Study Evaluating Ibuprofen 600 mg Extended Release (ER) For Dental Pain

Study Overview
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Brief Summary
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The purpose of this study is to assess the efficacy and safety of a single dose of an ibuprofen 600 mg extended release formulation in post-operative dental pain. There is concern that the manufacturing process may affect the performance characteristics of the selected prototype. Therefore, two formulations of this prototype manufactured by two different processes, [roller compaction] and [wet granulation] will be included in this study. The preferred prototype manufactured by two different methods will be compared to placebo and each other. This study will also characterize the pharmacokinetic/pharmacodynamic relationship with these formulations.

Official Title
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Ibuprofen 600 Mg Extended Release (er) Single-dose Dental Pain Study

Conditions
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Pain

Intervention / Treatment
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* Drug: ibuprofen
* Drug: ibuprofen
* Drug: naproxen
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: INCLUSION CRITERIA: Males and females 16 to 40 years of age. Outpatients who undergo surgical extraction of 1-2 third molars, one of which must be a partial or full bony mandibular impaction and have moderate to severe post-operative pain (confirmed by a VAS score of at least 50 mm on a 100 mm VAS) following surgical extraction; Use of only the following preoperative medication(s)/anesthetic(s): short-acting local anesthetic (mepivacaine or lidocaine) with or without vasoconstrictor, nitrous oxide, and/or midazolam; Reliable, cooperative, and of adequate intelligence to record the requested information on the analgesic questionnaire form; Examined by the attending dentist or physician and medically cleared to participate in the study; In general good health and have no contraindications to the study medication. Exclusion Criteria: EXCLUSION CRITERIA: Pregnancy, as verified by a urine-based pregnancy test, or breast feeding; Presence of a serious medical condition (e.g., poorly controlled hypertension, poorly controlled diabetes, significantly impaired cardiac, renal or hepatic function, poorly-controlled hyper- or hypothyroidism); Use of a prescription or nonprescription drug with which the administration of ibuprofen or any other NSAID is contraindicated; Use of a bisphosphonate (e.g., risedronate [Actonel], alendronate [Fosamax], or ibandronate [Boniva]) in the past 5-years; Acute localized dentalveolar infection at the time of surgery that could confound the post-surgical evaluation; Females who are of child-bearing potential, or post-menopausal for less than 2 years and not using a medically approved method of contraception (i.e., oral, transdermal, or implanted contraceptives, intrauterine device, diaphragm, condom, abstinence, or surgical sterility), or females who test positive on a urine-based pregnancy test; Presence or history (within 2 years of enrollment) of bleeding disorder(s) or peptic ulcer disease; History of alcoholism (i.e., on average, consumes 3 or more alcoholic drinks per day) or substance abuse within the last year, or is currently abusing alcohol or other mood-altering drugs (e.g., cannabis). Patients who are taking CNS or other psychotropic drugs (including St. John's Wort, or any other nutritional supplement known to have psychotropic effects) may be enrolled if they have been on stable doses of medication for at least 2 months, will maintain this dose throughout the study, and their condition is judged by the Principal Investigator to be well-controlled; Habituation to analgesic drugs (i.e., routine use of oral analgesics 5 or more times per week) History of allergic reaction (e.g., asthma, rhinitis, swelling, shock, or hives) to ibuprofen, naproxen, aspirin, or to any other NSAID; or to codeine, hydrocodone, or acetaminophen, or to their combinations; Prior use of any type of analgesic or NSAID five half-lives of that drug or less before taking the first dose of study medication, except for pre-anesthetic medication and anesthesia for the procedure; Ingestion of any caffeine-containing beverages, chocolate, or alcohol 4 hours or less before taking the first dose of study medication; The subject has taken an investigational product or participated in an investigational trial within 30 days of study enrollment; The subject has previously participated in this study; The subject is a member of the study site staff directly involved with the study, an employee of the Sponsor, or a relative of study site personnel directly involved with the study.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>1 x 600 mg ibuprofen IR/ER-roller compaction caplet | Drug: ibuprofen<br> <br> |
| Experimental: 2<br>1 x 600 mg ibuprofen IR/ER-Wet granulation caplet | Drug: ibuprofen<br> <br> |
| Active Comparator: 3<br>1x 220 mg naproxen sodium (Aleve caplet) | Drug: naproxen<br> <br> |
| Placebo Comparator: 4<br>1 x placebo caplet | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-weighted Sum of Pain Intensity Difference Score From 0 to 12 Hours (SPID 0-12) | Pain intensity difference (PID) score based on 4-point categorical pain intensity rating scale. Participants asked, How much pain do you have at this time? Range of scale: None (0), Mild (1), Moderate (2), Severe (3). SPID derived by adding the time-weighted sums of PID scores over the time interval. Scores could range from -12 to 36 where higher positive values indicated improvement (decrease in pain intensity). | Baseline (0 hour) to 12 hours post dose | 
| Time-weighted Sum of Pain Intensity Difference Score From 8 to 12 Hours (SPID 8-12) | PID score based on 4-point categorical pain intensity rating scale. Participants asked, How much pain do you have at this time? Range of scale: None (0), Mild (1), Moderate (2), Severe (3). SPID score derived by adding the time-weighted sums of PID scores over the time interval. Scores could range from -4 to 12 where higher positive values indicated improvement (decrease in pain intensity). | 8 to 12 hours post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Perceptible Pain Relief | Time to first perceptible relief (confirmed by meaningful relief) was defined as the elapsed time from dosing until the participant depresses the first stopwatch labelled first perceptible relief, if the participant also depressed the second stopwatch labelled as meaningful relief by 6 hours. If the confirmation was not achieved, the participant was censored at 6 hours. Perceptible relief defined as when participant first begins to feel any pain relieving effect whatsoever of the drug. Does not necessarily mean the participant feels completely better, but when the participant first feels any difference in the pain he/she has currently. | Baseline to 6 hours | 
| Time to Treatment Failure | Time to first rescue medication or discontinuation due to lack of efficacy | Baseline to 24 hours | 
| Percentage of Participants With Treatment Failure | Treatment failure defined as use of rescue medication or discontinuation due to lack of efficacy. | 8, 9, 10, 11, and 12 hours | 
| Time-weighted Sum of Pain Intensity Difference From 0 to 4 Hours (SPID 0-4) and 4 to 8 Hours (SPID 4-8) | Time-weighted sum of PID score. PID based on 4-point categorical pain intensity rating scale. Participants asked, How much pain do you have at this time? Range of scale: None (0), Mild (1), Moderate (2), Severe (3). SPID score derived by adding the time-weighted sums of PID scores over the time interval. Scores could range from -4 to 12 where higher positive values indicated improvement (decrease in pain intensity). | 0 to 4 hours and 4 to 8 hours | 
| Time-weighted Sum of Pain Relief and Pain Intensity Difference Scores (SPRID) | Time-weighted sum of PRID score where PRID=PID+PR. PID: 4-point categorical pain intensity difference scale, 0 (none) to 3 (severe), score derived by subtracting postdose score from baseline, ranged from -1 to 3. Baseline pain intensity score of at least 2 required for enrollment. Higher positive PID values = improvement. PR: 5-point categorical pain relief scale None (0), A Little (1), Some (2), A Lot (3) or Complete (4). SPRID 0-4, SPRID 4-8, and SRID 8-12 scores ranged from -4 to 28, SPRID 0-12 ranged from -12 to 84, higher scores = greater improvement. | 0 to 4 hours, 4 to 8 hours, 8 to 12 hours, and 0 to 12 hours | 
| Time-weighted Sum of Pain Relief Scores (TOTPAR) | TOTPAR based on 5-point categorical pain relief scale. Participants asked, How much relief do you have from your starting pain? Range of scale: None (0), A Little (1), Some (2), A Lot (3) or Complete (4). Higher scores indicated improvement (better pain relief). For time-weighted sum of pain relief scores from 0 to 4 hours (TOTPAR 0-4), from 4 to 8 hours (TOTPAR 4-8), and from 8 to 12 hours (TOTPAR 8-12): range of scores 0 (worst) to 16 (best). TOTPAR 0-12 range of scores 0 (worst) to 48 (best). | 0 to 4 hours, 4 to 8 hours, 8 to 12 hours, and 0 to 12 hours | 
| Percentage of Participants Achieving First Perceptible Relief Confirmed by Meaningful Relief | The elapsed time from dosing until the participant indicated first perceptible relief, provided the participant also indicated achieving meaningful relief. Perceptible relief defined as when participant first begins to feel any pain-relieving effect whatsoever of the drug. Does not necessarily mean the participant feels completely better, but when the participant first feels any difference in the pain he/she currently has now. | 15, 30, 45, 60, 90, and 120 minutes and every 60 minutes up to 360 minutes | 
| Time to Meaningful Pain Relief | Participants evaluated the time to meaningful relief by depressing a second stopwatch at the moment they first began to experience meaningful relief, defined as relief from the pain that is considered meaningful to the participant. | Baseline to 6 hours | 
| Percentage of Participants Achieving Meaningful Pain Relief | Participants evaluated the time to first perceptible pain relief by depressing a stopwatch at the moment they first began to experience perceptible relief and the time to meaningful relief by depressing a second stopwatch at the moment they first began to experience meaningful relief defined as relief from the pain that is considered meaningful to the participant. | 15, 30, 45, 60, 90, and 120 minutes and every 60 minutes up to 360 minutes | 
| Participant Global Evaluation of Study Medication at 12 Hours | Participant rated global evaluation of study medication; results reported by evaluation categories and included very poor (0), poor (1), fair (2), good (3), very good (4), and excellent (5). | 12 hours | 
| Participant Global Evaluation of Study Medication at 24 Hours | Participant rated global evaluation of study medication; results reported by evaluation categories and included very poor (0), poor (1), fair (2), good (3), very good (4), and excellent (5). | 24 hours | 
| Pain Intensity Difference (PID) Score | PID based on 4-point categorical pain intensity rating scale. Participants asked, How much pain do you have at this time? Range of scale: None (0), Mild (1), Moderate (2), Severe (3). PID score derived by subtracting postdose score from baseline score and could range from -1 to 3. A baseline pain intensity score of at least 2 was required for study enrollment. Higher positive PID values indicated greater improvement (decrease in pain intensity). | 15, 30, 45, 60, 90 minutes and 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, and 24 hours | 
| Pain Relief (PR) Score | PR score based on 5-point categorical pain relief scale. Participants asked, How much relief do you have from your starting pain? Range of scale: None [0], A Little [1], Some [2], A Lot [3] or Complete [4]. Higher scores indicated improvement (better pain relief). | 15, 30, 45, 60, 90 minutes and 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, and 24 hours | 
| Pain Relief Combined With Pain Intensity Difference (PRID) Score | PRID=PID+PR, where PID: 4-point categorical pain intensity difference scale, 0 (none) to 3 (severe), score derived by subtracting postdose score from baseline and could range from -1 to 3. Baseline pain intensity score of at least 2 was required for study enrollment. Higher positive PID values indicated improvement. PR: 5-point categorical pain relief scale (None [0], A Little [1], Some [2], A Lot [3], Complete [4]). PRID score could range from -1 to 7 where higher scores indicated better pain relief and decrease in pain intensity. | 15, 30, 45, 60, 90 minutes and 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, and 24 hours | 
| Peak Pain Relief Score | Maximum PR score over the scheduled pain relief assessments. PR score based on 5-point categorical pain relief scale. Participants asked, How much relief do you have from your starting pain? Range of scale: None (0), A Little (1), Some (2), A Lot (3) or Complete (4). Higher scores indicated improvement (better pain relief). | Baseline to 12 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Extended-release, ibuprofen