A Randomized, Double-blind, Multi-site, Comparator-controlled, Phase III Trial to Evaluate the Efficacy and Safety of a Fixed-dose Combination of Tramadol Hydrochloride and Diclofenac Sodium in Acute Moderate to Severe Pain After Third Molar Extraction
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 1,151
- 试验地点
- 2
- 主要终点
- Pain Relief Expressed as Total Pain Relief (TOTPAR) Over the 4 Hours Post-dose Period (TOTPAR4)
研究概览
简要总结
This study evaluated a new drug fixed-dose combination tablet (FDC) called tramadol/diclofenac at two different strengths (fixed doses of 25 milligrams [mg] of tramadol and of diclofenac or of 50 mg each). Tramadol and diclofenac each relieve pain, but they do so by different mechanisms. They were used alone as comparator drug in this study. Both are marketed drugs and are standard treatment for acute pain, including wisdom tooth removal.
详细描述
The purpose of this study was to demonstrate that the FDC of Tramadol and Diclofenac 50/50 has superior analgesic effect than the monotherapies and that the FDC of Tramadol and Diclofenac 25/25 has non-inferior analgesic effect than the monotherapies. There was an Enrollment Period, a blinded Treatment Period, and a Follow-up Period. Previously used analgesic medication was washed out for at least 24 hours before surgery. The Treatment Period starts on Day 1 with dental surgery and treatment allocation. Treatment was started within 4 hours after the end of surgery if the participant's pain intensity had reached at least 5 points on the 11-point numerical rating scale (NRS). Each participant received 3 doses of one of the four treatments within 24 hours. One fourth of the participants received the fixed-dose combination tablet at a low dose, one fourth at the higher dose, one fourth received 50 mg of the comparator tramadol alone, and one fourth 50 mg of the comparator diclofenac alone.
The first 2 doses of the investigational medicinal product (IMP) were taken at the site, the last dose in an out-patient setting. Participants returned to the site at 24 hours after the first dose. A Follow-up Period included a final visit at the site or a phone call on Day 14 to assess the participant's safety.
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 study used double-blind and double-dummy methods to guarantee the blinding of all personnel involved in the study. Participants, investigators, and all persons involved in the conduct, data management, and analysis of the study were fully blinded to the participant's treatment.
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •The participant has read the informed consent form, has understood the relevant aspects of the clinical study, and grants his/her authorization to participate by signing the informed consent form prior to the inclusion in the clinical study and the performance of any procedure.
- •Male and female participants above 18 years up to 60 years.
- •Female participants of childbearing potential must be practicing an acceptable method of birth control and must have a negative urine pregnancy test at enrollment with confirmation at the Allocation Visit.
- •Participants are in good health, i.e., the medical record, vital signs, physical examination, and laboratory parameter assessments do not show any abnormal deviations impeding the participation in the clinical study.
- •Participants requiring extraction of 3 or more third molars with 2 mandibular impacted third molars.
- •Clinical and radiological diagnosis of impacted lower third molars.
- •Class I and Class II molars according to Pell and Gregory's classification (Gay Escoda et al. 2004).
- •Participants must be able to swallow the IMPs.
- •Exclusion Criteria at Enrollment:
- •Findings in the medical record, vital signs, and/or physical examination demonstrating abnormal conditions of participant's general state of health preventing his/her participation in the clinical study according to the investigator's opinion.
- •Participant unable to speak, read, or write in Spanish language.
- •Clinical laboratory parameters exceed the pre-defined alert ranges (i.e., 1 standard deviation above or below the upper/lower limit of the normal ranges).
- •Known hypersensitivity to the IMPs, the anesthetic to be used during surgery, or to the rescue medication (ibuprofen, ketorolac).
- •Known alcohol or drug abuse in the last 6 months or any history of seizures. Alcohol abuse is defined as the consumption of more than 3 ounces (about 90 milliliters) of liquor or spirits or 18 ounces (about 530 milliliters) of beer per day, for 5 consecutive days during the 6-month period. Drug abuse is defined as the use of any recreational drug for 5 consecutive days during the 6 month period.
- •Participants who take analgesic medication for chronic pain, monoamine oxidase inhibitors, tricyclic antidepressants, neuroleptics, or other drugs that reduce the seizure threshold within 4 weeks of enrollment.
- •Pregnant or lactating women.
- •Participants who received systemic corticosteroids or opioid analgesics less than 2 weeks before surgery.
- •Participants with molars linked to the mandibular canal.
- •Participants requiring immediate dental procedures other than third and fourth molars extraction,
- •Exclusion Criteria at the Allocation Visit:
- •Participant received a long-acting non-steroidal anti-inflammatory drug within 24 hours or 5 times the elimination half-life of that drug prior to surgery, whatever the longer.
- •Participant received any analgesic medication other than short-acting pre-operative or intra-operative anesthetic agents within 24 hours before taking IMPs.
- •Participant received more than 300 mg of lidocaine in total.
- •Participant received any analgesic medication other than the IMPs immediately after the oral surgical procedure was completed.
- •Baseline pain intensity of the participant after oral surgical procedure remains below 5 points on the 11-point NRS.
排除标准
- 未提供
研究组 & 干预措施
Tramadol/Diclofenac 50/50
Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 50 mg/50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction.
干预措施: Tramadol/Diclofenac 50/50 (Drug)
Tramadol/Diclofenac 25/25
Participants received 3 doses of tramadol hydrochloride/diclofenac sodium 25 mg/25 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction.
干预措施: Tramadol/Diclofenac 25/25 (Drug)
Tramadol 50
Participants received 3 doses of tramadol hydrochloride 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction.
干预措施: Tramadol 50 (Drug)
Diclofenac 50
Participants received 3 doses of diclofenac sodium 50 mg over a 24-hour period if they developed acute moderate to severe pain within 4 hours after third molar extraction
干预措施: Diclofenac 50 (Drug)
结局指标
主要结局
Pain Relief Expressed as Total Pain Relief (TOTPAR) Over the 4 Hours Post-dose Period (TOTPAR4)
时间窗: Up to 4 hours after first dose
Pain relief was assessed by the participant at defined time points after the first IMP dose using a 5-point verbal rating scale (VRS) with categories 0 (none), 1 (a little), 2 (some), 3 (a lot), or 4 (complete). Total Pain Relief (TOTPAR4) is a time-weighted summary measure of the total area under the pain relief curve that integrates serial assessments of a participant's pain over the duration of 4 hours after IMP intake. Minimum and maximum values for TOTPAR4 were 0=worst score and 16=best score, a higher score indicates more pain relief.
次要结局
- Time to Achieve a 50 Percent Reduction in Baseline Pain (Pain at Least Half Gone)(Up to 24 hours after first dose)
- Time to Onset of First Perceptible Pain Relief(Up to 8 hours after first dose)
- Subject's Global Evaluation of the Treatment(8 hours after the first dose of IMP or before first intake of rescue medication (whatever the first) and 24 hours after the first dose of IMPs)
- Total Pain Relief at 6 Hours Post-dose (TOTPAR6)(Up to 6 hours after first dose)
- Time to Intake of First Rescue Medication Dose(First dose to 24 hours after first dose)
- Incidence and Type of Adverse Events(Day 1 to Day 14)
- Total Pain Relief at 8 Hours Post-dose (TOTPAR8)(Up to 8 hours after first dose)
- Summed Pain Intensity Difference (SPID) at 4, 6, 8, and 24 Hours Post-dose(Baseline; up to 24 hours after first dose)
- Time to Onset of Meaningful Pain Relief(Up to 8 hours after first dose)