Efficacy of 300mg Ibuprofen Prolonged-Release Tablets for the Treatment of Pain After Surgical Removal of Impacted Third Molars

Study Overview
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Brief Summary
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This is a single centre, randomised, double-blind, double-dummy, parallel group, multiple-dose, active and placebo-controlled efficacy study to evaluate the efficacy and safety of 2×300mg ibuprofen Prolonged Release (PR) tablets in subjects with postoperative dental pain.

Detailed Description
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This is a single centre, randomised, double blind, double-dummy, parallel group , multiple-dose, active and placebo controlled efficacy study to evaluate the efficacy and safety of ibuprofen 2×300 mg ibuprofen PR tablets in subjects with postoperative dental pain. Eligible subjects will complete all screening procedures within 28 days before the surgery and randomisation. At Screening, subjects will provide written informed consent to participate in the study before any protocol specified procedures or assessments are completed. On Day 1, subjects who continue to be eligible for study participation after completing screening procedures and assessments will undergo extraction of 2 or more third molars. At least 1 of the third molars must be a fully or partially bone impacted mandibular molar. If only 2 molars are removed, then they must be ipsilateral. All subjects will receive local anaesthesia (2% lidocaine with 1:100,000 epinephrine). Nitrous oxide will be allowed at the discretion of the investigator. Subjects who experience moderate to severe pain intensity (a score of ≥ 5 on a numeric rating scale [NRS] from 0-10 where 0 = no pain, 10 = worst pain ever) within 6 hours after surgery and who continue to meet all study entry criteria will be randomised in a 3:3:1 ratio to receive 2×300 mg ibuprofen PR tablets every 12 hours (Q12h), 2×200 mg ibuprofen IR tablets every 8 hours (Q8h), or placebo. The randomisation will be stratified by baseline pain category (moderate or severe) using a categorical scale that includes the categories of none (0), mild (1-4), moderate (5-7), and severe (8-10). Subjects will re-assess their baseline pain intensity using the NRS immediately before receiving study drug (pre-dose, Time 0) and their pain intensity (NRS) and pain relief (5 point categorical scale) at the following time points (pre-dose, if at one of the dosing timepoints of 0, 8, 12 and/or 16 hours): 15, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, and 24 hours after Time 0; and immediately before each dose of rescue medication, if any. For assessments less than 1 hour apart a window of +/-2 min is allowable whilst for assessments at least 1 hour apart a +/-5 min window is allowable. The double stopwatch method will be used to record the time to perceptible pain relief and time to meaningful pain relief during the 8 hours following the first dose or until subject takes rescue medication. Subjects will complete a global evaluation of study drug 24 hours (+/- 5 minutes) after Time 0 or immediately before the first dose of rescue medication (whichever occurs first). Vital signs will be recorded after the subject has been in a sitting position for 3 minutes at the following times: before surgery, within 30 minutes before Time 0, 12 and 24 hours after Time 0, and/or immediately before the first dose of rescue medication. Adverse events (AEs) will be monitored and recorded from the time of signing of the informed consent form (ICF) until the Follow up Visit (or Early Termination Visit). During the 24 hours following Time 0, subjects will complete efficacy and safety assessments. Subjects will remain at the study site overnight and will be discharged on Day 2. Paracetamol / acetaminophen (1000 mg) will be permitted as the initial rescue medication. Subjects will be encouraged to wait at least 60 minutes after receiving study drug before taking rescue medication. If acetaminophen rescue medication is not effective in relieving the subject's pain, 5 mg oxycodone rescue medication may be administered at the discretion of the investigator. Subjects are not permitted to take any concomitant medications that might confound assessments of pain relief, such as psychotropic drugs, antidepressants, sedative-hypnotics (other than those permitted for conscious sedation), or other analgesics taken within five times of their elimination half-lives (other than those used at the surgery). Selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) are permitted if the subject has been on a stable dose for at least four weeks prior to Visit 1 (screening). Other restrictions include the following: alcohol use is prohibited from 24 hours before surgery until discharge on Day 2; nothing by mouth from midnight before surgery until 1 hour after surgery; clear liquids only are allowed starting 1 hour after surgery until 1 hour after dosing; 1 hour after dosing, the subject's diet may be advanced according to standard practice. Upon discharge from the study site, subjects may be prescribed pain medication for use at home according to the standard practice of the study site. On Day 8 (± 2 days), subjects will return to the study site for an abbreviated confirmatory physical assessment and AE assessments.

Official Title
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A Randomised, Double-Blind, Double-Dummy, Parallel-Group, Multiple-Dose, Active and Placebo-Controlled Efficacy Study of Ibuprofen Prolonged-Release Tablets for the Treatment of Pain After Surgical Removal of Impacted Third Molars

Conditions
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Pain

Intervention / Treatment
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* Drug: Ibuprofen 300 mg Oral Tablet
* Drug: Ibuprofen 200 mg Oral Tablet
* Other: Placebo of PR tablet
* Other: Placebo of IR tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is male or female ≥ 18 and ≤ 50 years of age. Requires extraction of 2 or more third molars. At least 1 of the third molars must be a fully or partially bone impacted mandibular molar. If only 2 molars are removed, then they must be ipsilateral. Experiences moderate to severe pain intensity within 6 hours after surgery, as measured by a numeric rating scale (NRS) score of ≥ 5 on a 0-10 scale. Has a body weight ≥ 45 kg and a body mass index (BMI) ≤ 35 kg/m2. Female subjects of child-bearing potential must be willing to use a highly effective method of contraception throughout the study. A highly effective method of birth control is defined as one which results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly, such as the following: surgical sterilisation contraceptive implants or injectables combined oral contraceptives some intrauterine devices (IUDs) true sexual abstinence, when this is in line with the preferred and usual lifestyle of the subject (periodic abstinence such as calendar, ovulation, symptothermal, or post-ovulation methods; declaration of abstinence for the duration of the trial; or withdrawal are not acceptable methods of contraception), or vasectomised partner. To be considered not of child-bearing potential, females must be surgically sterile (defined as bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) or post-menopausal (defined as no menses for 12 months in women not using hormonal contraception or hormone replacement therapy, confirmed by a follicle stimulating hormone (FSH) level in the postmenopausal range at Screening). Free of clinically significant abnormal findings as determined by medical history, physical examination, vital signs, laboratory tests and ECG. Is able to provide written informed consent. Is willing and able to comply with study requirements (including diet and smoking restrictions), complete the pain evaluations, remain at the study site overnight, and return for followup 7 (± 2) days after surgery. Exclusion Criteria: Known hypersensitivity reactions or allergy (e.g., asthma, rhinitis, angioedema or urticaria) in response to nonsteroidal anti-inflammatory drugs (NSAIDs, including ibuprofen), acetylsalicylic acid (aspirin), ingredients of the study drug, or any other drugs used in the study, including anaesthetics and antibiotics that may be required on the day of surgery. A history of active or previous peptic ulceration/ haemorrhage, gastrointestinal bleeding or perforation, heart failure, renal or hepatic failure, uncontrolled hypertension, asthma, nasal polyps, or chronic rhinitis. Has complications from the tooth extraction or any other clinically significant medical history that, in the opinion of the investigator, would affect the subject's ability to comply or otherwise contraindicate study participation, including but not limited to the following: cardiac, respiratory, gastroenterological, neurological, psychological, immunological, haematological, oncological, or renal disease. Has undergone another dental surgery within 60 days prior to the day of surgery. A positive urine drugs of abuse screen or alcohol breathalyser test at screening and during the study (with the exception of a positive drugs of abuse screen that is a consequence of permitted prescription medicines). If female, has a positive pregnancy test at screening (serum) or on the day of surgery prior to surgery (urine), or is lactating. Has known or suspected, (in the opinion of the investigator), history of alcoholism or drug abuse within 2 years of screening or evidence of tolerance or physical dependence before dosing with study drug. Taking any concomitant medications that might confound assessments of pain relief, such as psychotropic drugs, antidepressants, sedative-hypnotics (other than those permitted for conscious sedation), or other analgesics taken within five times of their elimination half-lives. Selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) are permitted if the subject has been on a stable dose for at least four weeks prior to Visit 1 (screening). Is considered by the investigator, for any reason (including, but not limited to the risks described as precautions, warnings and contraindications in the current version of the investigator's brochure (IB) for 300 mg ibuprofen PR tablets), to be an unsuitable candidate to receive the study drug. Has a history of chronic use (defined as daily use for > 2 weeks) of nonsteroidal anti-inflammatory (NSAIDs), opiates, or glucocorticoids (except inhaled nasal steroids and topical corticosteroids), for any condition within 6 months before dosing with study drug. Has significant difficulties swallowing capsules or tablets or is unable to tolerate oral medication. Previously participated in another clinical study of 300 mg ibuprofen PR tablets, or received any investigational drug, device, or therapy within 90 days before screening. Enrolment of the Investigator, his / her family members, employees and other dependent persons. Failure to satisfy the investigator of fitness to participate for any other reason.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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
Interventional Model Description: The dental pain model used in this study is a robust and well established postsurgical pain model that produces pain that is predictable in its character, duration, and intensity. The model is widely accepted and has a proven record of assay sensitivity (i.e. separating active drugs from each other, as well as from placebo). The model is frequently used to evaluate NSAID type analgesics. Results from dental pain studies are accepted by the US Food and Drug Administration (FDA) and European authorities and have been widely extrapolated to other general pain conditions.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prolonged Release Group<br>Ibuprofen 300 mg Oral Tablet Placebo of IR tablet Placebo of PR tablet | Drug: Ibuprofen 300 mg Oral Tablet<br>* 2 x 300 mg tablets twice in 24 hours<br>* Other names: Prolonged Release Tablet;Other: Placebo of PR tablet<br>* Up to 2 tablets four times in 24 hours<br>Other: Placebo of IR tablet<br>* Up to 2 tablets four times in 24 hours<br>|
| Active Comparator: Immediate Release Group<br>Ibuprofen 200 mg Oral Tablet Placebo of IR tablet Placebo of PR tablet | Drug: Ibuprofen 200 mg Oral Tablet<br>* 2 x 200 mg tablets three times in 24 hours<br>* Other names: Nurofen, Immediate Release Tablet;Other: Placebo of PR tablet<br>* Up to 2 tablets four times in 24 hours<br>Other: Placebo of IR tablet<br>* Up to 2 tablets four times in 24 hours<br>|
| Placebo Comparator: Placebo Group<br>Placebo of IR tablet Placebo of PR tablet | Other: Placebo of PR tablet<br>* Up to 2 tablets four times in 24 hours<br>Other: Placebo of IR tablet<br>* Up to 2 tablets four times in 24 hours<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summed Pain Intensity Difference 0-12 hours (SPID12) vs placebo using the Numeric Rating Scale (NRS) for pain | SPID12 will be used to compare the test product (2×300 mg ibuprofen PR tablets) against the placebo product. The NRS will be used to assess the Pain Intensity, the NRS for pain is an 11-point scale (0-10) where a higher score indicates a greater amount of pain. | 0-12 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summed Pain Intensity Difference 0-24 hours (SPID24) vs active comparator using the NRS for pain | SPID24 will be used to compare the test product (2×300 mg ibuprofen PR tablets twice daily (BID)) and comparator product (2×200 mg ibuprofen IR tablets three times a day (TID)). The NRS will be used to assess the Pain Intensity, the NRS for pain is an 11-point scale (0-10) where a higher score indicates a greater amount of pain. | 0-24 hours | 
| Summed Pain Intensity Difference 0-4hours (SPID4) using NRS for pain | SPID4 after Time 0 will be assessed using the NRS to assess the Pain Intensity, the NRS for pain is an 11-point scale (0-10) where a higher score indicates a greater amount of pain. | 0-4 hours | 
| Summed Pain Intensity Difference 0-8 hours (SPID8) using NRS for pain | SPID8 after Time 0 will be assessed using the NRS to assess the Pain Intensity, the NRS for pain is an 11-point scale (0-10) where a higher score indicates a greater amount of pain. | 0-8 hours | 
| Summed Pain Intensity Difference 0-12 hours (SPID12) using NRS for pain | SPID12 after Time 0 will be assessed using the NRS to assess the Pain Intensity, the NRS for pain is an 11-point scale (0-10) where a higher score indicates a greater amount of pain. | 0-12 hours | 
| Sum of Total Pain Relief 0-4 hours (TOTPAR4) using Pain Relief Scale (PRS) | TOTPAR4 after Time 0 will be assessed using the PRS. PRS is used to measure pain relief and is a 5 point categorical scale, response choices of none = 0, a little = 1, some = 2, a lot = 3, and complete = 4 to be completed in response to the question How much relief have you had since your starting pain?. | 0-4 hours | 
| Sum of Total Pain Relief 0-8 hours (TOTPAR8) using PRS | TOTPAR8 after Time 0 will be assessed using the PRS. PRS is used to measure pain relief and is a 5 point categorical scale, response choices of none = 0, a little = 1, some = 2, a lot = 3, and complete = 4 to be completed in response to the question How much relief have you had since your starting pain?. | 0-8 hours | 
| Sum of Total Pain Relief 0-12 hours (TOTPAR12) using PRS | TOTPAR12 after Time 0 will be assessed using the PRS. PRS is used to measure pain relief and is a 5 point categorical scale, response choices of none = 0, a little = 1, some = 2, a lot = 3, and complete = 4 to be completed in response to the question How much relief have you had since your starting pain?. | 0-12 hours | 
| Sum of Total Pain Relief 0-24 hours (TOTPAR24) using PRS | TOTPAR24 after Time 0 will be assessed using the PRS. PRS is used to measure pain relief and is a 5 point categorical scale, response choices of none = 0, a little = 1, some = 2, a lot = 3, and complete = 4 to be completed in response to the question How much relief have you had since your starting pain?. | 0-24 hours | 
| Summed pain relief and intensity difference (sum of TOTPAR and SPID [SPRID]) 0-4 hours (SPRID4) using PRS and NRS for pain. | SPRID4 after Time 0 will be assessed using the PRS and NRS for pain. The PRS will be used to measure pain relief and is a 5 point categorical scale, response choices of none = 0, a little = 1, some = 2, a lot = 3, and complete = 4 to be completed in response to the question How much relief have you had since your starting pain?. The NRS will be used to assess the Pain Intensity, the NRS for pain is an 11-point scale (0-10) where a higher score indicates a greater amount of pain. SPRID4 will be determined by calculating the difference in NRS for pain at the 4-hour time point and the 0-hour timepoint and adding this value to the difference in the PRS at the 4-hour time point and the 0-hour timepoint. | 0-4 hours | 
| Summed pain relief and intensity difference 0-8 hours (SPRID8) using PRS and NRS for pain | SPRID8 after Time 0 will be assessed using the PRS and NRS for pain. The PRS will be used to measure pain relief and is a 5 point categorical scale, response choices of none = 0, a little = 1, some = 2, a lot = 3, and complete = 4 to be completed in response to the question How much relief have you had since your starting pain?. The NRS will be used to assess the Pain Intensity, the NRS for pain is an 11-point scale (0-10) where a higher score indicates a greater amount of pain. SPRID8 will be determined by calculating the difference in NRS for pain at the 8-hour time point and the 0-hour timepoint and adding this value to the difference in the PRS at the 8-hour time point and the 0-hour timepoint. | 0-8 hours | 
| Summed pain relief and intensity difference 0-12 hours (SPRID12) using PRS and NRS for pain | SPRID12 after Time 0 will be assessed using the PRS and NRS for pain. The PRS will be used to measure pain relief and is a 5 point categorical scale, response choices of none = 0, a little = 1, some = 2, a lot = 3, and complete = 4 to be completed in response to the question How much relief have you had since your starting pain?. The NRS will be used to assess the Pain Intensity, the NRS for pain is an 11-point scale (0-10) where a higher score indicates a greater amount of pain. SPRID12 will be determined by calculating the difference in NRS for pain at the 12-hour time point and the 0-hour timepoint and adding this value to the difference in the PRS at the 12-hour time point and the 0-hour timepoint. | 0-12 hours | 
| Summed pain relief and intensity difference 0-24 hours (SPRID24) using PRS and NRS for pain | SPRID24 after Time 0 will be assessed using the PRS and NRS for pain. The PRS will be used to measure pain relief and is a 5 point categorical scale, response choices of none = 0, a little = 1, some = 2, a lot = 3, and complete = 4 to be completed in response to the question How much relief have you had since your starting pain?. The NRS will be used to assess the Pain Intensity, the NRS for pain is an 11-point scale (0-10) where a higher score indicates a greater amount of pain.SPRID24 will be determined by calculating the difference in NRS for pain at the 24-hour time point and the 0-hour timepoint and adding this value to the difference in the PRS at the 24-hour time point and the 0-hour timepoint. | 0-24 hours | 
| Proportion of participants who show response to study drug using NRS for pain | A responder will be defined as a subject with ≥30% improvement in pain intensity without rescue medication during the first 8 hours. The NRS will be used to assess the Pain Intensity, the NRS for pain is an 11-point scale (0-10) where a higher score indicates a greater amount of pain. | 0-8 hours | 
| NRS (for pain) Pain Intensity Difference at each timepoint | NRS pain intensity difference (PID) at each scheduled time point after Time 0. The NRS will be used to assess the Pain Intensity, the NRS for pain is an 11-point scale (0-10) where a higher score indicates a greater amount of pain. | 0-24 hours | 
| Peak Pain intensity score using NRS for pain | Pain intensity score at each scheduled time point will be assessed using the NRS for pain. The NRS for pain is an 11-point scale (0-10) where a higher score indicates a greater amount of pain. | 0-24 hours | 
| Pain relief score using Pain Relief Scale | Pain relief score at each scheduled time point after Time 0 will be measured using the PRS. The PRS will be used to measure pain relief and is a 5 point categorical scale, response choices of none = 0, a little = 1, some = 2, a lot = 3, and complete = 4 to be completed in response to the question How much relief have you had since your starting pain?. | 0-24hours | 
| Peak Pain Relief at all timepoints using PRS | Peak Pain relief at each time point will be measured using PRS. The PRS will be used to measure pain relief and is a 5 point categorical scale, response choices of none = 0, a little = 1, some = 2, a lot = 3, and complete = 4 to be completed in response to the question How much relief have you had since your starting pain?. | 0-24hours | 
| Time to onset of analgesia using double stopwatch assessment | Time to onset of analgesia (measured as time to perceptible pain relief confirmed by time to meaningful pain relief) using double stopwatch. Two stopwatches will be started immediately after the subject has swallowed the study drug with 8 ounces of water. Each subject will be instructed, Stop the first stopwatch when you first feel any pain relief whatsoever. This does not mean you feel completely better, although you might, but when you first feel any relief in the pain you have now (perceptible pain relief). The subject will also be instructed, Stop the second stopwatch when you feel the pain relief is meaningful to you (meaningful pain relief). If the subject does not press the stopwatches within 8 hours after Time 0 the subject will discontinue use of the stopwatches. | 0-24 hours | 
| Time to first perceptible pain relief using double stopwatch assessment | Time to first perceptible pain relief using stopwatch assessment. Two stopwatches will be started immediately after the subject has swallowed the study drug with 8 ounces of water. Each subject will be instructed, Stop the first stopwatch when you first feel any pain relief whatsoever. This does not mean you feel completely better, although you might, but when you first feel any relief in the pain you have now (perceptible pain relief). If the subject does not press the stopwatches within 8 hours after Time 0 the subject will discontinue use of the stopwatches. | 0-8 hours | 
| Time to meaningful pain relief using double stopwatch assessment | Time to meaningful pain relief. Two stopwatches will be started immediately after the subject has swallowed the study drug with 8 ounces of water. The subject will be instructed, Stop the second stopwatch when you feel the pain relief is meaningful to you (meaningful pain relief). If the subject does not press the stopwatches within 8 hours after Time 0 the subject will discontinue use of the stopwatches. | 0-8 hours | 
| Time to peak pain relief using PRS | Time to peak pain relief. The PRS will be used to measure pain relief and is a 5 point categorical scale, response choices of none = 0, a little = 1, some = 2, a lot = 3, and complete = 4 to be completed in response to the question How much relief have you had since your starting pain?. | 0-24 hours | 
| Proportion of subjects using rescue medication | Proportion of subjects using rescue medication. | 0-24 hours | 
| Time to first use of rescue medication | Time to first use of rescue medication. | 0-24 hours |