Efficacy, Tolerability, Safety and Pharmacokinetic Study of DFN-15 in Post-Surgical Dental Pain.

This is a Phase 2, single-center, randomized, double blind, dose-ranging placebo-controlled, clinical study evaluating the efficacy, tolerability, safety, and the pharmacokinetic properties of a known drug (selective COX-2 inhibitor) administered as an alternative formulation/dosage form (DFN-15, a liquid oral formulation) in an accepted model of acute post-operative pain (acute pain following oral surgery for extraction of bilateral impacted mandibular third molar teeth in otherwise healthy subjects).120 female and male healthy subjects scheduled to undergo elective bilateral third molar extraction will be randomized, after they provide informed consent and are confirmed to meet all the study selection criteria, in a 1:1:1:1 ratio to receive a single oral dose of either DFN-15 Dose A DFN-15 Dose B, DFN-15 Dose C or matching placebo.

Subjects will undergo a screening procedure (within 28 days of the scheduled extraction of the impacted third molars) that will involve the collection of demographic information, height, weight and body mass index (BMI), urine pregnancy test (women of child-bearing potential,) medical and medicinal history, physical examination, dental examination, vital signs measurement (blood pressure, pulse rate, respiratory rate), clinical laboratory investigation (hematology,serology, coagulation parameters, serum chemistry and urinalysis),12-lead ECG and a panoramic x-ray to document the impacted mandibular third molar teeth. As a pre-requisite for randomization, subjects will be required to report "moderate" to "severe" baseline pain on the provided paper diary within 6 hours post-surgery (called the 'Baseline' period) as characterized on a 4-point categorical pain intensity (PI) scale (0= none, 1= mild, 2= moderate, 3= severe), and a score of ≥5, on the 11-point Numerical Pain Rating Scale (NPRS) where 0 represents 'no pain' and 10 represents 'worst pain imaginable'. Eligible subjects will be randomized and will receive a single dose of the assigned study treatment. Subjects will be randomized and administered the study medication within 15 minutes of meeting the post-operative inclusion criteria (baseline score).Subjects will be assessed at pre-specified time-points over an observation period of 8 hours from the time of randomization.

Subjects with inadequately controlled pain symptoms may request rescue analgesic medication. Subjects will be encouraged to delay using the rescue medication if their pain is tolerable until 120 minutes post-dose of study medication. A subject who is administered rescue pain medication will continue completing pain assessments until 8 hours after treatment initiation. All randomized subjects will be provided with a paper diary to record pain assessments (Pain Intensity on 11-point NPRS scale, followed by Pain Relief using a 5-point categorical scale [where 0= no pain relief, 1= little pain relief, 2= some pain relief, 3= a lot of pain relief, 4= complete pain relief]) At study medication administration, two stopwatches will be started, to measure times to 'perceptible' and 'meaningful' pain-relief. Subjects will be instructed to stop the first stopwatch when they first perceive pain relief to occur (time to perceptible relief). Subjects will be instructed to stop the second stopwatch when they first experience meaningful pain relief (time to meaningful relief). Stopwatch times of perceptible relief and meaningful relief will be recorded using exact stopwatch time displayed.

In addition, at 8 hours post-dose or within 5 minutes prior to first use of rescue medication (whichever is earlier), subjects will be asked to record within the provided patient diary: 'Patient Rating of Treatment Satisfactoriness' using a 5-point verbal rating scale (0 =poor, 1 =fair, 2 =good, 3=very good, 4 =excellent).

Subjects will remain NPO (nothing by mouth), including water, from Check-in (i.e., at least 2 hours before the administration of the dose of study medication to randomized subjects) until 2 hours post-dose, on Day 1 (study day). After 2 hours post-dose, subjects may be permitted to consume water, or gelatin snacks. Subjects are prohibited from ingesting solid foods or carbonated beverages for at least 6 hours post-dose.

12-lead ECG and Vital Signs were performed before surgery, at baseline and at periodic intervals post-dose until 8 hours .At discharge (8 hours post-randomization) from the clinical facility, all AEs reported for the subjects will be reviewed. A physical examination, including evaluation of the incision site for hematomas, and clinical laboratory evaluation (coagulation parameters and specific hematology, serum biochemistry and urinalysis parameters) will be conducted.

All subjects will have blood drawn at specified time points (pre-dose and over the 8 hour observation period) for pharmacokinetic evaluation.

Subjects will return to the research center 7 days (± 3 days) post-surgery for evaluation of their safety and well-being. Any AEs experienced post-surgery will be reviewed. A physical examination, of the subject will be performed, 12-lead ECG, and vital signs parameters will be repeated. Hematology, coagulation parameters, serum biochemistry and urinalysis parameters will be repeated only if there is a clinically significant abnormality or ongoing AE(s). Any changes to the prior and concomitant medication made after discharge will be reviewed and recorded.

Inclusion Criteria:

1. Subjects scheduled to undergo elective bilateral lower (mandibular) third molar extraction under local anesthesia.
2. Subjects must be generally healthy, ambulatory, able to understand and willing to comply with study procedures, study restrictions, assessments, and requirements per the discretion of the investigator.
3. Subjects must voluntarily sign written informed consent prior to any study-specific procedures.
4. Subjects must have a body mass index (BMI) greater than or equal to 19.0 to less than or equal to 35.0

Exclusion Criteria:

1. History of migraine or frequent headaches, low back pain, or other acute or chronic pain conditions.
2. Acute illness or unresolved local infection prior to surgery that can interfere with the conduct of the study.
3. Positive results on urine drug screen or alcohol breath test indicative of illicit drug (Cocaine Metabolites, Marijuana (THC), MDMA (Ecstasy) and Phencyclidine) or alcohol abuse at screening and/or prior to extraction procedure.
4. Positive results for the following (prescription included): Amphetamines, Barbiturates, Benzodiazepines, Methadone, Methamphetamine, Opiates, Oxycodone, and Tricyclic Antidepressants.
5. Frequent use of nicotine-containing products.
6. Excessive intake of caffeine-containing foods or beverages within 48 hours prior to surgery.
7. Routinely uses pain medication.
8. Currently taking any corticosteroid chronically (except for an inhaled steroid for pulmonary disease, and local topical or ophthalmic steroid) or has taken systemic corticosteroids within 4 weeks of the proposed date of surgery.
9. Currently taking central nervous system active drugs such as hypnotics, sedatives, monoamine oxidase inhibitors, sympathomimetic amines, benzodiazepines, tricyclic antidepressants, or serotonin norepinephrine reuptake inhibitors, and anticonvulsants for pain.
10. Donated blood products or had blood loss greater than 500 mL 30 days prior to Screening or between Screening and surgery.
11. Member or relative of study staff or the Sponsor directly involved in the study.
12. Previous participation in this study.
13. Has received another new chemical entity (defined as a compound which has not been approved for marketing) or has participated in any other clinical study that included drug treatment within 30 days prior to the Screening visit.
14. Currently receiving or have received within 7 days prior to investigational product administration in the study, any drug (s) that is metabolized by hepatic microsomal enzyme CYP 2D6.
15. Clinically significant disease or disorder which may put the subject at risk, influence the results or the subject's ability to participate in the study.

All AEs, whether volunteered, elicited, or noted on physical examination, and regardless of causality or seriousness, were assessed and recorded in the CRF beginning after administration of study drug through the final follow-up assessment (approximately 7 ± 3 days after the last study drug administration). Additionally, if the investigator became aware of the occurrence of an SAE within 30 days of the last visit, the SAE was reported.