |
|  |  | JRA, aggravated |  |
|  |  | Asthma |  |

**n (% of patients)**

## Study 195:  Safety Results 

**Adverse events**
**Body weight**
**Cardiorenal**
**Hematology and biochemistry**

## Study 195:  Body WeightDouble-Blind Phase

|  | Celecoxib 3 mg/kg BID
N=77 | Celecoxib 6 mg/kg BID
N=82 | Naproxen 7.5 mg/kg BID
N=83 |
| --- | --- | --- | --- |
| LS mean change from baseline to Week 12/Final Visit ± SE (kg) | 1.01 ± 0.17 | 1.01 ± 0.16 | 0.87 ± 0.16 |
| ≥5% decrease from baseline,     n (%) |  |  |  |
|      Week 12/Final visit | 0 / 69 (0) | 1 /  77 (1.3) | 1 / 79 (1.3) |
|      Any visit | 0 / 69 (0) | 1 / 77 (1.3) | 1 / 79 (1.3) |
|  |  |  |  |

## Study 195:  Safety Results 

**Adverse events**
**Body weight**
**Cardiorenal**
**Hematology and biochemistry**

## Study 195:  Systolic Blood PressureDouble-Blind Phase—Changes at Week 12/Final Visit

|  | Celecoxib 3 mg/kg BID
N=77 | Celecoxib 6 mg/kg BID
N=82 | Naproxen 7.5 mg/kg BID
N=83 |
| --- | --- | --- | --- |
| Baseline mean (mmHg) | 99.3 | 101.3 | 101.9 |
| LS mean change from baseline ± SE | 0.91 ± 1.09 | 0.76 ± 1.06 | 1.60 ± 1.05 |
| ≥15% increase from baseline | 7 / 73 (9.6) | 5 / 80 (6.3) | 11 / 83 (13.3) |
| ≥15% decrease from baseline | 5 / 73 (6.8) | 2 / 80 (2.5) | 1 / 83 (1.2) |
|  |  |  |  |
|  |  |  |  |
|  |  |  |  |
|  |  |  |  |
|  |  |  |  |

## Study 195:  Creatinine Double-Blind Phase

|  | Celecoxib 3 mg/kg BID
N=73 | Celecoxib 6 mg/kg BID
N=80 | Naproxen 7.5 mg/kg BID
N=81 |
| --- | --- | --- | --- |
| Baseline mean (μmol/L) | 39.9 | 39.3 | 40.5 |
| Mean change from baseline to Week 12/Final Visit ± SE | -0.03 ± 0.97 | 0.74 ± 0.86 | -0.60 ± 0.80 |
| Shift from normal value at baseline  above normal, n (%) |  |  |  |
|      Week 12/Final visit | 0 / 73 (0) | 0 / 80 (0) | 0 / 81 (0) |
|      Any visit | 0 / 73 (0) | 0 / 80 (0) | 0 / 81 (0) |
|  |  |  |  |

**2 – 12 years:  normal = ****≤92 μmol/L**
**≥****13 years:  normal = ≤110 μmol/L**

## Study 195:  Safety Results 

**Adverse events**
**Body weight**
**Cardiorenal**
**Hematology and biochemistry**

## Study 195:  HemoglobinDouble-Blind Phase

|  | Celecoxib 3 mg/kg BID
N=71 | Celecoxib 6 mg/kg BID
N=75 | Naproxen 7.5 mg/kg BID
N=77 |
| --- | --- | --- | --- |
| Baseline mean (g/L) | 123.2 | 123.5 | 123.6 |
| Mean change from baseline to Week 12/Final Visit ± SE | -2.1 ± 0.96 | -1.2 ± 0.95 | -4.4 ± 1.01* |
| >10 g/L decrease from baseline and below lower limit of normal, n (%) |  |  |  |
|      Any visit | 1 / 71 (1.4) | 2 / 75 (2.7) | 2 / 77 (2.6) |

*** p < 0.05 vs. celecoxib 6 mg/kg BID**
**2 years:  normal = 110-140 g/L**
**3-5 ****years: normal = 118-147 g/L (F), 110-145 g/L (M)**
**6-11 years: normal = 112-155 g/L**
**≥****12 years:  normal = 116-164 g/L (F), 127-181 g/L (M)**

## Study 195:  ALTDouble-Blind Phase

|  | Celecoxib 3 mg/kg BID
N=73 | Celecoxib 6 mg/kg BID
N=80 | Naproxen 7.5 mg/kg BID
N=80 |
| --- | --- | --- | --- |
| Baseline mean (U/L) | 16.5 | 16.2 | 17.2 |
| Mean change from baseline to Week 12/Final Visit ± SE | 3.3 ± 2.84 | 2.0 ± 2.19 | -0.9 ± 1.00 |
| Shift from normal value at baseline  above normal, n (%) |  |  |  |
|      Week 12/Final visit | 1 / 73 (1.4) | 1 / 80 (1.3) | 0 / 80 (0.0) |
|      Any visit | 1 / 73 (1.4) | 3 / 80 (3.8) | 0 / 80 (0.0) |
|  |  |  |  |

**All patients:  normal = ****≤75 U/L**

## Study 195:  Safety SummaryDouble-Blind Phase

**GI disorders, infections and nervous system disorders most commonly reported**
**Similar safety profile for both celecoxib doses relative to naproxen**
**No apparent effect on growth and no developmental     adverse events reported**
**Mean effects and changes in SBP similar between      celecoxib and naproxen**
**Few serious adverse events and withdrawals from ****the study **

## Study 195 Open-Label Phase

## Study 195:  Patient Disposition12-Week Open-Label Phase 

**Celecoxib 6 mg/kg BID**
**Completed Double Blind**
**N = 71**

**Entered Open Label**
**N = 62**** (92.5%)**

**Entered Open Label**
**N = 70 (98.6%)**** **

**Entered Open Label**
**N = 70**** (94.6%)**

| Patients Withdrawn
n = 7 (3.5%)  |  |
| --- | --- |
| Adverse event | 3 (1.5%) |
| Consent withdrawn | 2 (1.0%) |
| Protocol specific withdrawal criteria | 1 (0.5%) |
| Protocol violation | 1 (0.5%) |

**Celecoxib 6 mg/kg BID**
**N= 202**

**Patients Completed**
**n = 195 (96.5%)**

**Naproxen 7.5 mg/kg BID**
**Completed Double Blind**
**N = 74**

**Celecoxib 3 mg/kg BID**
**Completed Double Blind**
**N = 67**

## Study 195:  Physician’s Global Assessment of Disease Activity—Double Blind and Open Label

**Study 195:  Physician’s Global Assessment of Disease**** Activity—Double Blind and Open Label**

- *

**Week**

**Open-Label Phase**

***p < 0.05, celecoxib 3 mg/kg BID vs naproxen**
**Scale ranges from 0-100 mm.**

## Study 195:  Parent’s Assessment of Child’s Arthritis Pain—Double Blind and Open Label

**Study 195:  Parent’s Assessment of Child’s Arthritis**** Pain—Double Blind and Open Label**

**Scale ranges from 0-100 mm**

**Week**

**Open-Label Phase**

## Study 195:  Adverse Events by System Organ Class Double-Blind and Open-Label Phases

|  | Double-Blind Phase |  |  | Open-Label Phase
All Patients |
| --- | --- | --- | --- | --- |
|  | Celecoxib 3 mg/kg BID
N=77 | Celecoxib 6 mg/kg BID 
N=82 | Naproxen 7.5 mg/kg BID
N=83 | Celecoxib                     6 mg/kg BID
N = 202 |
| Any event | 49 (63.6) | 57 (69.5) | 60 (72.3) | 96 (47.5) |
| Eye disorders | 4 (5.2) | 4 (4.9) | 4 (4.8) | 3 (1.5) |
| GI disorders | 20 (26.0) | 20 (24.4) | 30 (36.1) | 35 (17.3) |
|    Abdominal pain | 3 (3.9) | 6 (7.3) | 6 (7.2) | 2 (1.0) |
|    Abdominal pain upper | 6 (7.8) | 5 (6.1) | 8 (9.6) | 9 (4.5) |
|    Vomiting | 2 (2.6) | 5 (6.1) | 9 (10.8) | 6 (3.0) |
|    Diarrhea | 4 (5.2) | 3 (3.7) | 7 (8.4) | 11 (5.4) |
|    Nausea | 5 (6.5) | 3 (3.7) | 9 (10.8) | 4 (2.0) |
| General disorders | 10 (13.0) | 9 (11.0) | 15 (18.1) | 14 (6.9) |
|    Pyrexia | 6 (7.8) | 7 (8.5) | 9 (10.8) | 9 (4.5) |

**n (% of patients)**

## Study 195:  Adverse Events by System Organ Class Double-Blind and Open-Label Phases

|  | Double-Blind Phase |  |  | Open-Label Phase
All Patients |
| --- | --- | --- | --- | --- |
|  | Celecoxib 3 mg/kg BID
N=77 | Celecoxib 6 mg/kg BID 
N=82 | Naproxen 7.5 mg/kg BID
N=83 | Celecoxib                     6 mg/kg BID
N = 202 |
| Any event | 49 (63.6) | 57 (69.5) | 60 (72.3) | 96 (47.5) |
| Infections  | 19 (24.7) | 16 (19.5) | 22 (26.5) | 38 (18.8) |
|    Nasopharyngitis | 4 (5.2) | 5 (6.1) | 4 (4.8) | 8 (4.0) |
| Injury and poisoning | 3 (3.9) | 5 (6.1) | 4 (4.8) | 3 (1.5) |
| Investigations | 2 (2.6) | 9 (11.0) | 6 (7.2) | 6 (3.0) |
| Musculoskeletal disorders | 6 (7.8) | 8 (9.8) | 14 (16.9) | 18 (8.9) |
|    Arthralgia | 2 (2.6) | 6 (7.3) | 3 (3.6) | 7 (3.5) |
| Nervous system disorders | 13 (16.9) | 9 (11.0) | 17 (20.5) | 17 (8.4) |
|    Headache | 10 (13.0) | 8 (9.8) | 13 (15.7) | 13 (6.4) |
|    Dizziness | 1 (1.3) | 1 (1.2) | 6 (7.2) | 0 (0.0) |

**n (% of patients)**

**Study 195:  Adverse Events by System Organ Class ****Double-Blind and Open-Label Phases**

## Study 195:  Adverse Events by System Organ Class Double-Blind and Open-Label Phases

|  | Double-Blind Phase |  |  | Open-Label Phase
All Patients |
| --- | --- | --- | --- | --- |
|  | Celecoxib 3 mg/kg BID
N=77 | Celecoxib 6 mg/kg BID 
N=82 | Naproxen 7.5 mg/kg BID
N=83 | Celecoxib                     6 mg/kg BID
N = 202 |
| Any event | 49 (63.6) | 57 (69.5) | 60 (72.3) | 96 (47.5) |
| Respiratory disorders | 6 (7.8) | 12 (14.6) | 12 (14.5) | 8 (4.0) |
|    Cough | 5 (6.5) | 6 (7.3) | 7 (8.4) | 4 (2.0) |
| Skin  disorders | 8 (10.4) | 6 (7.3) | 15 (18.1) | 10 (5.0) |

**n (% of patients)**

## Study 195:  Withdrawals due to Adverse Events Open-Label Phase

|  | Celecoxib 6 mg/kg BID
N  = 202 |
| --- | --- |
| Any Event | 3 (1.5) |
|  | Allergic dermatitis |
|  | Gastritis |
|  | Gastroenteritis |

**n (%) of patients**

## Study 195:  Serious Adverse Events Open-Label Phase

|  | Celecoxib 6 mg/kg BID
N  = 202 |
| --- | --- |
| Any Event | 4 (2.0) |
|  | Myopericarditis |
|  | Non-accidental overdose, upper abdominal pain,  vomiting |
|  | Lower respiratory tract infection |
|  | Sore throat, lymphadenopathy, pyrexia, torticollis |

**n (%) of patients**

## Study 195:  Summary of Open-Label Phase

**Efficacy response to celecoxib was sustained for     24 weeks of treatment**
**The general safety profile during the open-label phase was similar to the double-blind phase**
**No new safety findings emerged**

## Pharmacokinetics

**Steady state PK evaluated in 152 JRA patients**
**Compared to adults, JRA patients require higher mg/kg doses to achieve similar plasma levels**

## Parallel Pediatric Formulation Development Suspension  Sprinkle Capsule

**Multi-year development effort for traditional ****pediatric dosage forms**
**Suspension used in Study 195 **
**Orally disintegrating tablet**
**Chewable tablet **

**Non-viable due to production, scaling, stability or bioavailability problems**

## Parallel Pediatric Formulation Development Suspension  Sprinkle Capsule

**Multi-year development effort for traditional ****pediatric dosage forms**
**Suspension used in Study 195 **
**Orally disintegrating tablet**
**Chewable tablet **
**Bridging strategy based on PK data to support ****use of sprinkle capsule (in applesauce) ****developed by sponsor**
**Proposal accepted by FDA (pre sNDA meeting, Jan 2006)**

**Non-viable due to production, scaling, stability or bioavailability problems**

## Parallel Pediatric Formulation Development Suspension  Sprinkle Capsule

**Multi-year development effort for traditional ****pediatric dosage forms**
**Suspension used in Study 195 **
**Orally disintegrating tablet**
**Chewable tablet **
**Bridging strategy based on PK data to support ****use of sprinkle capsule (in applesauce) ****developed by sponsor**
**Proposal accepted by FDA (pre sNDA meeting, Jan 2006)**
**Capsule dosing in JRA**
**JRA patients 10-25 kg: 50 mg BID**
**JRA patients    >25 kg: 100 mg BID**
**Administration: As sprinkles or swallowed intact**

**Non-viable due to production, scaling, stability or bioavailability problems**

## Study 195:  Conclusions

**Both doses of celecoxib were as effective as naproxen  in treating the signs and symptoms of JRA**
**Adverse event profiles were similar between celecoxib and naproxen**
**The efficacy response to celecoxib was durable **
**Similar efficacy results after 24 weeks of ****treatment as after 12 weeks**

## Other Relevant Safety Data

**Review of available safety data from various sources:**
**Development / Growth**
**General safety**
**CV safety**

## Summary of Data Review

| Source | Study | Focus | Conclusions |
| --- | --- | --- | --- |
| Nonclinical | Juvenile toxicology
rat / dog | Development
Growth | No effect on development or growth |

## Summary of Data Review

| Source | Study | Focus | Conclusions |
| --- | --- | --- | --- |
| Nonclinical | Juvenile toxicology
rat / dog | Development
Growth | No effect on development or growth |
| COX-2 inhibitor use in JRA | Rofecoxib study | General safety | Similar to naproxen |
| Adult arthritis | RCTs | General safety
GI safety | Similar to ns-NSAIDs
Favorable GI profile |
| Pediatric adverse reports | Spontaneous reports | General safety | Similar to adult reports |

**Summary of Data Review**

## Summary of Data Review

| Source | Study | Focus | Conclusions |
| --- | --- | --- | --- |
| Nonclinical | Juvenile toxicology
rat / dog | Development
Growth | No effect on development or growth |
| COX-2 inhibitor use in JRA | Rofecoxib study | General safety | Similar to naproxen |
| Adult arthritis | RCTs | General safety
GI safety | Similar to ns-NSAIDs
Favorable GI profile |
| Pediatric adverse reports | Spontaneous reports | General safety | Similar to adult reports |
| Long-term placebo studies
Non-arthritis | APC
PreSAP
ADAPT | CV safety | CV risk vs placebo in APC |
| CV Meta-analysis | RCTs | CV safety | No increase in CV risk vs ns-NSAIDs |
| Epidemiology studies | Case control
cohort | CV safety | CV risk profile similar to ns-NSAIDs |

**Summary of Data Review**

## Hypertension unusual, but increasingly diagnosed in general pediatric population

**NSAIDs (selective + nonselective) associated with destabilization of controlled hypertension in adults**
**Hypertension second only to asthma and obesity as chronic conditions affecting children in the US **
**Review of 8 studies from 47,196 school aged children **
**Systolic hypertension diagnosed in 4.4%**
**40-50% of JRA patients extend disease into young ****adult life**
**Association of hypertension and adverse long term CV outcomes well established in adults **

- National High Blood Pressure Working Group on High Blood Pressure in Children and Adolescents. Pediatrics 2004:114:555-5765; Cassidy and Petty. Textbook of Pediatric Rheumatology, 2005

## 24-Hour Mean Systolic Blood Pressure Change OA Type II Diabetes Mellitus and Hypertensive Patients

**Rofecoxib**
**25 mg QD**
**N=138**

**6 Wks**

**12 Wks**

**Naproxen**
**500 mg BID**
**N=130**

**6 Wks**

**12 Wks**

**Celecoxib**
**200 mg QD**
**N=136**

**6 Wks**

**12 Wks**

- Sowers et al. Arch Int Med; 2005;165:161-168

**Mean SBP Change (mm Hg)**

## Safety Conclusions

**Celecoxib has a similar safety / tolerability profile ****vs nonselective NSAIDs**
**Use in children has not identified unique safety concerns**
**Adult data demonstrated significant increase in serious ****CV events (MI, CVA, CV death) in one of 3 placebo-controlled studies**
**No evidence for increased CV risk vs nonselective NSAIDs**
**Class-labeled CV warnings for all NSAIDs**
**All NSAIDs associated with hypertension and destabilized blood pressure control**
**No evidence that profile in children may be different**

## Unknown Risks

**Size and duration of Study 195 unable to exclude risk for rare events or latent toxicity beyond ****6 months of treatment in JRA**
**Long term sequelae of effects on blood pressure by celecoxib in JRA and serious CV morbidity and mortality in adult life unknown**
**This effect is equally unknown for NSAIDs**

## Pharmacovigilance and Postmarketing Activities 

| Tool | Methodology | Population | Event of Interest |
| --- | --- | --- | --- |
| Enhanced Data Capture | Spontaneous reports | Adult and pediatric cases
Attention to indication / co-medications | CV / Cardiorenal events and 
SCAR |
| Expert Dermatology Panel | Spontaneous reports | Adult and pediatrics
cases | SCAR |
| PRECISION | Ongoing RCT | Adult OA/RA | CV / Cardiorenal events vs. NSAIDs |
| FAP Trial | Ongoing RCT | Pediatric FAP population | Latent/Delayed events |
| Expert Pediatric Panel | Spontaneous reports | All pediatric cases | Unexpected or rare events |

- * RCT = randomized clinical trial; FAP = familial  adenomatous polyposis; SCAR = severe cutaneous adverse reactions

## Overall Conclusions

**Study 195 demonstrated efficacy noninferior to naproxen and met the requirements of the PWR**
**To inform physicians on appropriate use, labeling could range from minimal information through to approval of the indication**
**JRA affects many thousands of children **
**Characterized by pain, inflammation and impact ****on function**
**Medical need for NSAIDs in this population**
**No evidence of a unique safety concern with ****celecoxib compared to other NSAIDs**
**There may be unknown risks of treatment shared ****by all NSAIDs**

## Slide 91