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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 280
- 试验地点
- 1
- 主要终点
- Summed Pain Intensity Difference Over 0 to 12 Hours (SPID12) After Time 0
研究概览
简要总结
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.
详细描述
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 immediate release (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 time points 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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 have been using an acceptable method of contraception for at least 30 days prior to randomisation and be willing to continue use until at least 48 hours post discharge from the clinic.
- •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 without an alternative medical cause).
- •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 follow up 7 (± 2) days after surgery (Day 8 ± 2 days).
排除标准
- •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 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.
- •Subject has received an investigational product or participated in another trial involving a marketed or investigational drug in the 30 days (or for investigational agents with a long half-life, a washout of 5 half-lives) prior to first drug administration (washout period between studies is defined as the period of time elapsed between the last dose of the previous study and first dose for this study), or if the investigator believes that any previous participation in an investigational study would be to the detriment of the safety of the participant or the conduct of the study.
- •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.
研究组 & 干预措施
Prolonged Release Group
2 × 300 mg ibuprofen PR tablets at Hours 0 and 12
2 × placebo of PR tablets at Hours 8 and 16
2 × placebo of IR tablets at Hours 0, 8, 12, and 16
干预措施: Ibuprofen 300 mg Oral Tablet (Drug)
Prolonged Release Group
2 × 300 mg ibuprofen PR tablets at Hours 0 and 12
2 × placebo of PR tablets at Hours 8 and 16
2 × placebo of IR tablets at Hours 0, 8, 12, and 16
干预措施: Placebo of PR tablet (Drug)
Prolonged Release Group
2 × 300 mg ibuprofen PR tablets at Hours 0 and 12
2 × placebo of PR tablets at Hours 8 and 16
2 × placebo of IR tablets at Hours 0, 8, 12, and 16
干预措施: Placebo of IR tablet (Drug)
Immediate Release Group
2 × 200 mg ibuprofen IR tablets at Hours 0, 8, and 16
2 × placebo of IR tablets at Hour 12
2 × placebo of PR tablets at Hours 0, 8, 12, and 16
干预措施: Ibuprofen 200 mg Oral Tablet (Drug)
Immediate Release Group
2 × 200 mg ibuprofen IR tablets at Hours 0, 8, and 16
2 × placebo of IR tablets at Hour 12
2 × placebo of PR tablets at Hours 0, 8, 12, and 16
干预措施: Placebo of PR tablet (Drug)
Immediate Release Group
2 × 200 mg ibuprofen IR tablets at Hours 0, 8, and 16
2 × placebo of IR tablets at Hour 12
2 × placebo of PR tablets at Hours 0, 8, 12, and 16
干预措施: Placebo of IR tablet (Drug)
Placebo Group
2 × placebo of PR tablets at Hours 0, 8, 12, and 16
2 × placebo of IR tablets at Hours 0, 8, 12, and 16
干预措施: Placebo of PR tablet (Drug)
Placebo Group
2 × placebo of PR tablets at Hours 0, 8, 12, and 16
2 × placebo of IR tablets at Hours 0, 8, 12, and 16
干预措施: Placebo of IR tablet (Drug)
结局指标
主要结局
Summed Pain Intensity Difference Over 0 to 12 Hours (SPID12) After Time 0
时间窗: 0-12 hours
SPID12 was used to compare the test product (2 × 300 mg ibuprofen PR tablets) and comparator product (2 × 200 mg ibuprofen IR tablets three times a day \[TID\]) against the placebo product. An 11-point (0-10) numeric rating scale (NRS) for pain was used to assess pain intensity, where a higher score indicates a greater amount of pain. SPID12 was calculated using the summed pain intensity difference (change from Time 0) under the NRS-time curve from 15 minutes through 12 hours calculated using the linear trapezoidal rule and the actual time points, where Time 0 is the time of the first dose of study drug. The minimum value of SPID12 is 0 (no change in pain intensity from Time 0 to 12 hours); the theoretical maximum is 120 (if a patient had a score of 10 \[worst pain intensity\] at baseline, which decreased to 0 \[no pain\] at the next time point and remained at 0 after); a higher SPID12 score indicates a better outcome.
次要结局
- Summed Pain Intensity Difference Over 0 to 4 Hours (SPID4) After Time 0(0-4 hours)
- Summed Pain Intensity Difference Over 0 to 8 Hours (SPID8) After Time 0(0-8 hours)
- Summed Pain Relief and Intensity Difference (Sum of TOTPAR and SPID [SPRID]) Over 0 to 4 Hours (SPRID4) After Time 0(0-4 hours)
- Sum of Total Pain Relief Over 0 to 4 Hours (TOTPAR4) After Time 0(0-4 hours)
- Sum of Total Pain Relief Over 0 to 8 Hours (TOTPAR8) After Time 0(0-8 hours)
- Sum of Total Pain Relief Over 0 to 24 Hours (TOTPAR24) After Time 0(0-24 hours)
- Summed Pain Intensity Difference Over 0 to 24 Hours (SPID24) After Time 0(0-24 hours)
- Sum of Total Pain Relief Over 0 to 12 Hours (TOTPAR12) After Time 0(0-12 hours)
- Summed Pain Relief and Intensity Difference (Sum of TOTPAR and SPID [SPRID]) Over 0 to 8 Hours (SPRID8) After Time 0(0-8 hours)
- Summed Pain Relief and Intensity Difference (Sum of TOTPAR and SPID [SPRID]) Over 0 to 12 Hours (SPRID12) After Time 0(0-12 hours)
- Summed Pain Relief and Intensity Difference (Sum of TOTPAR and SPID [SPRID]) Over 0 to 24 Hours (SPRID24) After Time 0(0-24 hours)
- Number of Subjects With Response to Study Drug(0-8 hours)
- Time to Peak Pain Relief(0-24 hours)
- Numeric Rating Scale (NRS) Pain Intensity Difference (PID) at Each Time Point After Time 0(0-24 hours)
- Pain Relief at Each Scheduled Time Point After Time 0(0-24 hours)
- Time to First Use of Rescue Medication (Median and 95% Confidence Interval)(0-24 hours)
- Number of Subjects Using Rescue Medication(0-24 hours)
- Pain Intensity Score at Each Scheduled Time Point After Time 0(0-24 hours)
- Time to Meaningful Pain Relief(0-8 hours)
- Peak Pain Relief(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(0-24 hours)
- Time to First Perceptible Pain Relief(0-8 hours)
- Time to First Use of Rescue Medication (Hazard Ratios Versus Placebo)(0-24 hours)