Efficacy Of PF-05089771 In Treating Postoperative Dental Pain

Study Overview
=================
Brief Summary
-----------------
The objective of this study is to evaluate the overall pain relief of a single dose of PF-05089771 against placebo following third molar extraction.

Official Title
-----------------
A Randomized, Double-blind, Double-dummy, Parallel Group, Placebo Controlled Study Assessing The Efficacy Of Single Doses Of Pf-05089771 For The Treatment Of Postoperative Dental Pain Using Ibuprofen 400 Mg As Positive Control

Conditions
-----------------
Postoperative Dental Pain

Intervention / Treatment
-----------------
* Drug: PF-05089771
* Other: Placebo
* Drug: PF-05089771
* Other: Placebo
* Drug: PF-05089771
* Other: Placebo
* Drug: Ibuprofen
* Other: Placebo
* Other: Placebo
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Oral surgery having removed 2 unilateral third molar teeth. Pre-dose pain intensity score (100 mm VAS [VAS]) of at least 50mm within 5 hours of oral surgery Pre-dose pain intensity score of moderate or severe within 5 hours of oral surgery Exclusion Criteria: Presence or known history of any clinically significant hematological, hepatic, renal, endocrine, cardiovascular, neurological, psychiatric, gastrointestinal, pulmonary, allergic (including known drug hypersensitivities or allergies, but excluding untreated asymptomatic seasonal allergy) or any metabolic disorder that may increase risk associated with study participation, investigational drug administration or may interfere with interpretation of study results. Prior use of any type of analgesic or NSAID within 5-half lives of that drug or less before taking the first dose of study medication, except for anesthesia for the procedure. Active dental infection at the time of surgery. Recent (within the previous 12 months) history of chronic analgesic or tranquiliser dependency. Any significant oral surgery complication at the time of surgery or in the immediate postoperative period, or oral surgery that has lasted more than 30 minutes (time from first incision to last suture placement). Subjects who smoke more than 1 pack (20 cigarettes) per day, more than 3 cigars per day or use smokeless tobacco on a daily basis are excluded from the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-05089771 1600 mg<br> | Drug: PF-05089771<br>* A single dose of PF-05089771 1600 mg oral solution administered once to the subject on Day 1 postoperatively<br>Other: Placebo<br>* Placebo tablets for ibuprofen: 2 X 200 mg placebo tablets administered orally once to the subject on Day 1 postoperatively<br>|
| Experimental: PF-05089771 450 mg<br> | Drug: PF-05089771<br>* A single dose of PF-05089771 450 mg oral solution administered once to the subject on Day 1 postoperatively<br>Other: Placebo<br>* Placebo tablets for ibuprofen: 2 X 200 mg placebo tablets administered orally once to the subject on Day 1 postoperatively<br>|
| Experimental: PF-05089771 150 mg<br> | Drug: PF-05089771<br>* A single dose of PF-05089771 150 mg oral solution administered once to the subject on Day 1 postoperatively<br>Other: Placebo<br>* Placebo tablets for ibuprofen: 2 X 200 mg placebo tablets administered orally once to the subject on Day 1 postoperatively<br>|
| Active Comparator: Ibuprofen 400 mg<br> | Drug: Ibuprofen<br>* 2 X 200 mg tablets of ibuprofen administered orally once to the subject on Day 1 postoperatively<br>Other: Placebo<br>* Placebo solution for PF-05089771: A single dose of Placebo solution administered once to the subject on Day 1 postoperatively<br>|
| Placebo Comparator: Placebo<br> | Other: Placebo<br>* Placebo solution for PF-05089771:A single dose of Placebo solution administered once to the subject on Day 1 postoperatively<br>Other: Placebo<br>* Placebo tablets for Ibuprofen: 2 X 200 mg placebo tablets administered orally once to the subject on Day 1 postoperatively<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Pain Relief From 0 to 6 Hours (TOTPAR[6]) | TOTPAR(6) was defined as the total area under pain relief (PR) curve through first 6 hours after dosing, calculated using trapezoidal rule. PR was assumed to be 0 at 0 hour. PR assessed on a 5-point categorical scale: 0(none), 1 (a little), 2 (some), 3 (a lot) and 4 (complete), at different time points during study up to 6 hours. Total score range for TOTPAR(6): 0 (worst) to 24 (best), higher value indicated greater degree of PR. Posterior mean, standard deviation were estimated based on analysis of covariance (ANCOVA) model with non-informative priors within outlier robust Bayesian framework. | 0 to 6 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Pain Relief From 0 to 24 Hours (TOTPAR[24]) | TOTPAR(24) was defined as the total area under the PR curve through the first 24 hours after dosing, calculated using trapezoidal rule. PR was assumed to be 0 at 0 hour. PR assessed on a 5-point categorical scale: 0 (none), 1 (a little), 2 (some), 3 (a lot) and 4 (complete), at different time points during the study up to 6 hours. Total score range for TOTPAR (24): 0 (worst) to 96 (best), higher value indicated greater degree of PR. The least square mean and standard error are based on ANCOVA model with treatment as a fixed effect and baseline pain intensity as a covariate | 0 to 24 hours | 
| Time to Onset of First Perceptible Pain Relief | Participants evaluated the time to first perceptible pain relief by stopping a stopwatch labeled 'first perceptible pain relief' at the moment they first began to experience any relief. | 0 to 24 hours | 
| Time to Onset of Meaningful Pain Relief | Participants evaluated the time to first meaningful relief by stopping a stopwatch labeled 'meaningful pain relief' at the moment they first began to experience meaningful relief. | 0 to 24 hours | 
| Time to First Use of Rescue Medication | Time to first use of rescue medication (acetaminophen 500 mg or hydrocodone 5 mg) was calculated by subtracting time of first administration of study medication from the rescue medication administration time. | 0 to 24 hours | 
| Number of Participants With Global Evaluation of Study Medication | Participant rated the study medication at 6 hours, 24 hours and immediately prior to rescue medication intake (only for participants who took rescue medication[RM]), on 5-point categorical scale: 1=poor, 2=fair, 3=good, 4=very good, and 5=excellent. | 6, 24 hours, prior to rescue medication (assessed up to 24 hours) | 
| Number of Participants With Study Medication Satisfaction | Participants provided assessment regarding satisfaction with study medication (SM) for pain relief (PR) and overall performance (OP) on a 5-point categorical scale, 1=very dissatisfied (VD), 2=somewhat dissatisfied (SD), 3=neither satisfied nor dissatisfied (NSND), 4=somewhat satisfied (SS) and 5=very satisfied (VS). | 6, 24 hours, prior to rescue medication (assessed up to 24 hours) | 
| Plasma PF-05089771 Concentration |  | 0 (pre-dose), 0.5, 1, 2, 4, 6, 8, 10, 24 hours post-dose | 
| Plasma Ibuprofen Concentration | Ibuprofen concentration was reported separately for 2 isomers of ibuprofen: (S)-Ibuprofen, and (R)-Ibuprofen, where S implied sinister (clockwise configuration) and R implied rectus (anti-clockwise configuration). | 0 (pre-dose), 0.5, 1, 2, 4, 6, 8, 10, 24 hours post-dose | 
| Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between administration of study drug and up to 28 days that were absent before treatment or that worsened relative to pretreatment state. | Baseline up to Day 28 (follow-up) | 
| Number of Participants With Clinically Significant Laboratory Findings | Hematology (hemoglobin, hematocrit, red blood cell count, platelets, leukocytes, total neutrophils, eosinophils, basophils, lymphocytes, monocytes), blood chemistry (total bilirubin, direct bilirubin, indirect bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, creatinine, blood urea nitrogen, fasting glucose, uric acid, sodium, potassium, chloride, bicarbonate, calcium, albumin, total protein, creatine kinase), and urinalysis (urine white blood cells, urine red blood cells) were performed. | Baseline up to Day 7 to 10 (follow-up) | 
| Number of Participants With Clinically Significant Vital Signs | Clinically significant vital signs: supine/sitting pulse rate (PR) less than (<) 40 or more than (>) 120 beats per minute (bpm), standing PR <40 or >140 bpm; systolic blood pressure (BP) >=30 millimeters of mercury (mmHg) change from baseline; absolute systolic BP <90 mmHg; diastolic BP >=20 mmHg change from baseline; absolute systolic BP <50 mmHg. | Baseline up to Day 7 to 10 (follow-up) | 
| Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities | Clinically significant ECG abnormalities: PR interval >=300 milliseconds (msec); 25% increase from baseline in PR interval when baseline PR was >200 msec; an increase from baseline of >=50% in PR interval when baseline PR was <=200 msec; QRS interval >=140 msec; an increase from baseline of >=50% in QRS interval; corrected QT interval (QTc) >=500 msec. | Baseline up to Day 7 to 10 (follow-up) | 
| Number of Participants With Peak Pain Relief (PPR) | PPR was defined as the highest PR score achieved at any time point during the evaluation period, prior to rescue medication. PR was assessed on a 5-point categorical scale: 0 (none), 1 (a little), 2 (some), 3 (a lot) and 4 (complete). | 0 to 24 hours | 
| Pain Relief (PR) Score | PR was assessed on a 5-point categorical scale; 0 (none), 1 (a little), 2 (some), 3 (a lot) and 4 (complete). | 15, 30, 45, 60, 90 minutes, 2, 3, 4, 6, 8, 24 hours | 
| Pain Intensity Difference (PID) | PID was calculated as pain intensity at baseline (baseline pain severity score range 2 [moderate] to 3 [severe]) minus pain intensity at the respective post-baseline visit (pain severity score range 0 [none] to 3 [severe]). Total possible score range for PID: -1 (worst) to 3 (best). | 15, 30, 45, 60, 90 minutes, 2, 3, 4, 6, 8, 24 hours | 
| Summed Pain Intensity Difference (SPID) | SPID: area under the PID effect curve from 0 to 6 hours (SPID[6]) and 0 to 24 hours (SPID[24]). AUC was calculated using the trapezoidal rule. Total score range: -6 (worst) to 18 (best) for SPID(6), and -24 (worst) to 72 (best) for SPID(24). Higher value of SPID indicated greater degree of pain relief. PID was calculated as pain intensity at baseline minus pain intensity at the respective post-baseline visit. Pain intensity was assessed on a categorical scale ranging from 0 (none), 1 (mild), 2 (moderate) and 3 (severe). | 0 to 6 hours; 0 to 24 hours | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Postoperative dental pain