Discontinuation vs Continuation of Long-term Opioid Therapy in Suboptimal and Optimal Responders With Chronic Pain

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effect on pain intensity (PI) of structured discontinuation of long-term opioid analgesic therapy compared to continuation of opioid therapy in Suboptimal and Optimal Responders to high-dose, long-term opioid analgesic therapy for chronic low back pain (CLBP).

Detailed Description
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This was a multicenter, randomized, double-blind, placebo-controlled study which consisted of a common Screening Visit for all subjects, then different schedules for Optimal and Suboptimal Responders, followed by a common schedule for the Blinded Structured Opioid Discontinuation Period (BSODP) and Follow-up Period. The original protocol (10 Jan 2016) was amended twice: Amendment 1 (07 Jul 2016) and Amendment 2 (08 Feb 2017). Screening of subjects only started after Amendment 1 approval. Approximately half the subjects were screened under Amendment 1 and half under Amendment 2. The original statistical analysis plan (SAP) was amended twice as well based on the protocol amendments. The current SAP is version 1.3, dated 11 April 2018, which added a section to list the analyses that were not being completed as a result of the premature termination of this study. The duration of the entire study for each subject was approximately 33 to 37 weeks. For Suboptimal Responders: the study duration included Screening Period of up to 3 weeks, Run-in Period of 1 week, Baseline Period of 1 week, Blinded Structured Opioid Discontinuation Period of 24 weeks, and Follow-up Period of 4 weeks. For Optimal Responders: the study duration included Screening Period of up to 3 weeks, Observation Period of 1 week, Taper Period up to 2 weeks, Open Label Titration Period of 3 weeks, Blinded Structured Opioid Discontinuation Period of 24 weeks, and Follow-up Period of 4 weeks. The primary endpoint was the change in the mean Average PI score on the 0-10 Numerical Ratings Scale (NRS) from Baseline to the 1 week period before the Week 12 visit. Data were summarized using descriptive statistics (number of observations [n], mean, standard deviation, median, first and third quartiles, minimum, and maximum for continuous variables; and frequency and percentage for categorical variables). Due to the inability to recruit a sufficient number of subjects over an acceptable period of time, the study was terminated prematurely and efficacy analyses were reduced and only a brief summary of the statistical analyses of the primary endpoint in each group (Suboptimal Responders and Optimal Responders) were performed.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Clinical Trial of Structured Opioid Discontinuation Versus Continued Opioid Therapy in Suboptimal and Optimal Responders to High-dose Long-term Opioid Analgesic Therapy for Chronic Pain.

Conditions
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Opioid-Related Disorders, Opiate Addiction, Narcotic Abuse, Drug Abuse

Intervention / Treatment
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* Drug: Structured discontinuation of opioid therapy (morphine sulfate ER, oxycodone ER, oxymorphone ER)
* Drug: Continuation of opioid therapy (morphine sulfate ER, oxycodone ER, oxymorphone ER)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be male or non-pregnant, non-lactating female aged 18 to 75 years, inclusive. Have a clinical diagnosis of non-radicular CLBP (pain that occurs in an area with boundaries between the lowest rib and the crease of the buttocks) of Class 1 or proximal radicular (above the knee) pain of Class 2 based on the Quebec Task Force Classification for Spinal Disorders (subjects with previous surgery or chronic pain syndrome, i.e., classes 9.2 or 10, will be allowed if their pain does not radiate or radiates only proximally) for a minimum of 12 months and For the Suboptimal Responder group, pain must have been present for at least several hours a day and have an Average PI score of 6-9 on an 11-point NRS within the past 24 hours of screening. For the Optimal Responder group, subjects must have an Average PI score of 1-4 on an 11-point NRS within the past 24 hours of screening. Have been taking ER/LA opioids or immediate release opioids (at least 4 times at day) for at least 12 months. Have been taking one of the 3 index ER opioid drugs around-the-clock at a twice-a-day frequency for at least 3 consecutive months at a total daily dose within the range shown below. Daily Dose Range Morphine sulfate extended-release: 120-540mg Oxycodone extended-release: 80-360mg Oxymorphone extended-release: 40-180mg Be considered, in the opinion of the Investigator, to be in generally good health other than CLBP at screening based upon the results of a medical history, physical examination, 12-lead ECG, and laboratory profile. Speak, read, write, and understand English (to reduce heterogeneity of data), understand the consent form, and be able to effectively communicate with the study staff. Have access to the Internet (to access the patient support program). Voluntarily provide written informed consent. Be willing and able to complete study procedures. Exclusion Criteria: Have any clinically significant condition that would, in the opinion of the Investigator, preclude study participation or interfere with the assessment of pain and other symptoms of CLBP or increase the risk of opioid-related AEs. Have a primary diagnosis of fibromyalgia, complex regional pain syndrome, neurogenic claudication due to spinal stenosis, spinal cord compression, acute nerve root compression, severe or progressive lower extremity weakness or numbness, bowel or bladder dysfunction as a result of cauda equina compression, diabetic amyotrophy, meningitis, diskitis, back pain because of secondary infection or tumor, or pain caused by a confirmed or suspected neoplasm. Have undergone a surgical procedure for back pain within 6 months prior to the Screening Visit. Have had a nerve or plexus block, including epidural steroid injections or facet blocks, within 1 month prior to the Screening Visit or botulinum toxin injection in the lower back region within 3 months prior to screening. Have a history of confirmed malignancy within past 2 years, with exception of basal cell or squamous cell carcinoma of the skin that has been successfully treated. Have uncontrolled blood pressure, i.e., subject has a sitting systolic blood pressure >180 mm Hg or <90 mm Hg, or a sitting diastolic blood pressure >110 mmHg or <40 mm Hg at screening. Have a body mass index (BMI) >45 kg/m2. Anyone with a BMI >40 but <45 will complete a screening tool (STOPBang Questionnaire) to rule out high risk of obstructive sleep apnea. Have clinically significant depression based on a score of ≥20 on the Patient Health Questionnaire (PHQ-8) Have suicidal ideation associated with actual intent and a method or plan in the past year: Yes answers on items 4 or 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS). Have a previous history of suicidal behaviors in the past 5 years: Yes answer (for events that occurred in the past 5 years) to any of the suicidal behavior items of the C-SSRS. Have any lifetime history of serious or recurrent suicidal behavior. (Non-suicidal self-injurious behavior is not a trigger for a risk assessment unless in the Investigator's judgment it is indicated.) Have clinically significant abnormality in clinical chemistry, hematology or urinalysis, including serum glutamic-oxaloacetic transaminase/aspartate aminotransferase or serum glutamic pyruvic transaminase/alanine aminotransferase ≥3 times the upper limit of the reference range or a serum creatinine >2 mg/dL at screening. Have severe enough psychiatric or substance abuse disorder to compromise the subject's safety or scientific integrity of the study. Have on-going litigation associated with back pain or pending applications for workers compensation or disability issues or subjects who plan on filing litigation or claims within the next 12 months; subjects with settled past litigations will be allowed as will subjects who have been on workers compensation or disability claims for at least 3 months. Have used a monoamine oxidase inhibitor within 14 days prior to the start of study medication. Are taking agonist-antagonists (pentazocine, butorphanol or nalbuphine), buprenorphine, methadone, barbiturates, or more than one type of benzodiazepine within 1 month prior to screening. Have a positive urine drug test (UDT) for illicit drugs (including marijuana), non-prescribed controlled substances (opioid or non-opioid), or alcohol at screening. Have taken any investigational drug within 30 days prior to the Screening Visit or are currently enrolled in another investigational drug study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Structured discontinuation opioid therapy Suboptimal Responder<br> | Drug: Structured discontinuation of opioid therapy (morphine sulfate ER, oxycodone ER, oxymorphone ER)<br>* Structured discontinuation of opioid therapy (morphine sulfate ER, oxycodone ER, oxymorphone ER)<br>Drug: Continuation of opioid therapy (morphine sulfate ER, oxycodone ER, oxymorphone ER)<br>* Continuation of opioid therapy (morphine sulfate ER, oxycodone ER, oxymorphone ER)<br>|
| Experimental: Structured discontinuation opioid therapy Optimal responders<br> | Drug: Structured discontinuation of opioid therapy (morphine sulfate ER, oxycodone ER, oxymorphone ER)<br>* Structured discontinuation of opioid therapy (morphine sulfate ER, oxycodone ER, oxymorphone ER)<br>Drug: Continuation of opioid therapy (morphine sulfate ER, oxycodone ER, oxymorphone ER)<br>* Continuation of opioid therapy (morphine sulfate ER, oxycodone ER, oxymorphone ER)<br>|
| Experimental: Continuation of opioid therapy Suboptimal responders<br> | Drug: Structured discontinuation of opioid therapy (morphine sulfate ER, oxycodone ER, oxymorphone ER)<br>* Structured discontinuation of opioid therapy (morphine sulfate ER, oxycodone ER, oxymorphone ER)<br>Drug: Continuation of opioid therapy (morphine sulfate ER, oxycodone ER, oxymorphone ER)<br>* Continuation of opioid therapy (morphine sulfate ER, oxycodone ER, oxymorphone ER)<br>|
| Experimental: Structured Continuation of opioid therapy Optimal responders<br> | Drug: Structured discontinuation of opioid therapy (morphine sulfate ER, oxycodone ER, oxymorphone ER)<br>* Structured discontinuation of opioid therapy (morphine sulfate ER, oxycodone ER, oxymorphone ER)<br>Drug: Continuation of opioid therapy (morphine sulfate ER, oxycodone ER, oxymorphone ER)<br>* Continuation of opioid therapy (morphine sulfate ER, oxycodone ER, oxymorphone ER)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Mean Average Pain Intensity (PI) Score on the 0-10 Numerical Ratings Scale (NRS) | Baseline is defined as the mean of the available Average PI scores on the 0-10 Numerical Ratings Scale (NRS) over the 7-day Baseline Period. For the scheduled post-randomization visits, mean Average Pain Intensity is defined as the means of the respective PI scores over the 7 days preceding the visit. If there is only one daily PI score available, the mean is not calculated, and the data point is considered missing. PI = Pain Intensity. Higher scores indicate more pain intensity; lower scores less pain intensity. Scale range 0-10. | From baseline to the 1 week period prior to the Week 12 visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Mean Average Pain Intensity Score (PI) Score on the 0-10 Numerical Ratings Scale (NRS) | Baseline is defined as the mean of the available Average PI scores on the 0-10 Numerical Ratings Scale (NRS) over the 7-day Baseline Period. For the scheduled post-randomization visits, mean Average Pain Intensity is defined as the means of the respective PI scores over the 7 days preceding the visit. If there is only one daily PI score available, the mean is not calculated, and the data point is considered missing. PI = Pain Intensity. Higher scores indicate more pain intensity; lower scores less pain intensity. Scale range 0-10. | From baseline to weeks 4, 8, 16, 20, and 24 | 
| Number of Suboptimal Responders With Pain Intensity (PI) Score Improvement Relative to Baseline PI Measured on the 0-10 Numerical Ratings Scale (NRS) | Percent pain intensity difference (PID) relative to baseline is defined as 100* ((baseline Average PI - mean Average PI at visit)/baseline Average PI). The percentages are based on number of subjects in the Intent-to-Treat set per treatment group. PI is measured on the Numerical Ratings Scale (NRS). Higher scores indicate more pain intensity; lower scores less pain intensity. Scale range 0-10. This outcome measure applies only to Suboptimal Responders. | Weeks 12 and 24 | 
| Number of Suboptimal Responders With Pain Intensity (PI) Score Worsening Relative to Baseline PI Measured on the 0-10 Numerical Ratings Scale (NRS) | Percent pain intensity difference (PID) relative to baseline is defined as 100* ((baseline Average PI - mean Average PI at visit)/baseline Average PI). The percentages are based on number of subjects in the Intent-to-Treat set per treatment group. PI is measured on the Numerical Ratings Scale (NRS). Higher scores indicate more pain intensity; lower scores less pain intensity. Scale range 0-10. This outcome measure applies only to Optimal Responders. | Weeks 12 and 24 | 
| Change From Baseline on Sleep Quality Measured by Medical Outcomes Study (MOS) | The MOS Sleep Scale is a 12-item questionnaire which measures sleep quality in 7 scales over the past 4 weeks: sleep disturbance, snoring, sleep short of breath or headache, sleep adequacy, sleep somnolence, and 2 sleep problems indexes. In addition, the average hours of sleep over the past 4 weeks is recorded as a raw measure and also coded as an optimal sleep index. The MOS is scored and the sleep scales calculated according to the MOS Sleep Scale User's Manual v1.0 (Spritzer and Hays, 2003). The scores on the dimensions and the sleep indices were converted to a 0-100 scale, with higher scores reflecting more of the attribute implied by the name (e.g. greater sleep disturbance, greater sleep adequacy of sleep). | Weeks 12 and 24 | 
| Participants Sleep Quantity Measured by Medical Outcomes Study (MOS) | Optimal Sleep Index is based on the average number of hours of sleep each night during the past 4 weeks. Index=1 represents 7-8 hours and Index=0 represents < 7 hours or > 8 hours. | 4 weeks prior to baseline and prior to 12 and 24 week visits | 
| Change From Baseline in the Patient Health Questionnaire Depression Scale (PHQ-8) | The PHQ-8 is an 8-item questionnaire that aims at assessing the level of mood of a subject. Each item is scored from 0 = not at all to 3= nearly every day; the total score, which is the sum of the score for each item, can be from 0 to 24. A score ≥10 is considered major depression and ≥20 is severe major depression. | Weeks 12 and 24 | 
| Number of Participants Reporting Major or Severe Major Depression Using Patient Health Questionnaire Depression Scale (PHQ-8) | The PHQ-8 is an 8-item questionnaire that aims at assessing the level of depression of a subject. Each item is scored from 0 = not at all to 3= nearly every day; the total score, which is the sum of the scores for each item, can be from 0 to 24. A score >= 10 is considered major depression and >= 20 is severe major depression. | Baseline, 12 and 24 week visit | 
| Participant Reported Quality of Life Assessment Using EQ-5D-5L Standardized Instrument | The EQ-5D-5L is a self-administered general measure of health outcome applicable to a wide range of health conditions and treatments.The EQ-5D-5L measures quality of life in 5 dimensions: Mobility, Self-care, Usual activities, Pain/discomfort, and Anxiety/depression. Each is rated in 5 levels from no problems/pain/anxiety to being unable/extreme pain/extreme anxiety. The responses for each category are summarized by treatment and visit with frequencies and percentages reporting each level. | Baseline and weeks 12, 24 | 
| Participant Reported Quality of Life Assessment Using Visual Analog Scale (EQ-5D-5L Standardized Instrument) | The EQ-5D-5L is a self-administered general measure of health outcome applicable to a wide range of health conditions and treatments. The visual analog scale (VAS) rates the subject's health on a 0-100 scale from the worst imaginable health state to the best imaginable health state. | Baseline to 12 and 24 week visit | 
| Digit Symbol Substitution Test | Overall neuropsychological function is assessed using the DSST, a test that is sensitive to brain damage, dementia, age, and depression, and is a widely used instrument for measuring the neuropsychological effects of opioid therapy. The digits (1-9) are paired with symbols, and the test consists of matching the symbol for a series of digits as fast as possible. Score is number of correct symbols in 90 seconds. A decrease from baseline detects deterioration in processing speed. An increase from baseline detects improvement in processing speed. | Change from Baseline to 12 and 24 week visit | 
| Patient Global Impression of Change (PGIC) | The Patient Global Impression of Change (PGIC) is a self-administered questionnaire that assesses the participant's level of improvement/worsening from the beginning to the end of treatment. Participants are asked to select the category of change that most closely describes any change experienced in the pain of their painful areas from the beginning of the Blinded Structured Opioid Discontinuation Period to Week 12 and to Week 24. The scale has levels describing change as: very much improved, much improved, minimally improved, no change, minimally worse, much worse, very much worse. | Baseline to 12 and 24 week visit | 
| Sexual Function Measured Using the International Index of Erectile Function (IIEF) for Men and the Female Sexual Function Index (FSFI) for Women | For the International Index of Erectile Function (IIEF)(15-items) each question is scored on a scale of 0 or 1 to 5, with 0 as no sexual attempts, 1 as the highest frequency, and 5 as the lowest, except where 1=1-2, 2=3-4, 3=5-6, 4=7-10 attempts, and 5=11 or more attempts. Missing responses are scored as 0. For the Female Sexual Function Index (FSFI)(19 items) each question is scored on a scale of 0-5 or 1-5. The FSFI examines the following 6 domains with minimum and maximum scores as indicated: desire(1.2-6.0), arousal(0-6.0), lubrication(0-6.0), orgasm(0-6.0), satisfaction(0.8-6.0), and pain(0-6.0). A computational formula sums the scores within each domain and multiplies that sum by a prescribed weighting factor: desire 0.6, arousal 0.3, lubrication 0.3, orgasm 0.4, satisfaction 0.4, pain 0.4. Higher scores indicate greater functionality. The single final score range is 2.0 to 36, which is reported as an average for each group of female study participants as change from baseline. | Change from Baseline to 12 and 24 week visit |