A Randomized Withdrawal, Active- and Placebo-controlled, Double-blind, Multi-center Phase III Trial Assessing Safety and Efficacy of Oral CG5503 (Tapentadol) PR* in Subjects With Moderate to Severe Chronic Malignant Tumor-related Pain
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 622
- 试验地点
- 71
- 主要终点
- Number of Participants Scored as Responder in Maintenance Phase.
研究概览
简要总结
The purpose of this study will be to determine whether tapentadol (CG5503) is effective and safe in the treatment of chronic tumor related pain compared to placebo. In addition tapentadol (CG5503) will also be compared to morphine controlled release, also referred to as slow release (SR).
*Tapentadol prolonged-release (PR) is the term used in the European Union and is referred to as extended release (ER) in the United States.
详细描述
Normally chronic tumor related pain is controlled when participants receive repeated doses of opioid analgesics. However, opioid therapy is commonly associated with side effects such as nausea, vomiting, sedation, constipation, addiction, tolerance, and respiratory depression. Tapentadol (CG5503), a newly synthesized drug with an prolonged release (PR) formulation, also acts as a centrally acting pain reliever but has 2 mechanisms of action. The aim of this trial is to investigate the effectiveness (level of pain control) and safety (side effects) of tapentadol (CG5503) PR compared with no drug (placebo) and corresponding dose of morphine (an opioid commonly used to treat tumor related pain). This trial is a randomized, double-blind (neither investigator nor patient will know which treatment was received), active- and placebo-controlled, parallel-group, randomized withdrawal design, multicenter trial.
The trial includes a 2 week titration phase starting with either 40 mg morphine (PR) bid (bid = twice daily dosing, one dose in the morning and one dose in the evening) or 100 mg tapentadol (CG5503) PR bid. Based on effectiveness and side effects subjects can up-titrate in steps of 50 mg tapentadol (CG5503 PR) to a maximal dose of 250 mg tapentadol (CG5503) PR bid or 100 mg morphine PR bid. If participants meet the stabilisation criteria at the end of the titration phase they will be re-randomized to either placebo or active treatment and will continue 4 weeks at the last dose level in the maintenance phase. Only participants on tapentadol in the titration phase will be re-randomized to either matching placebo or to tapentadol. To maintain the blinding nature of the trial participants in the morphine arm during the titration phase will also be re-randomized however they will all remain on morphine controlled release in the maintenance phase. Placebo to match tapentadol tablets, as well as placebo to match morphine capsules, will be used to mask the treatment allocation.
Participants will be issued with an electronic diary (eDiary) to capture Numeric Rating Scale (NRS) pain intensities.
Assessments of pain relief include the pain intensity numeric rating scale (NRS) and patient global impression of change (PGIC). Safety evaluations include monitoring of adverse events, physical examinations, clinical laboratory tests and electrocardiograms. Venous blood samples will be collected for the determination of serum concentrations of tapentadol (CG5503).
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)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- •Subjects will be excluded from the study if they have a history of seizure disorder or epilepsy;
- •known history and/or presence of cerebral tumor or cerebral metastases.
- •history of alcohol or drug abuse;
- •uncontrolled hypertension,
- •clinical laboratory values reflecting severe renal insufficiency,
- •moderate or severe hepatic impairment,
- •hepatitis B or C, HIV,
- •inadequate bone marrow reserve
- •currently treated with radiotherapy,
- •pain-inducing chemotherapy,
- •anti-parkinsonian drugs, neuroleptics, monoamine oxidase inhibitors, serotonin norepinephrine reuptake inhibitor (SNRI) or any other analgesic therapy than investigational medication or rescue medication during the trial.
- •selective serotonin reuptake inhibitor (SSRI) treatments are allowed if taken for at least 30 days before the screening period of the study at an unchanged dose.
研究组 & 干预措施
Matching Placebo after Tapentadol in Titration Phase
Oral Tapentadol 100 mg to 250 mg twice daily. Participants randomized to placebo in the maintenance phase received 100 mg tapentadol prolonged release twice daily for 3 days to taper them off the tapentadol dose they had received in the Titration Phase. From the 4th day (Day 18) all participants received matching placebo in the maintenance (i.e. randomized withdrawal) phase.
干预措施: Tapentadol Extended Release (Drug)
Matching Placebo after Tapentadol in Titration Phase
Oral Tapentadol 100 mg to 250 mg twice daily. Participants randomized to placebo in the maintenance phase received 100 mg tapentadol prolonged release twice daily for 3 days to taper them off the tapentadol dose they had received in the Titration Phase. From the 4th day (Day 18) all participants received matching placebo in the maintenance (i.e. randomized withdrawal) phase.
干预措施: Matching Placebo after Tapentadol in the Titration Phase. (Drug)
Morphine Controlled Release
Oral Morphine 40 mg to 100 mg twice daily. Capsule taken orally, twice daily, morning & evening with preferably 12 hours (not less than 6 hours) between doses. Maintenance phase: continuing on dose level established in titration phase.
干预措施: Morphine Sulphate Controlled Release (Drug)
Tapentadol Prolonged Release
Oral Tapentadol 100 mg to 250 mg twice daily. Tablet taken orally, twice daily, morning & evening with preferably 12 hours (not less than 6 hours) between doses.
干预措施: Tapentadol Extended Release (Drug)
结局指标
主要结局
Number of Participants Scored as Responder in Maintenance Phase.
时间窗: Day 18 through Day 43 (End of Maintenance Phase)
A "responder" is a participant in the study that: 1. completed 28 days of the maintenance phase 2. had a numeric rating scale score below 5 on the 11 point scale (where 0 indicates no pain and 10 indicates worst possible pain. This twice daily current pain score was averaged over Day 18 to Day 43. 3. did not use more than 20 mg of rescue medication per day on average in the 28 day maintenance period (from Day 18 to Day 43). A participant that met all 3 of the above-mentioned criteria is counted as a responder, in other words the participant benefited from the assigned drug treatment. A participant that failed to meet only 1 of the 3 criteria is not counted as a responder.
次要结局
- Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Titration Phase in the Morphine Treatment Arm.(Day 1 through Day 14 (End of Titration Phase))
- Use of Rescue Medication in the Titration Phase.(Day 1 through Day 14 (End of Titration Phase))
- Current Pain Intensity Scores, Averaged Per Week, During the Titration Phase in the Tapentadol Arm.(Day 1 through Day 14 (End of Titration Phase))
- Clinical Opioid Withdrawal Score (COWS) at the End of the Maintenance Phase.(Day 43 (End of Maintenance Phase))
- Change in the Patient Assessment of Constipation Symptoms (PAC-SYM) During the Titration Phase(Day 1 (Start of Titration); Day 14 (End of Titration Phase))
- Change in the Patient Assessment of Constipation Symptoms (PAC-SYM) During the Maintenance Phase(Day 15 (Start of Maintenance); Day 43 (End of Maintenance Phase))
- Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Titration Phase in the Tapentadol Treatment Arm.(Day 1 through Day 14 (End of Titration Phase))
- Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Maintenance Phase.(Day 18 through Day 43 (End of Maintenance Phase))
- Current Pain Intensity Scores, Averaged Per Week, During the Titration Phase in the Morphine Arm.(Day 1 through Day 14 (End of Titration Phase))
- Current Pain Intensity Scores, Averaged Per Week by Treatment, During the Maintenance Phase.(Day 15 through Day 43 (End of Maintenance Phase))
- Number of Participants Using Immediate Release Morphine Rescue Medication in the Maintenance Phase(Day 15 through Day 43 (End of Maintenance Phase))
- The Average Mean Total Daily Dose of Rescue Medication.(Day 1 (Start of Titration Phase) through Day 43 (End of Maintenance Phase))
- Changes in the Short Form 36® Health Survey (SF-36®) During the Maintenance Phase.(Day 15 (Start of Maintenance); Day 43 (End of Maintenance Phase))
- Change in the EuroQoL (EQ-5D) Health Status Index (United Kingdom Time Trade-off Value Set) Change From Start of Titration to Endpoint Titration.(Day 1 (Start of Titration); Day 14 (End of Titration Phase))
- Change in the EuroQoL (EQ-5D) Health Status Index (United Kingdom Time Trade-off Value Set) Over Time in the Maintenance Phase for Tapentadol and the Placebo Randomized Withdrawal Treatment Arms.(Day 15 (Start of Maintenance); Day 43 (End of Maintenance Phase))
- Changes in the Short Form 36® Health Survey (SF-36®) During the Titration Phase.(Day 1 (Start of Titration); Day 14 (End of Titration Phase))
- Clinical Opioid Withdrawal Scale (COWS) at the End of the Titration Phase.(Day 14 (End of Titration Phase))
- Health Related Quality of Life: EuroQol-5D Health State Visual Analog Scale (VAS) Titration Phase.(Day 1 (Start of Titration); Day 14 (End of Titration Phase))
- Changes in Health Related Quality of Life: EuroQol-5D Health State Visual Analog Scale (VAS) Maintenance Phase.(Day 15 (Start of Maintenance); Day 43 (End of Maintenance Phase))
- Quality of Sleep (Sleep Questionnaire) in the Titration Phase.(Day 1 (Start of Titration); Day 14 (end of Titration Phase))
- Quality of Sleep (Sleep Questionnaire) During the Maintenance Phase of the Trial.(Day 15 (Start of Maintenance); Day 43 (End of Maintenance Phase))
- Patient Global Impression of Change(Day 43 (End of Maintenance Phase))