Efficacy and Safety of Ibuprofen and Caffeine in Dental Pain

Study Overview
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Brief Summary
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The primary objective of this study is to compare the efficacy of a combination product containing ibuprofen 400 mg and caffeine 100 mg versus either ingredient alone as well as placebo for the treatment of post-surgical dental pain over an eight-hour period followed by a single dose of study medication (study stage 1). A secondary objective is to evaluate efficacy of multiple doses of the combination in comparison to ibuprofen alone over a 5-day post-surgical period (study stage 2).

Official Title
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A Single-centre, Double-blind, Randomised, Two-stage, Parallel-group Study to Assess the Efficacy and Safety of the Fixed Dose Combination of Ibuprofen 400 mg and Caffeine 100 mg Versus Ibuprofen 400 mg, Caffeine 100 mg and Placebo in Patients With Postoperative Dental Pain

Conditions
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Pain, Postoperative, Tooth Diseases

Intervention / Treatment
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* Drug: ibuprofen + caffeine
* Drug: ibuprofen
* Drug: ibuprofen
* Drug: caffeine
* Drug: ibuprofen + caffeine
* Drug: placebo
* Drug: placebo
* Drug: caffeine
* Drug: ibuprofen
* Drug: ibuprofen + caffeine


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Males and females 18 to 55 years of age; Outpatients scheduled to undergo surgical extraction of 3-4 impacted third molar(s), with a minimum of two mandibular extractions. The two mandibular third molars may be partial bony impactions or full bony impactions (as long as the trauma rating is not severe and the surgeons do not feel the subject will have extreme post-surgical pain) OR there may be a combination of one full bony impaction with the second mandibular being a soft tissue impaction or partial bony impaction. Maxillary third molars (or supernumerary teeth) of any type can be extracted; Use of only the following preoperative medication(s)/ anesthetic(s): topical benzocaine, short-acting local anesthetic (mepivacaine or lidocaine) with or without vasoconstrictor and/or nitrous oxide; Reliable, cooperative, and of adequate intelligence to record the requested information on the analgesic questionnaire form; Examined by the attending oral surgeon or physician and medically cleared to participate in the study; Scheduled to undergo a qualifying surgical procedure; In good general health, with a BMI of 30 or less, and have no contraindications to any of the study medications or anesthetic drugs; Subjects have at least a categorical pain score of moderate and a numerical rating scale (NRS) score of 5 or greater within 4.5 hours from the time of the last suture. Exclusion criteria: Presence of a serious medical condition (e.g., poorly controlled hypertension, poorly controlled diabetes, significantly impaired cardiac, renal or hepatic function, hyper- or hypothyroidism); Use of a prescription or non-prescription drug with which the administration of ibuprofen or any other non steroidal anti inflammatory or caffeine is contraindicated; Acute local infection at the time of surgery that could confound the post-surgical evaluation; Females who are pregnant, lactating, 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, intravaginal 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 or substance abuse within the last year, or is currently abusing alcohol or other mood-altering drugs (e.g., cannabis). Subjects who are taking central nervous system or other psychotropic drugs (including St. Johns 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 or caffeine (i.e., routine use of oral analgesics 5 or more times per week or ingestion of 4 or more caffeine-containing drinks daily); use of high energy drinks more than once per week; Use of any type of systemic corticosteroid within the past 30 days or a history of current or previous use of anabolic steroids; History of allergic reaction (e.g., asthma, rhinitis, swelling, shock, or hives) to acetaminophen, ibuprofen, naproxen, aspirin, celecoxib, or any other non steroidal anti inflammatory or caffeine; Prior use of any type of analgesic or non steroidal anti inflammatory within 5 half-lives of that drug before surgery, except for pre-anesthetic medication and anesthesia for the procedure; Ingestion of any caffeine-containing beverages, chocolate, or alcohol 6 hours or less before surgery; Has impaired liver function, e.g., serum Alanine transaminase, aspartate aminotransferase, alkaline phosphatase, or Gamma-glutamyltransferase greater than 2.5 times the upper limit of normal, or blood urea nitrogen, creatinine, or bilirubin greater than 1.5 times the upper limit of normal without a known benign explanation; Has known history of a positive HIV antibody test or known HIV infection; Has a known history of Hepatitis B or C; Has a clinically significant abnormal electrocardiogram (ECG) at screening as determined by the Investigator: Has taken an investigational product within the past 30 days; Has previously been entered into this study; The subject is a member of the study site staff either directly involved with the study, an employee of the Sponsor, or a relative of study site personnel directly involved with the study or Sponsor.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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 |
| --- | --- |
| Other: Caffeine-Ibuprofen<br>Study Stage 1: One Caffeine 100 mg tablet after dental surgery; Arm Type: Active Comparator - Study Stage 2: Subsequent to Stage 1, every 6-8 hours one ibuprofen 400 mg tablet, while awake, over 5 days; Arm Type: Active Comparator | Drug: ibuprofen<br>* tablet<br>Drug: caffeine<br>* tablet<br>|
| Other: Placebo-Ibuprofen/Caffeine<br>Study Stage 1: One Placebo tablet after dental surgery Arm Type: Placebo Comparator - Study Stage 2: Subsequent to Stage 1, every 6-8 hours one Ibuprofen 400 mg/Caffeine tablet, while awake, over 5 days; Arm Type: Experimental | Drug: ibuprofen + caffeine<br>* FDC tablet<br>Drug: placebo<br>* tablet<br>|
| Other: Ibuprofen/Caffeine-Ibuprofen/Caffeine<br>Study Stage 1: One Ibuprofen 400 mg/Caffeine 100 mg tablet after dental surgery: Arm Type Experimental - Study Stage 2: Subsequent to Stage 1, every 6-8 hours one Ibuprofen 400 mg/Caffeine 100 mg tablet, while awake, over 5 days; Arm Type Experimental | Drug: ibuprofen + caffeine<br>* Fixed Dose Combination (FDC) tablet<br>|
| Other: Ibuprofen-Ibuprofen<br>Study Stage 1: One Ibuprofen 400 mg tablet after dental surgery; Arm Type Active Comparator - Study Stage 2: Subsequent to stage 1, every 6-8 hours one Ibuprofen 400 mg tablet, while awake, over 5 days; Arm type; Active Comparator | Drug: ibuprofen<br>* tablet.<br>|
| Other: Caffeine-Ibuprofen/Caffeine<br>Study Stage 1: One Caffeine 100 mg tablet after dental surgery. Arm Type; Active Comparator - Study Stage 2: Subsequent to Stage 1, every 6-8 hours one Ibuprofen 400mg/Caffeine 100 mg tablet, while awake, over 5 days; Arm Type: Experimental | Drug: caffeine<br>* tablet<br>Drug: ibuprofen + caffeine<br>* FDC tablet<br>|
| Other: Placebo-Ibuprofen<br>Study Stage 1: One Placebo tablet after dental surgery Arm Type: Placebo Comparator - Study Stage 2: Subsequent to Stage 1, every 6-8 hours one Ibuprofen 400 mg tablet, while awake over 5 days; Arm Type: Active Comparator | Drug: placebo<br>* tablet<br>Drug: ibuprofen<br>* tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-weighted Sum of Pain Relief (PAR) and Pain Intensity Difference (PID) From 0 to 8 Hours (SPRID0-8h) | SPRID0-8h: Time-weighted sum of PAR and PID from 0 to 8 hours, score range: -40 (worst) to 112 (best). PI was assessed on a 0-10 numerical pain rating scale (NPRS), where 0=no pain and 10=worst possible pain, pre-dose and at 0.25,0.5,0.75,1,1.5,2,3,4,5, 6,7 and 8 hours; PAR was assessed on a 5-point verbal rating scale (VRS) (0=none to 4=complete) at the same post-dose time points. Time-weights were equal to the elapsed time (hour) between the time point of interest and the preceding time point. All PAR and pain intensity (PI) assessments completed after the patient had taken rescue medication or the second dose of study medication, whichever was first, until hour 8 were considered missing. Last observation carried forward (LOCF) was used with the last completed PI/PAR assessments prior to first rescue/second study medication, whichever was first, to impute missing values up to 8 hours. | 0 to 8 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-weighted Sum of Pain Relief (PAR) and Pain Intensity Difference (PID) From 0 to 2 Hours (SPRID0-2h) | SPRID0-2h: Time-weighted sum of PAR and PID from 0 to 2 hours, score range: -10 (worst) to 28 (best). PI was assessed on a 0-10 numerical pain rating scale (NPRS), where 0=no pain and 10=worst possible pain, pre-dose and at 0.25,0.5,0.75,1,1.5 and 2 hours; PAR was assessed on a 5-point verbal rating scale (VRS) (0=none to 4=complete) at the same post-dose time points. Time-weights were equal to the elapsed time (hour) between the time point of interest and the preceding time point. All PAR and pain intensity (PI) assessments completed after the patient had taken rescue medication or the second dose of study medication, whichever was first, until hour 2 was considered missing. Last observation carried forward (LOCF) was used with the last completed PI/PAR assessments prior to first rescue/second study medication, whichever was first, to impute missing values up to 2 hours. | 0 to 2 hours | 
| Duration of Pain Relief | Duration of pain relief was defined as the time between the administration of first dose of trial medication and first dose of rescue medication or second dose of trial medication, whichever was first. Duration of pain relief was censored at 8 hours. | 8 hours | 
| Time to Meaningful Pain Relief | Time to meaningful pain relief was captured by a stopwatch, which was started by the study staff immediately after the administration of the first dose of trial medication and which was to be stopped by the patient as soon as he/she felt meaningful pain relief. Time to meaningful pain relief was censored at 8 hours. | 8 hours |