A 12-Week, Randomized, Double-Blind, Placebo-Controlled, Randomized-Withdrawal Study to Evaluate the Efficacy and Safety of Hydrocodone Bitartrate Extended-Release Tablets (CEP-33237) at 30 to 90 mg Every 12 Hours for Relief of Moderate to Severe Pain in Patients With Chronic Low Back Pain Who Require Opioid Treatment for an Extended Period of Time
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 625
- 试验地点
- 87
- 主要终点
- Change From Baseline to Week 12 of the Treatment Period in Weekly Average of Daily Worst Pain Intensity (WPI)
研究概览
简要总结
The primary objective of this study is to evaluate the efficacy of hydrocodone bitartrate extended-release tablets at doses of 30 to 90 mg every 12 hours compared with placebo in alleviating moderate to severe pain in patients with chronic low back pain. Patients may be opioid-naïve or opioid-experienced.
详细描述
The study consisted of a screening period of approximately 7 to 14 days, an open label titration period of up to 6 weeks, and a double blind treatment period of 12 weeks.
The objective of the open label titration period was to find the successful dose of hydrocodone extended release (ER) tablets that produced stable pain relief without unacceptable adverse events (AEs). Stable pain relief was defined as an average pain intensity (API) score over the previous 24 hours of 4 or less and a worst pain intensity (WPI) score of 6 or less on the 11-point numerical rating scale (NRS-11) (0=no pain to 10=worst pain imaginable) for either 4 consecutive days or 4 out of 7 consecutive days, while the same dose of study drug was maintained for up to 7 days. Scores for WPI and API were recorded daily in individual patient electronic diaries. Patients returned to the study center prior to each dose adjustment.
The starting dose of hydrocodone ER tablets depended on whether the subject was opioid-naïve or opioid-experienced. Opioid-naïve participants started at a 15-mg dose of hydrocodone ER tablets every 12 hours. For opioid-experienced participants, the starting dose of hydrocodone ER tablets was to be approximately equivalent to 50% of the dose of opioid analgesic that they were receiving at screening and administered every 12 hours. Investigators switched participants from previous opioid therapy to hydrocodone ER tablets on the basis of predefined dose equivalents.
Participants who met the criterion of a stabilized dose were randomly assigned into the 12 week, double-blind, placebo controlled treatment period on the final day of the open label titration period (baseline visit). Participants began treatment with double blind study drug at the effective dose of hydrocodone ER tablets achieved during the titration period or matching placebo. Rescue medication was permitted in addition to the study drug during the double blind treatment period.
Participants who participated in the study in compliance with the protocol and complete 12 weeks of double-blind treatment with study drug, were considered to have completed the study and could have been eligible to enroll in a 6-month open-label study (study C32337/3104, NCT01922739).
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 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •The patient has had moderate to severe chronic low back pain for at least 3 months duration before screening.
- •The patient is able to speak English and is willing to provide written informed consent, including a written opioid agreement, to participate in this study.
- •The patient is willing and able to successfully self-administer the study drug, comply with study restrictions, complete the electronic diary, and return to the study center for scheduled study visits, as specified in the protocol.
- •The patient is 18 through 80 years of age at the time of screening.
- •Women of childbearing potential (not surgically sterile or 2 years postmenopausal) must use a medically accepted method of contraception, agree to continue use of this method for the duration of the study and for 30 days after participation in the study, and have a negative pregnancy test at screening. - Acceptable methods of contraception include barrier method with spermicide, intrauterine device (IUD), or steroidal contraceptive (oral, transdermal, implanted, and injected) in conjunction with a barrier method. NOTE: A woman will be considered surgically sterile if she has had a tubal ligation, hysterectomy, bilateral salpingo-oophorectomy or bilateral oophorectomy, or hysterectomy with bilateral salpingo-oophorectomy.
- •Other criteria apply.
排除标准
- •The patient is taking a total of more than 135 mg/day of oxycodone, or equivalent, during the 14 days before screening.
- •The patient's primary painful condition under study is related to any source of chronic pain other than low back pain.
- •The patient has radicular (nerve compression) pain or another type of purely neuropathic pain.
- •The patient has known or suspected hypersensitivities, allergies, or other contraindications to any ingredient in the study drug.
- •The patient has a recent history (within 5 years) or current evidence of alcohol or other substance abuse, with the exception of nicotine.
- •The patient has medical or psychiatric disease that, in the opinion of the investigator, would compromise collected data.
- •Other criteria apply.
研究组 & 干预措施
Placebo
Participants were administered hydrocodone ER tablets orally at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain during the titration period. During the treatment period, participants were administered placebo tablets twice a day that matched the dosage deemed successful for managing their pain during the titration period. A step-wise, double-blind schedule to tamper off active drug was implemented during the first 2 weeks of the 12-week, double-blind, placebo-controlled treatment period to reduce the risk of withdrawal effects in participants randomly assigned to placebo.
干预措施: Hydrocodone ER (Drug)
Placebo
Participants were administered hydrocodone ER tablets orally at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain during the titration period. During the treatment period, participants were administered placebo tablets twice a day that matched the dosage deemed successful for managing their pain during the titration period. A step-wise, double-blind schedule to tamper off active drug was implemented during the first 2 weeks of the 12-week, double-blind, placebo-controlled treatment period to reduce the risk of withdrawal effects in participants randomly assigned to placebo.
干预措施: Placebo (Drug)
Hydrocodone ER
Participants were administered hydrocodone ER tablets orally at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain during the titration period. During the 12-week, double-blind, placebo-controlled treatment period, participants randomly assigned to hydrocodone ER were administered tablets twice a day at the dosage deemed successful for managing their pain during the titration period.
干预措施: Hydrocodone ER (Drug)
结局指标
主要结局
Change From Baseline to Week 12 of the Treatment Period in Weekly Average of Daily Worst Pain Intensity (WPI)
时间窗: Days -6 to 0 of Treatment Period (baseline), Week 12 of Treatment Period
The WPI was recorded daily by participants in an electronic diary using an 11-point numerical rating scale (NRS-11), a Likert-type scale in which 0=no pain and 10=the worst pain imaginable. Participants selected the number that best described their worst pain intensity over the last 24 hours. Weekly WPI scores averaged daily scores collected over the previous 7 days for each analysis visit. Negative change from baseline scores indicate improvement in pain control. The analysis included WPI data observed before discontinuation of study drug and was based on the multiple imputations (MI) method to handle missing scores at week 12. Consistent with the recommendations of the National Academy of Sciences (NAS) report (Panel on Handling Missing Data in Clinical Trials 2010), the MI method includes an assumption of missing at random (MAR) and takes into account a potential bias toward the active-drug treatment group for patients who discontinued study drug because of adverse events.
次要结局
- Change From Baseline to Week 12 of the Treatment Period in Weekly Average Pain Intensity (API)(Days -6 to 0 of Treatment Period (baseline), Week 12)
- Kaplan-Meier Estimates for Time to Loss of Efficacy(Day 1 to Week 12 of Treatment Period)
- Percentage of Participants With a 30% or Greater Increase in Weekly Average Pain Intensity (API) From Baseline to Week 12 Visit, and an Average API Score of 5 or Higher at Week 12(Days -6 to 0 of Treatment Period (baseline), Week 12)
- Change From Baseline to Final On-Treatment Visit in Roland Morris Disability Questionnaire (RMDQ) Score(Days 7-14 of Titration Period (baseline), Week 12 or end of study visit during the Treatment Period)
- Participants With Adverse Events During Open-Label Titration and Double-Blind Treatment Periods(Day 1 of Titration Period up to Week 12 of Treatment Period (maximum treatment duration was 127 days))
- Participants With Clinically Significant Hearing Changes From Baseline to Final Assessment in Pure Tone Audiometry Test Results(Days 7-14 of Titration Period (baseline), Day 0 of Treatment Period (last day of Titration Period), Week 12 or end of study visit during the Treatment Period)
- Subjective Opiate Withdrawal Scales (SOWS) Total Scores During the Double-Blind Treatment Period(Weeks 1, 2, 4 and Endpoint of the Treatment Period)
- Clinical Opiate Withdrawal Scales (COWS) Total Scores During the Double-Blind Treatment Period(Weeks 1, 2, 4 and Endpoint of the Treatment Period)
- Participants With Potentially Clinically Significant Abnormal Laboratory Values During the Double-Blind Treatment Period(Day 1 up to Week 12 of the Treatment Period)
- Participants With Potentially Clinically Significant Abnormal Vital Sign Values During the Double-Blind Treatment Period(Day 1 to Week 12 of the Treatment Period)
- Participants With Potentially Clinically Significant Abnormal Electrocardiogram Findings During the Double-Blind Treatment Period(Final study visit (week 12 or end of treatment visit))