A Randomised, Double-blind, Double-dummy, Parallel-group, Single Dose, Active and Placebo-controlled Efficacy and Pharmacokinetics/Pharmacodynamics Study of 2 x 200 mg Ibuprofen Liquid Capsules 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
- 294
- 试验地点
- 1
- 主要终点
- Summed Pain Intensity Difference 0-8 hours (SPID0-8) vs placebo using the Numeric Rating Scale (NRS) for pain
研究概览
简要总结
This is a single centre, three-arm randomised, double-blind, double-dummy, parallel group, single-dose, active and placebo-controlled efficacy and pharmacokinetics/ pharmacodynamics study to evaluate the efficacy and safety of 2 x 200 mg Ibuprofen Liquid Capsules in subjects with post-operative dental pain.
详细描述
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.
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 a single dose of 2×200 mg Ibuprofen Liquid Capsules, 2×200 mg ibuprofen tablets, or placebo. The randomisation will be stratified by baseline pain category (moderate or severe) using a categorical scale based on the NRS score 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, 10, 20, 30 and 45 minutes, and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10 and 12 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 and satisfaction with pain relied assessment 12 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 hours after Time 0, immediately before the first dose of rescue medication(if required) and at the follow-up visit. 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 12 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.
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 (200mg Ibuprofen Liquid Capsules and 200mg Ibuprofen Tablets) 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
- 16 Years 至 55 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subject has provided written informed consent (for subjects who are below the age of legal consent, parent(s) or legally authorized representative(s) provides written informed consent and the subject provides written assent).
- •Subject is male or female and aged ≥16 and ≤55 years of age at screening.
- •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.
- •Experiences moderate to severe pain intensity within 6 hours after surgery, as measured by a NRS score of ≥ 5 on a 0-10 scale.
- •Has a body weight ≥ 45 kg and a BMI ≥17 kg/m2 and ≤ 30 kg/m
- •Female subjects or the female partners of male subjects of childbearing potential must be using a highly effective method of contraception for at least one month prior to screening, throughout the study and for one menstrual cycle after last drug administration. [A highly effective method of contraception is defined as a method that can achieve a low failure rate of less than 1% per year when used consistently and correctly. Such methods include combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, injectable & implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), vasectomised partner (who has received medical assessment of the surgical success), or sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments and must be the preferred and usual lifestyle of the subject)].
- •Free of clinically significant abnormal findings as determined by medical history, physical examination, vital signs, laboratory tests and ECG.
- •Is willing and able to comply with study requirements (including diet and smoking restrictions), complete the pain evaluations, remain at the study site overnight (if necessary) 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.
- •In the opinion of the investigator, any subject with a clinically relevant history of peptic ulceration, gastrointestinal bleeding or perforation, heart failure, renal or hepatic failure, uncontrolled hypertension, nasal polyps, or chronic rhinitis.
- •In the opinion of the investigator, the participant has a clinically significant history of asthma or a documented intolerance to NSAIDs resulting in exacerbation of symptoms.
- •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 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) or positive alcohol breathalyser test during the study.
- •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.
- •Is a current smoker (including any nicotine products e.g., e-cigarettes or chewing tobacco) or ex-smoker who has smoked or used nicotine replacement products within 1 year of screening
- •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.
- •Those taking medicinal products prone to drug-drug interactions described in the investigator's brochure [IB]. These include Acetyl Salicylic Acid, other NSAIDs including cyclo-oxygenase-2 selective inhibitors, anticoagulants, antihypertensives (ACE inhibitors and Angiotensin II receptor antagonists) and diuretics, corticosteroids, anti-platelet agents and Selective Serotonin Re-uptake Inhibitors (SSRIs), cardiac glycosides, lithium, methotrexate, ciclosporin, mifepristone, tacrolimus, zidovudine and quinolone antibiotics.
- •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 200 mg ibuprofen liquid capsules), 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, including topical), opiates, or corticosteroids (except inhaled nasal steroids), for any condition within 3 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 90 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
Reference Product
Ibuprofen 200mg Oral Tablet, Placebo of Ibuprofen 200mg Oral Liquid Capsule
干预措施: Placebo Liquid Capsule (Other)
Placebo
Placebo of Ibuprofen 200mg Oral Liquid Capsule, Placebo of Ibuprofen 200mg Oral Tablet
干预措施: Placebo Liquid Capsule (Other)
Test Product
Ibuprofen 200mg Oral Liquid Capsule, Placebo of Ibuprofen 200mg Oral Tablet
干预措施: Ibuprofen 200Mg Oral Cap (Drug)
Test Product
Ibuprofen 200mg Oral Liquid Capsule, Placebo of Ibuprofen 200mg Oral Tablet
干预措施: Placebo Tablets (Other)
Reference Product
Ibuprofen 200mg Oral Tablet, Placebo of Ibuprofen 200mg Oral Liquid Capsule
干预措施: Ibuprofen 200Mg Oral Tablet (Drug)
Placebo
Placebo of Ibuprofen 200mg Oral Liquid Capsule, Placebo of Ibuprofen 200mg Oral Tablet
干预措施: Placebo Tablets (Other)
结局指标
主要结局
Summed Pain Intensity Difference 0-8 hours (SPID0-8) vs placebo using the Numeric Rating Scale (NRS) for pain
时间窗: 0-8 hours
SPID0-8 will be used to compare the test product against the placebo product. Pain Intensity Difference (Difference in NRS for baseline and each timepoint) will be plotted against timepoint up to the 8 hour timepoint, the SPID0-8 will be take as the area under the curve. 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.
Time to Meaningful pain relief vs active comparator using double stopwatch method
时间窗: 0-8 hours
Time to onset of meaningful pain relief (measured as time to meaningful pain relief) using double stopwatch will be used to compare the test product with the active comparator. 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.
次要结局
- Time to onset of pain relief using double stopwatch method vs Placebo(0-8 hours)
- Total Pain Relief 0-6 hours (TOTPAR6) for Test Product vs Active Comparator After Time 0(0-6 hours)
- Proportion of subjects using rescue medication vs Placebo(0-6 hours)
- Proportion of subjects using rescue medication vs Active Comparator(0- 6 hours)
- Time to onset of pain relief using double stopwatch method vs Active Comparator(0-8 hours)
- Time to peak pain relief using Pain Relief Scale (PRS) vs active comparator and placebo(0-12 hours)
- PK Subset: AUC0-t will be evaluate for each treatment (test and active comparator)(0-12 hours)
- Minimum Effective Concentration (MEC) for onset of analgesia (SC1) and meaningful pain relief (SC2)- test product (TP) and active comparator (AC), and combined (COM)(10-90mins)
- Total Pain Relief 0-8 hours (TOTPAR8) for Test Product vs Placebo(0-8 hours)
- Pain intensity Score at each scheduled timepoint After Time 0(0-12 hours)
- Pain intensity difference score at each scheduled timepoint after Time 0.(0-12 hours)
- Summed Pain Intensity Difference over 0 to 2 hours (SPID2), test product vs active comparator and test vs against placebo using the Numeric Rating Scale (NRS) for pain.(0-2 hours)
- Proportion of subjects using rescue medication vs Placebo and Active Comparator(0-12 hours)
- Total Pain Relief 0-6 hours (TOTPAR6) for Test Product vs Placebo(0-6 hours)
- Time to first use of rescue medication vs Active Comparator(0-12 hours)
- Proportion of Subjects achieving at least "a lot" of pain relief at 1 and 2 hours post dose vs Placebo and Active Comparator(0-2 hours)
- Proportion of subjects with at least 50% decrease in pain intensity at any time 6 hours after T0 using NRS vs active comparator and placebo(0-6 hours)
- Total Pain Relief 0-2 hours (TOTPAR2) for Test Product vs Active Comparator After Time 0(0-2 hours)
- Total Pain Relief 0-4 hours (TOTPAR4) for Test Product vs Active Comparator After Time 0(0-4 hours)
- Total Pain Relief 0-8 hours (TOTPAR8) for Test Product vs Active Comparator After Time 0(0-8 hours)
- PK Subset: Cmax will be evaluate for each treatment (test and active comparator)(0-12 hours)
- PK Subset: tmax will be evaluate for each treatment (test and active comparator)(0-12 hours)
- Occupancy Time(0-12 hours)
- Time to meaningful pain relief compared to the placebo(0-8 hours)
- Total Pain Relief 0-2 hours (TOTPAR2) for Test Product vs Placebo(0-2 hours)
- Proportion of subjects with "Complete" pain relief at 30 minutes, assessed using PRS, after Time 0 vs Active Comparator and Placebo(0-30 minutes)
- Time to first use of rescue medication vs Placebo(0-12 hours)
- PK Subset: tlag will be evaluate for each treatment (test and active comparator)(0-12 hours)
- Total Pain Relief 0-4 hours (TOTPAR4) for Test Product vs Placebo(0-4 hours)
- Summed Pain Intensity Difference over 0 to 4 hours (SPID4), test product vs active comparator and test vs against placebo using the Numeric Rating Scale (NRS) for pain.(0-4 hours)
- Summed Pain Intensity Difference over 0 to 6 hours (SPID6), test product vs active comparator and test vs against placebo using the Numeric Rating Scale (NRS) for pain(0-6 hours)
- Time to first perceptible pain relief.(0-8 hours)
- Pain relief score at each scheduled time point after Time 0.(0-12 hours)
- Subject's global evaluation of study drug.(0-12 hours)
- Subject satisfaction with pain relief.(0-12 hours)
- Peak pain relief.(0-12 hours)
- Summed pain relief and intensity difference (sum of TOTPAR and SPID [SPRID]) over 0 to 4 hours (SPRID4).(0-4 hours)
- Summed pain relief and intensity difference (sum of TOTPAR and SPID [SPRID]) over 0 to 8 hours (SPRID8).(0-8 hours)
- The summed pain intensity difference (SPID) over 0 to 8 hours (SPID8) will be used to compare the test product and active comparator product.(0-8 hours)
- Proportion of subjects who achieve at least 50% of the maximum TOTPAR (maxTOTPAR) over 0 to 6 hours will be used to compare the test product against active comparator and the placebo(0-6 hours)
- Relationship between speed of onset of pain relief and overall pain over 0-60 minutes.(0-1 hours)
- Relationship between speed of onset of pain relief and time to rescue medication over 0-60 minutes.(0-1 hour)