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

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ClinicalTrials.gov Identifier: NCT03785756
Recruitment Status : Recruiting
First Posted : December 24, 2018
Last Update Posted : August 29, 2019
Sponsor:
Collaborator:
Premier Research Group plc
Information provided by (Responsible Party):
Reckitt Benckiser Healthcare (UK) Limited

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Pain Drug: Ibuprofen 300 mg Oral Tablet Drug: Ibuprofen 200 mg Oral Tablet Other: Placebo of PR tablet Other: Placebo of IR tablet Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 280 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: This is a double-blind, double dummy study. There will be two placebo tablets designed to be comparable to each of the active products (PR and Immediate Release (IR)) in both shape, size, colour and weight. All subject packs have been designed and labelled to ensure blinding is maintained. Subjects, investigators and site staff will all be blind to the treatments.
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : April 29, 2019
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Prolonged Release Group
Ibuprofen 300 mg Oral Tablet Placebo of IR tablet Placebo of PR tablet
Drug: Ibuprofen 300 mg Oral Tablet
2 x 300 mg tablets twice in 24 hours
Other Name: Prolonged Release Tablet

Other: Placebo of PR tablet
Up to 2 tablets four times in 24 hours

Other: Placebo of IR tablet
Up to 2 tablets four times in 24 hours

Active Comparator: Immediate Release Group
Ibuprofen 200 mg Oral Tablet Placebo of IR tablet Placebo of PR tablet
Drug: Ibuprofen 200 mg Oral Tablet
2 x 200 mg tablets three times in 24 hours
Other Name: Nurofen, Immediate Release Tablet

Other: Placebo of PR tablet
Up to 2 tablets four times in 24 hours

Other: Placebo of IR tablet
Up to 2 tablets four times in 24 hours

Placebo Comparator: Placebo Group
Placebo of IR tablet Placebo of PR tablet
Other: Placebo of PR tablet
Up to 2 tablets four times in 24 hours

Other: Placebo of IR tablet
Up to 2 tablets four times in 24 hours




Primary Outcome Measures :
  1. Summed Pain Intensity Difference 0-12 hours (SPID12) vs placebo using the Numeric Rating Scale (NRS) for pain [ Time Frame: 0-12 hours ]
    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.


Secondary Outcome Measures :
  1. Summed Pain Intensity Difference 0-24 hours (SPID24) vs active comparator using the NRS for pain [ Time Frame: 0-24 hours ]
    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.

  2. Summed Pain Intensity Difference 0-4hours (SPID4) using NRS for pain [ Time Frame: 0-4 hours ]
    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.

  3. Summed Pain Intensity Difference 0-8 hours (SPID8) using NRS for pain [ Time Frame: 0-8 hours ]
    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.

  4. Summed Pain Intensity Difference 0-12 hours (SPID12) using NRS for pain [ Time Frame: 0-12 hours ]
    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.

  5. Sum of Total Pain Relief 0-4 hours (TOTPAR4) using Pain Relief Scale (PRS) [ Time Frame: 0-4 hours ]
    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?".

  6. Sum of Total Pain Relief 0-8 hours (TOTPAR8) using PRS [ Time Frame: 0-8 hours ]
    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?".

  7. Sum of Total Pain Relief 0-12 hours (TOTPAR12) using PRS [ Time Frame: 0-12 hours ]
    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?".

  8. Sum of Total Pain Relief 0-24 hours (TOTPAR24) using PRS [ Time Frame: 0-24 hours ]
    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?".

  9. Summed pain relief and intensity difference (sum of TOTPAR and SPID [SPRID]) 0-4 hours (SPRID4) using PRS and NRS for pain. [ Time Frame: 0-4 hours ]
    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.

  10. Summed pain relief and intensity difference 0-8 hours (SPRID8) using PRS and NRS for pain [ Time Frame: 0-8 hours ]
    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.

  11. Summed pain relief and intensity difference 0-12 hours (SPRID12) using PRS and NRS for pain [ Time Frame: 0-12 hours ]
    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.

  12. Summed pain relief and intensity difference 0-24 hours (SPRID24) using PRS and NRS for pain [ Time Frame: 0-24 hours ]
    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.

  13. Proportion of participants who show response to study drug using NRS for pain [ Time Frame: 0-8 hours ]
    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.

  14. NRS (for pain) Pain Intensity Difference at each timepoint [ Time Frame: 0-24 hours ]
    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.

  15. Peak Pain intensity score using NRS for pain [ Time Frame: 0-24 hours ]
    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.

  16. Pain relief score using Pain Relief Scale [ Time Frame: 0-24hours ]
    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?".

  17. Peak Pain Relief at all timepoints using PRS [ Time Frame: 0-24hours ]
    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?".

  18. Time to onset of analgesia using double stopwatch assessment [ Time Frame: 0-24 hours ]
    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.

  19. Time to first perceptible pain relief using double stopwatch assessment [ Time Frame: 0-8 hours ]
    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.

  20. Time to meaningful pain relief using double stopwatch assessment [ Time Frame: 0-8 hours ]
    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.

  21. Time to peak pain relief using PRS [ Time Frame: 0-24 hours ]
    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?".

  22. Proportion of subjects using rescue medication [ Time Frame: 0-24 hours ]
    Proportion of subjects using rescue medication.

  23. Time to first use of rescue medication [ Time Frame: 0-24 hours ]
    Time to first use of rescue medication.


Other Outcome Measures:
  1. Incidence of Treatment Emergent Adverse Events as assessed by patient response to questions and spontaneous reporting of TEAEs [ Time Frame: 0-10 days ]
    Incidence of treatment emergent adverse events (TEAEs). Data listings will be provided for protocol specified safety data.

  2. Vital signs measurements - Blood pressure in mm/Hg [ Time Frame: 0-10 days ]
    Incidence of changes in vital sign measurements. Descriptive statistics will be provided at each scheduled time point for each treatment group. Changes from Baseline for vital signs will be calculated for each subject.

  3. Vital signs measurements - Heart rate in beats per minute [ Time Frame: 0-10 days ]
    Incidence of changes in vital sign measurements. Descriptive statistics will be provided at each scheduled time point for each treatment group. Changes from Baseline for vital signs will be calculated for each subject.

  4. Vital signs measurements - Respiratory rate in breaths per minute [ Time Frame: 0-10 days ]
    Incidence of changes in vital sign measurements. Descriptive statistics will be provided at each scheduled time point for each treatment group. Changes from Baseline for vital signs will be calculated for each subject.

  5. Vital signs measurements - Body Temperature in ºC [ Time Frame: 0-10 days ]
    Incidence of changes in vital sign measurements. Descriptive statistics will be provided at each scheduled time point for each treatment group. Changes from Baseline for vital signs will be calculated for each subject.

  6. Global Evaluation of efficacy using 5 point categorical scale [ Time Frame: 0-24 hours ]
    Patient's global evaluation of study drug using 5 point categorical scale, response choices of 0 = poor, 1 = fair, 2 = good, 3 = very good, or 4 = excellent to be completed by the patient in response to the question "How effective do you think the study drug is as a treatment for pain?". Subjects will complete the global evaluation of study drug 24 hours after Time 0 or immediately before the first dose of rescue medication (whichever occurs first).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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:

    1. surgical sterilisation
    2. contraceptive implants or injectables
    3. combined oral contraceptives
    4. some intrauterine devices (IUDs)
    5. 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
    6. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03785756


Contacts
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Contact: Paul Brittain, M.P.H +15128526917 paul.brittain@premier-research.com

Locations
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United States, Utah
JBR Clinical Research Recruiting
Salt Lake City, Utah, United States, 84107
Contact: Todd M Bertoch, MD    928-830-7354    tbertoch@jbrutah.com   
Principal Investigator: Todd M Bertoch, MD         
Sponsors and Collaborators
Reckitt Benckiser Healthcare (UK) Limited
Premier Research Group plc
Investigators
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Principal Investigator: Todd Bertoch, MD JBR Clinical Research
Additional Information:
Publications:
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Responsible Party: Reckitt Benckiser Healthcare (UK) Limited
ClinicalTrials.gov Identifier: NCT03785756    
Other Study ID Numbers: 5003601
First Posted: December 24, 2018    Key Record Dates
Last Update Posted: August 29, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Tooth, Impacted
Tooth Diseases
Stomatognathic Diseases
Ibuprofen
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action