PhRMA Web SynopsisProtocol A3191200 – 5 July 2011 – Final

PFIZER CONFIDENTIALPage 1

PFIZER INC.

These results are supplied for informational purposes only.Prescribing decisions should be made based on the approved package insert.

For publications based on this study, see associated bibliography.

PROPRIETARY DRUG NAME®/GENERIC DRUG NAME: Celebrex® / Celecoxib

THERAPEUTIC AREA AND FDA APPROVED INDICATIONS: See USPI.

NATIONAL CLINICAL TRIAL NO.: NCT01062113

PROTOCOL NO.: A3191200

PROTOCOL TITLE: A Randomized, Double-Blind, Multicenter, Comparative Study To Evaluate Efficacy And Safety Of An Additional Dose Of Celecoxib (YM177) In The Treatment Of Acute Pain After Oral Surgery Lateral Mandibular Impacted Third Molar Tooth Extraction

Study Center(s): Twenty-two (22) centers in Japan

Study Initiation and Completion Dates: 1 April 2010 to 19 August 2010

Phase of Development: Phase 2

Study Objective(s): The primary objective was to evaluate the efficacy and safety of the additional dose of celecoxib 200 mg, as compared to placebo, which was administered to apatient who experienced pain even after the initial administration of celecoxib 400 mg for “moderate pain” or “severe pain” post lateral mandibular impacted third molar tooth extraction.

METHODS

Study Design: The study was conducted in a multicenter, randomized, placebo-controlled, double-blind intergroup comparison design. The study design is shown in Figure S1. The initial 400 mg dose of celecoxib was administered to subjects, who experienced moderate or severe pain and whose pain intensity score on a visual analog scale (VAS) was 45.0 mm or more after mandibular impacted third molar tooth extraction. Another 200 mg dose of celecoxib was administered for the patients who subsequently required an additional analgesic therapy from 5 to 12 hours after the initial dose of celecoxib. The efficacy and safety for this additional administration of 200 mg celecoxib were evaluated.

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PhRMA Web SynopsisProtocol A3191200 – 5 July 2011 – Final

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Figure S1. Study Design

Number of Subjects (Planned and Analyzed): A total of 112 subjects (56 subjects for each group) were planned. 64 subjects in celecoxib group and 58 subjects in placebo group wereanalyzed.

Diagnosis and Main Criteria for Inclusion: The initial dose of celecoxib was administered to 20 to 64 year old subjects who experienced moderate or severe pain and whose pain intensity was rated as 45.0 mm or more on a VAS after mandibular impacted third molartooth extraction. Another dose of the study drug was administered to subjects who required additional treatment but did not take any rescue medication.

Study Treatment: After eligibility was confirmed based on the inclusion and exclusion criteria before an initial dose administration, each patient took the initial 400 mg dose of celecoxib (two tablets of celecoxib 200 mg) by water. Subsequently after 5 up to 12 hours post-initial dose, the patients, who met the inclusion criteria for the additional dose, took an additional study drug (a tablet of celecoxib 200 mg or placebo) by water.

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PhRMA Web SynopsisProtocol A3191200 – 5 July 2011 – Final

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Efficacy Evaluations:

Primary endpoint: Patient’s impression from the time of the additional dose through 2 hours post additional dose.

Secondary endpoints: Pain Intensity (PI), Pain Intensity Difference (PID)

Safety Evaluations: Adverse events, laboratory test, blood pressure, and pulse rate

Statistical Methods: Primary and secondary endpoints were both analyzed using the Full Analysis Set (FAS). Per Protocol Set (PPS), which was defined as a secondly group of patients without any major protocol deviations (e.g., violation of the inclusion or exclusion criteria), was used for the primary endpoint analysis.

For the primary endpoint, the efficacy rate based on the patient’s impressions was calculatedfor the celecoxib group and the placebo group, respectively. The difference in the efficacy rates was tested using normal distribution at a significance level of 2-sided 5%. In addition, 2-sided 95% confidence interval (CI) for the difference in the efficacy rates was calculated using normal approximation. For the difference in the efficacy rates and CI configuration, the Mantel-Haenszel method with the baseline PI as an adjustment factor was used. When almost all patients result in a certain category of the baseline PI (4-category), the test statistic and CI configuration for the efficacy rate was calculated not using adjustment factor and Mantel-Haenszel method.

The secondary endpoints were pain intensity (PI) and pain intensity difference (PID) in the celecoxib group and the placebo group at 2 hours post-additional dose. The PIs (4-category) were summarized using descriptive statistics for the frequency and proportion at each time point. PIs (VAS) at 2 hours postadditional dose or discontinuation within 2-hours post-additional dose were tested by t-test. The PIDs (VAS) were summarized using descriptive statistic at each time point and t-test was also performed at 2-hours post-additional dose or discontinuation within 2 hours post-additional dose to baseline PID (pre-additional dose).

Other measurements were planned using the safety analysis set and the initial dose evaluationset (IDES) in which the patients received the initial 400 mg celecoxib alone, not requiring additional study medication or rescue medications. PIs (4-category) for IDES were summarized using descriptive statistics. Also, with the safety analysis set, the proportion of patients who received rescue analgesic drugs and the time to rescue medication were summarized in cumulative distribution

The safety analysis set was defined as a population consisting of subjects who had received at least one dose of the study drug. The safety was analyzed and displayed on 3 groups; all subjects, those without additional dose, and those with additional dose. In principle, the safety analysis was performed in accordance with the Pfizer Data Standards (PDS) specifying the sponsor’s standard methods of data collection and reporting of safety data.

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PhRMA Web SynopsisProtocol A3191200 – 5 July 2011 – Final

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RESULTS

Subject Disposition and Demography: The disposition of subjects is summarized inTable S1. A total of 295 subjects were screened in this study. A total of 255 subjects took the initial dose of celecoxib 400 mg. After the initial dose, 64 and 58 subjects received celecoxib and placebo, respectively, as an additional dose. 42 subjects (65.6%) in the celecoxib and 27 subjects (46.6%) in the placebo group completed the study. 22 subjects (34.4%) in the celecoxib group and 31 subjects (53.4%) in the placebo group discontinued the study. The reason for discontinuation was insufficient efficacy in all the subjects discontinued.

133 subjects received the initial 400 mg dose of celecoxib alone. Of them, 93 subjects (69.9%) completed the study without receiving either rescue analgesic medication or additional study drug. 40 subjects (30.1%) discontinued the study. The reasons for discontinuation were insufficient efficacy in 38 subjects (28.6%), an adverse event not related to the study drug in 1 (0.8%), and other (for patient’s wife giving birth) in 1 (0.8%).

The mean age of subjects was 27.5 years (range, 22 to 47 years) in the celecoxib group and 28.6 years (range, 21 to 57 years) in the placebo group. The male-female ratio did not differ between the groups, approximately 40% males and 60% females in both groups. The mean height and weight were also comparable between the groups. The baseline mean PI (VAS)score was 69.2 mm in the celecoxib group and 64.2 mm in the placebo group. Othercharacteristics were distributed similarly in the treatment groups.

The mean age of the subjects receiving the initial dose alone was 27.7 years (range, 20 to 62 years). Except the male-female ratio, no major difference was seen in demographic characteristics for the subjects receiving an additional dose of celecoxib or placebo.

Table S1. Subject Disposition

Screening~ randomization

Screened 295Took the initial dose 255Not randomized 12Randomized 243

Celecoxib 400 mg Additional doseRandomization ~ completion

Initial dose Celecoxib 200 mg Placebo

Randomized － 121 122

Did not take the additional dose 133 *1 57 64Took the additional dose － 64 58

Completed 93 (69.9) *2 42 (65.6) 27 (46.6)Discontinued 40 (30.1) 22 (34.4) 31 (53.4)Relation to Study Drug not Defined: 39 (29.3) 22 (34.4) 31 (53.4)

Insufficient efficacy 38 (28.6) 22 (34.4) 31 (53.4)Other 1 (0.8) *3 0 0

Not Related to study drug: 1 (0.8) 0 0AE 1 (0.8) 0 0

*1: Subjects who did not randomized (12 subjects) and who did not take the additional dose (celecoxib group 57 subjects, placebo group 64 subjects)

*2: Subjects who did not take the rescue medicine and additional study drug*3: Patient’s wife giving birth

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Efficacy Results: The results of efficacy rate based on patient’s impression are shown inTable S2. Efficacy rate for the primary endpoint was 64.1% (41/64) in the celecoxib group and 25.9% (15/58) in the placebo group in FAS, which was higher in celecoxib than placebo. The difference in the efficacy rate was 38.2% between the groups (95% CI, 20.3% to 56.1%) and statistically significant (p<0.0001). The efficacy rate was also statistically significant in PPS with the higher rate in the celecoxib group as observed in FAS (p<0.0001). The test statistic and CI configuration for the efficacy rate was calculated not using adjustment factor and Mantel-Haenszel method because most subjects evaluated the pain as moderate in PI (4-category).

Table S2. Efficacy rate (2hours after additional dose, FAS)

Celecoxib 200 mgN=64

PlaceboN=58

Excellent 11 (17.2%) 1 (1.7%)Good 30 (46.9%) 14 (24.1%)Fair 10 (15.6%) 22 (37.9%)Poor 12 (18.8%) 21 (36.2%)Missing 1 (1.6%) 0

Efficacy rate *1 41 (64.1%) 15 (25.9%)

Differences (95%CI) 38.2% (20.3, 56.1)

p-value p<0.0001

*1: The proportion of subjects who rated the syudy drug as “good” or “excellent”

PI (4-category and VAS) and PID (VAS) as the secondary endpoints were analyzed based on FAS. The proportion of subjects whose PI was “no pain” or “a little” at 2 hours after additional dose (BOCF) was higher in the celecoxib group than the placebo group. The mean PI (VAS) at BOCF was 35.8 mm in the celecoxib group and 51.9 mm in the placebo group, and the difference was statistically significant (p=0.0003). The mean PID (VAS) at BOCF was 33.4 mm in the celecoxib group and 12.3 mm in the placebo group. The PID in celecoxibgroup is greater than that in placebo group with statistical significance (p<0.0001).

Table S3. PID (VAS, FAS)

Celecoxib 200 mg Placebo

N mean SD N mean SD

1hr post tooth extraction 64 3.8 13.1 58 1.0 14.6Before additional dose (baseline) *1 64 - - 58 - -2hrs after additional dose 63 33.9 24.1 57 12.5 19.78:00 AM (Day 2) 55 41.7 23.2 32 27.9 26.6

2hrs after additional dose (BOCF) 64 33.4 24.2 58 12.3 19.5p-value p<0.0001unit: mmPID=PI at baseline – PI at each point*1: The mean (SD) PI (VAS) at baseline: 69.2 mm (13.5) in celecoxib 200 mg group, 64.2 mm (12.8) in placebo group

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In IDES, PI (4-category) at post-initial dose from 2 ~12 hours was “no pain” (39.1% to 48.9%) or “mild pain” (48.4% to 57.6%). These results suggested that the initial 400 mg dose of celecoxib had provided sustainable effects to relieve the pain for this population. The proportion of subjects who received rescue analgesic medication up to 10 o’clock on day 2 was also compared with the safety analysis set. The proportion was smaller in the celecoxib group than the placebo (28.1% and 51.7%, respectively).

Safety Results: The adverse events reported in the study are summarized in Table S4. The incidence of treatment-emergent adverse events was 20.3% (13/64 subjects) and 31.0% (18/58 subjects) in the celecoxib and placebo groups, respectively. The incidence of treatment-related adverse events was 17.2% (11/64 subjects) and 27.6% (16/58 subjects) in the celecoxib and placebo groups, respectively. In the subjects with the initial dose of celecoxib alone, the incidence of treatment-emergent adverse events and treatment-related adverse events was 18.8% (25/133 subjects) and 15.8% (21/133 subjects), respectively.

Table S4. Summary of Adverse Events

All causality Treatment related

Additional dose Additional doseInitial doseCelecoxib

400 mgCelecoxib 200 mg

Placebo

Initial dose

Celecoxib 400 mg

Celecoxib 200 mg

Placebo

Subjects evaluable for safety 133 64 58 133 64 58Subjects with adverse events (%) 25 (18.8) 13 (20.3) 18 (31.0) 21 (15.8) 11 (17.2) 16 (27.6)Number of adverse events 27 15 24 23 13 21Subjects with serious adverse events (%) 0 0 0 0 0 0Subjects with severe adverse events (%) 0 1 (1.6) 0 0 0 0Subjects who discontinued the study due to adverse events (%)

1 (0.8) 0 0 0 0 0

Subjects with dose reduced or temporary discontinuation due to adverse events(%)

0 0 0 0 0 0

The incidence of all treatment-emergent adverse events is shown in Table S5. Most frequent treatment-emergent adverse events were β2 microglobulin increased and blood bilirubin increased in the celecoxib group, and β2 microglobulin increased and N-acetyl-glucosamine (NAG) increased in the placebo group. In the subjects who received the initial dose alone, most frequent treatment-emergent adverse events were β2 microglobulin increased, NAG increased, and blood bilirubin increased. Any of these most frequent adverse events were mild and no event was reported in renal impairment, renal tubular disorders, and hepatic function disorder.

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PhRMA Web SynopsisProtocol A3191200 – 5 July 2011 – Final

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Table S5. Treatment-Emergent Adverse Events (All-Causality)

Additional doseSystem Organ Class andMedDRA (version 13.0) Preferred Term

Initial doseCelecoxib 400 mg

N=133Celecoxib 200 mg

N=64PlaceboN=58

Subjects with adverse events (%) 25 (18.8) 13 (20.3) 18 (31.0)

Injury, poisoning and procedural complications 1 (0.8) 0 0Post procedural haemorrhage 1 (0.8) 0 0

Investigations 18 (13.5) 11 (17.2) 17 (29.3)Beta 2 microglobulin increased 7 (5.3) 5 (7.8) 9 (15.5)Beta-N-acetyl-D-glucosaminidase increased 4 (3.0) 1 (1.6) 5 (8.6)Blood bilirubin increased 4 (3.0) 3 (4.7) 1 (1.7)Blood creatine phosphokinase increased 1 (0.8) 1 (1.6) 1 (1.7)Blood phosphorus decreased 1 (0.8) 0 0Blood phosphorus increased 0 0 2 (3.4)Blood urea increased 0 0 1 (1.7)Blood urine present 1 (0.8) 0 0Protein urine present 0 1 (1.6) 1 (1.7)Urobilin urine present 1 (0.8) 1 (1.6) 1 (1.7)White blood cell count increased 1 (0.8) 1 (1.6) 2 (3.4)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

0 1 (1.6) 0

Adenocarcinoma of the cervix 0 1 (1.6) 0

Nervous system disorders 2 (1.5) 1 (1.6) 1 (1.7)Presyncope 1 (0.8) 0 0Somnolence 1 (0.8) 1 (1.6) 1 (1.7)

Skin and subcutaneous tissue disorders 4 (3.0) 0 0Eczema 2 (1.5) 0 0Hypoaesthesia facial 1 (0.8) 0 0Rash 1 (0.8) 0 0

No serious adverse events were reported in this study. A severe adverse event (adenocarcinoma of the cervix) occurred in 1 subject of the celecoxib 200 mg group. This event was diagnosed at the same day with the last visit in another clinical institute (a different site from the investigational site) based on the results from cytology and biopsy tested before the administration of the initial dose of celecoxib. The investigator did not consider that the event was related to the study drug. One subject discontinued the study with the initial dose alone because of an adverse event (post procedural haemorrhage). No clinically relevant findings were observed from laboratory test data, vital sign measurements, or electrocardiograms.

CONCLUSION(S): This was the placebo-controlled, comparative study to evaluate the efficacy and safety of additional 200 mg dose of celecoxib administered from 5 to 12 hours after the initial 400 mg dose on the same day for post-tooth extraction pain.

A total of 255 subjects were took the initial dose of celecoxib 400 mg. Following the randomization, 64 subjects in celecoxib, and 58 in placebo received an additional dose. 133 subjects received an initial 400 mg dose of celecoxib alone.

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For the primary endpoint, efficacy rate calculated based on patient’s impression with FASwas significantly higher in the celecoxib group than in the placebo group (64.1% vs. 25.9%, p<0.0001). The mean PID (VAS) 2 hours after additional dose (BOCF) was statistically significantly greater in the celecoxib group than in the placebo group (33.4 vs. 12.3 mm, p<0.0001).

The incidence of treatment-emergent adverse events was 20.3% (13/64 subjects) in the celecoxib group, 31.0% (18/58 subjects) in the placebo group, and 18.8% (25/133 subjects) among those receiving the initial dose alone. No serious adverse events were reported in this study. A severe adverse event (adenocarcinoma of the cervix) occurred in 1 subject of the celecoxib 200 mg group. Most of adverse events reported, however, were classified as mild. A subject discontinued the study with the initial dose alone because of an adverse event (post procedural haemorrhage). No clinically relevant findings were observed from laboratory test data, vital sign measurements, or electrocardiograms.

In conclusion, this study demonstrated that the additional treatment with celecoxib 200 mg, following the initial dose of celecoxib 400 mg, was effective, well tolerated, and safe in patients with post-tooth extraction pain.

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