A Study of Acetaminophen for Post Surgical Dental Pain

Study Overview
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Brief Summary
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To assess the safety, tolerability, analgesic, efficacy and pharmacokinetics of high dose acetaminophen relative to placebo and low dose acetaminophen relative to placebo over a 24 hour period in patient experiencing moderate to severe pain following the surgical removal of third molar.

Detailed Description
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This will be a randomized, double-blind, single-site, placebo-controlled, parallel-group study to assess similarities in safety, tolerability, efficacy, and pharmacokinetics of high dose acetaminophen given relative to placebo, and low dose acetaminophen given relative to placebo over a 24-hour period in patients experiencing moderate to severe postsurgical pain within 7 hours following surgical removal of 2 or more molars

Official Title
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A Randomized, Double-Blind, Multi-Dose, Single-Site, Placebo- and Active-Controlled, Efficacy, Tolerability, Safety and Pharmacokinetic Study of Two Different Dosing Regimens of Acetaminophen in Post-Surgical Dental Pain.

Conditions
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Pain, Postoperative, Dental Pain

Intervention / Treatment
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* Drug: Acetaminophen
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be capable of reading, comprehending, and signing the informed consent/assent form; Male and female patients between 17-55 years of age; Body Mass Index (BMI) ≤35.0 kg/m2 Body weight of >50 kg Patients are American Society of Anaesthesiologists (ASA) Category I or II and are in good physical health as judged by a thorough history and physical examination; Patients without infections in the area of the impacted teeth; Patients must agree to refrain from ingesting any systemic or applying any topical analgesic medication for 3 days or 5 half-lives of the drug prior to and during the study; No alcohol for a minimum of 24 hours prior to the surgery; Female patients must be of non-child bearing potential, defined as postmenopausal for more than 1 year or surgically sterile (hysterectomy, tubal ligation/occlusion) or practicing an acceptable method of contraception (hormonal oral, patch, or implant, double barrier method, intrauterine device, vasectomized or same sex partner, or abstinence). Patients using hormonal birth control must have been on a stable dose of treatment for at least 30 days and received at least 1 cycle of treatment prior to randomization. At Screening and at the day of surgery, all females of childbearing potential must have a negative (serum at screening and urine on day of surgery 1) pregnancy test and not be breastfeeding; Patients must have a negative urine drug screen for drugs of abuse at Screening and on the day of surgery. At the discretion of the Principal Investigator, a positive drug screen result may be permitted if the patient has been on a stable dose of an allowed medication for >30 days; Patients who are scheduled to undergo the surgical removal of up to 4 third molars of which at least two have to be mandibular molars with a difficulty rating of 4 or 5 and meeting the following criteria: two full bony impactions two partial bony impactions one full bony impaction in combination with one partial bony impaction (see Appendix 1 for Impaction Difficulty Rating Scale); Patients able to comprehend and follow the requirements of the study (including availability on scheduled visit dates) based upon the research site's judgment. Exclusion Criteria: Patients with a history of any significant medical condition that, in the opinion of the Principal Investigator or his designee, would place the patient at increased risk such as: hepatic, renal, endocrine, cardiac, neurological, psychiatric, gastrointestinal, pulmonary, hematologic, or metabolic disorders, including glaucoma, diabetes, emphysema, and chronic bronchitis; Patients with a history of any type of malignancy within the past 5 years other than minor skin related cancers; Patients with a history of alcohol or substance abuse in the past three years according to Diagnostic and Statistical Manual (DSM) V and who do not satisfy Inclusion Criteria 10 (including a positive urine drug screen test); Patients with a known allergy or hypersensitivity to any local anesthetic drug, acetaminophen, ibuprofen, or other NSAIDS; Patients who are taking any concomitant medications that might confound assessments of pain relief, such as psychotropic drugs, antidepressants, sedative hypnotics or any analgesics taken within three days or five times of their elimination half-lives, whichever is longer. Selective serotonin reuptake inhibitors (SSRIs) and selective noradrenaline reuptake inhibitors (SNRIs) are permitted if the patient has been on a stable dose for at least 30 days prior to screening; Patients who have smoked or chewed tobacco-containing substances within 48 hours prior to the day of surgery; Patients judged by the Principal Investigator to be unable or unwilling to comply with the requirements of the protocol; Patients who have used an investigational drug within 30 days prior to the screening day or have previously participated in any Nevakar trial; Patients who have donated blood within 3 months prior to the screening day; Patients who are employees or relatives of employees of JBR Clinical Research or Nevakar, Inc. Patients with liver function tests (ALT, AST) that are above the normal reference range. -

Ages Eligible for Study
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Minimum Age: 17 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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
Interventional Model Description: High Dose Acetaminophen (APAP) versus Placebo, Low Dose APAP versus Placebo
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: High Dose Acetaminophen<br>High Dose Acetaminophen Post Op | Drug: Acetaminophen<br>* Acetaminophen is an analgesic and antipyretic<br>* Other names: APAP;|
| Active Comparator: Low Dose Acetaminophen<br>Low Dose Acetaminophen Post Op | Drug: Acetaminophen<br>* Acetaminophen is an analgesic and antipyretic<br>* Other names: APAP;|
| Placebo Comparator: Placebo<br>Placebo Post Op | Other: Placebo<br>* Saline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sum of Pain Intensity Difference From 0 to 24 Hours (SPID24) Based on the 11 Point Numeric Pain Rating Scale | Pain Intensity was self-reported over 24 hours, using a pain rating of 0-10 on the Numerical Rating Scale (NRS), with score between 0-10 (0= no pain; 10 = worst imaginable pain). Time weighted sum of pain intensity difference from 0 to 24 hours was reported. Pain Intensity (PI-NPRS) was collected at initiation of Dose 1 (T0) and post dose 0.5, 0.75, 1, 1.25, 1.75, 2.25 3.25, 4.25, 5.25, 6.25, 7.25, 8.25, 9.25, 10.25, 11.25, 12.25 (± 5 min) and 14.25, 16.25, 18.25, 20.25, 22.25, and 24.25 (± 10 min). SPID24 was include all nominal timepoints from T0 to T24.25 hours. SPID is calculated as Σ[T(i) -T(i-1)] x [(PID(i-1) + PID(i))/2], where T(0)=0, T(i) is the scheduled time, and PID(i) is the pain intensity difference (PID) score at time i. Pain intensity differences were calculated with respect to Baseline. A baseline assessment is defined as the last non-missing result prior to administration of the first dose of study medication. | Baseline (0.0) and 0.5, 0.75, 1, 1.25, 1.75, 2.25 3.25, 4.25, 5.25, 6.25, 7.25, 8.25, 9.25, 10.25, 11.25, 12.25 (± 5 min) and 14.25, 16.25, 18.25, 20.25, 22.25, and 24.25 (± 10 min) hours | 
| Sum of Pain Relief From 0 to 24 Hours (TOTPAR24) Based on a 5-point Likert Scale. | Pain Relief Rating (PR) was scored on a 5-point scale (0=no-, 1=a little-, 2=some-, 3=a lot of-, and 4=complete- PR). PR was collected at initiation of Dose 1 (T0) and post dose 0.5, 0.75, 1, 1.25, 1.75, 2.25 3.25, 4.25, 5.25, 6.25, 7.25, 8.25, 9.25, 10.25, 11.25, 12.25 (± 5 min) and 14.25, 16.25, 18.25, 20.25, 22.25, and 24.25 (± 10 min) hours. TOTPAR24 is calculated as Sum ([T(i) - T(i-1)] x (PR(i-1) + PR(i)) / 2), where T(0)=0, T(i) is the actual time, and PR(i) is the pain relief score at time i. and calculated as Σ[T(i) -T(i-1)] x [(PR(i-1) + PR(i))/2], where T(0)=0, T(i) is the scheduled time, and PR(i) is the pain relief (PR) score at time i. | Baseline (0.0) and 0.5, 0.75, 1, 1.25, 1.75, 2.25 3.25, 4.25, 5.25, 6.25, 7.25, 8.25, 9.25, 10.25, 11.25, 12.25 (± 5 min) and 14.25, 16.25, 18.25, 20.25, 22.25, and 24.25 (± 10 min) hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Perceptible Pain Relief Confirmed (FPR-C) After Dose 1 Administration Stratified by Baseline Pain Score of Moderate or Severe for the 3 Treatment Groups | Upon initiation of the infusion of Dose 1, the participants were given stopwatch #1 and asked to press the stopwatch when they first perceived any pain relief (first perceptible pain relief [FPR]) ; a record of the time was noted in the participant record. If a participant does not record perceptible pain relief and prematurely discontinued from the study prior to 24 hours, then the participant was censored at time of drop out. If a participant does not record perceptible pain relief prior to taking rescue medication, the participant was censored at 24 hours | 0 to 24 Hours | 
| Time to Meaningful Perceptible Relief (MPR) Measure Stratified by Baseline Pain Score of Moderate or Severe for the 3 Treatment Groups | Upon initiation of the infusion of Dose 1, the participants were given a second stopwatch and asked to press the stopwatch if and when they feel any meaningful perceptible relief; a record of the time was noted in the participant record. If a participant does not record perceptible pain relief and was prematurely discontinued from the study prior to 24 hours, then the participant was censored at time of drop out. If a participant does not record perceptible pain relief prior to taking rescue medication, the participant was censored at 24 hours. | 0 to 24 Hours | 
| Patient Global Evaluation of the Study Medication | Patients Global Evaluation was assessed on a scale of 0 (Poor), 1 (Fair), 2 (Good), 3 (Very Good) and 4 (Excellent) at 24.25 hours post-dose 1 or at participant withdrawal (if applicable), whichever occurred first. Least squares mean of the score are reported. | 0 to 24 Hours | 
| Pain Intensity Difference Rating (PID) at Different Timepoints After Dose 1 Administration | Pain Intensity was self-reported over 24 hours, using a pain rating of 0-10 on the Numerical Rating Scale (NRS), with score between 0-10 (0= no pain; 10 = worst imaginable pain). Pain intensity differences were calculated with respect to Baseline at each time point after Dose 1 administration. A baseline assessment was defined as the last non-missing result prior to administration of the first dose of study medication | Baseline (0.0) and 0.5, 0.75, 1, 1.25, 1.75, 2.25 3.25, 4.25, 5.25, 6.25, 7.25, 8.25, 9.25, 10.25, 11.25, 12.25 (± 5 min) and 14.25, 16.25, 18.25, 20.25, 22.25, and 24.25 hours (± 10 min) | 
| Pain Intensity Rating at Different Timepoints After Dose 1 Administration | Pain intensity is reported using the 11-point Numerical Rating Scale (NRS), with score between 0-10 (0= no pain; 10 = worst imaginable pain). | 0 to 24 hours | 
| Pain Relief (PR) Ratings at Each Observation Time After Dose 1 Administration | Pain Relief is reported on a 5-Point Categorical Pain Relief Assessment scale: 0 = No Pain Relief, 1 = A Little Pain Relief, 2 = Some Pain Relief, 3 = A Lot of Pain Relief, 4 = Complete Pain Relief. | 0 to 24 hours | 
| Time to Treatment Failure | Time to treatment failure is defined as time to first dose of rescue medication after Dose 1 or withdrawal from the study for any reason. If a participant does not take rescue medication or withdraw from the study prior to 24 hours, the participant was censored at 24 hours | 0 to 24 Hours |