Clinical trial NCT02741076: Discontinuation vs Continuation of Long-term Opioid Therapy in Suboptimal and Optimal Responders With Chronic Pain
Official title: 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.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Opioid-Related Disorders
Opiate Addiction
Narcotic Abuse
Drug Abuse
Lead sponsor: Member Companies of the Opioid PMR Consortium
Sponsor class: INDUSTRY
First posted: 2016-04-18
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Be male or non-pregnant, non-lactating female aged 18 to 75 years, inclusive.
2. 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

   1. 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.
   2. 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.
3. Have been taking ER/LA opioids or immediate release opioids (at least 4 times at day) for at least 12 months.
4. 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
   1. Morphine sulfate extended-release: 120-540mg
   2. Oxycodone extended-release: 80-360mg
   3. Oxymorphone extended-release: 40-180mg
5. 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.
6. 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.
7. Have access to the Internet (to access the patient support program).
8. Voluntarily provide written informed consent.
9. Be willing and able to complete study procedures.

Exclusion Criteria:

1. 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.
2. 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.
3. Have undergone a surgical procedure for back pain within 6 months prior to the Screening Visit.
4. 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.
5. 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.
6. 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.
7. 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.
8. Have clinically significant depression based on a score of ≥20 on the Patient Health Questionnaire (PHQ-8)
9. 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).
10. 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.
11. 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.)
12. 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.
13. Have severe enough psychiatric or substance abuse disorder to compromise the subject's safety or scientific integrity of the study.
14. 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.
15. Have used a monoamine oxidase inhibitor within 14 days prior to the start of study medication.
16. Are taking agonist-antagonists (pentazocine, butorphanol or nalbuphine), buprenorphine, methadone, barbiturates, or more than one type of benzodiazepine within 1 month prior to screening.
17. Have a positive urine drug test (UDT) for illicit drugs (including marijuana), non-prescribed controlled substances (opioid or non-opioid), or alcohol at screening.
18. Have taken any investigational drug within 30 days prior to the Screening Visit or are currently enrolled in another investigational drug study.

Primary outcomes:
measure: Change in the Mean Average Pain Intensity (PI) Score on the 0-10 Numerical Ratings Scale (NRS)
timeFrame: From baseline to the 1 week period prior to the Week 12 visit
Secondary outcomes:
measure: Change in Mean Average Pain Intensity Score (PI) Score on the 0-10 Numerical Ratings Scale (NRS)
timeFrame: From baseline to weeks 4, 8, 16, 20, and 24
measure: Number of Suboptimal Responders With Pain Intensity (PI) Score Improvement Relative to Baseline PI Measured on the 0-10 Numerical Ratings Scale (NRS)
timeFrame: Weeks 12 and 24
measure: Number of Suboptimal Responders With Pain Intensity (PI) Score Worsening Relative to Baseline PI Measured on the 0-10 Numerical Ratings Scale (NRS)
timeFrame: Weeks 12 and 24
measure: Change From Baseline on Sleep Quality Measured by Medical Outcomes Study (MOS)
timeFrame: Weeks 12 and 24
measure: Participants Sleep Quantity Measured by Medical Outcomes Study (MOS)
timeFrame: 4 weeks prior to baseline and prior to 12 and 24 week visits
measure: Change From Baseline in the Patient Health Questionnaire Depression Scale (PHQ-8)
timeFrame: Weeks 12 and 24
measure: Number of Participants Reporting Major or Severe Major Depression Using Patient Health Questionnaire Depression Scale (PHQ-8)
timeFrame: Baseline, 12 and 24 week visit
measure: Participant Reported Quality of Life Assessment Using EQ-5D-5L Standardized Instrument
timeFrame: Baseline and weeks 12, 24
measure: Participant Reported Quality of Life Assessment Using Visual Analog Scale (EQ-5D-5L Standardized Instrument)
timeFrame: Baseline to 12 and 24 week visit
measure: Digit Symbol Substitution Test
timeFrame: Change from Baseline to 12 and 24 week visit
measure: Patient Global Impression of Change (PGIC)
timeFrame: Baseline to 12 and 24 week visit
measure: Sexual Function Measured Using the International Index of Erectile Function (IIEF) for Men and the Female Sexual Function Index (FSFI) for Women
timeFrame: Change from Baseline to 12 and 24 week visit
Other outcomes:
Locations:
city: Foley
country: United States
facility: G & L Research
state: Alabama
city: Mobile
country: United States
facility: Horizon Research Partners
state: Alabama
city: Montgomery
country: United States
facility: Healthscan Clinical Trials
state: Alabama
city: Phoenix
country: United States
facility: Center for Pain and Supportive Care
state: Arizona
city: Phoenix
country: United States
facility: The Pain Center of Arizona
state: Arizona
city: Tucson
country: United States
facility: Quality of Life Medical and Research Centers
state: Arizona
city: Carlsbad
country: United States
facility: Coastal Pain and Spinal Diagnostics
state: California
city: Escondido
country: United States
facility: Aviva Research
state: California
city: Irvine
country: United States
facility: Global Clinical Trials
state: California
city: Laguna Woods
country: United States
facility: The Helm Center for Pain Management
state: California
city: Los Angeles
country: United States
facility: Alexander Ford, MD
state: California
city: Los Gatos
country: United States
facility: Samaritan Center for Medical Research
state: California
city: Montclair
country: United States
facility: Catalina Research Institute
state: California
city: Oceanside
country: United States
facility: North Country Clinical Research
state: California
city: Placentia
country: United States
facility: Westview Clinical Research
state: California
city: Pomona
country: United States
facility: Foothills Pain Management Clinic
state: California
city: Sacramento
country: United States
facility: Northern California Research
state: California
city: San Bernardino
country: United States
facility: Breakthrough Clinical Trials
state: California
city: San Francisco
country: United States
facility: Optimus Medical Group
state: California
city: Denver
country: United States
facility: Mountain View Clinical Research
state: Colorado
city: Doral
country: United States
facility: Care Research Center
state: Florida
city: Hialeah
country: United States
facility: Direct Helpers Research Center
state: Florida
city: Hialeah
country: United States
facility: Eastern Research
state: Florida
city: Miami Lakes
country: United States
facility: Empire Clinical Research
state: Florida
city: Miami
country: United States
facility: Finlay Medical Research
state: Florida
city: Miami
country: United States
facility: Future Clinical Research
state: Florida
city: Miami
country: United States
facility: South Florida Clinical Research
state: Florida
city: Plantation
country: United States
facility: Martin E Hale, MD
state: Florida
city: Saint Petersburg
country: United States
facility: Florida Medical Pain Management
state: Florida
city: Tampa
country: United States
facility: Clinical Research of West Florida
state: Florida
city: West Palm Beach
country: United States
facility: Palm Beach Research Center
state: Florida
city: Marietta
country: United States
facility: Georgia Institute for Clinical Research
state: Georgia
city: Marietta
country: United States
facility: Sestron Clinical Research
state: Georgia
city: Blue Island
country: United States
facility: Healthcare Research Network II
state: Illinois
city: South Bend
country: United States
facility: Indiana Pain and Spine Clinic
state: Indiana
city: Overland Park
country: United States
facility: Mid-American Psysiatrists
state: Kansas
city: Shreveport
country: United States
facility: WK River Cities Clinical Research Center
state: Louisiana
city: Watertown
country: United States
facility: MedVadis Research Corporation
state: Massachusetts
city: Troy
country: United States
facility: Oakland Medical Research
state: Michigan
city: Hazelwood
country: United States
facility: Healthcare Research Network
state: Missouri
city: Saint Louis
country: United States
facility: St Louis Clinical Trials
state: Missouri
city: Las Vegas
country: United States
facility: Red Rock Clinical Research
state: Nevada
city: Mooresville
country: United States
facility: OnSite Clinical Solutions
state: North Carolina
city: Winston-Salem
country: United States
facility: Clinical Trials of America
state: North Carolina
city: Winston-Salem
country: United States
facility: The Center for Clinical Research
state: North Carolina
city: Franklin
country: United States
facility: Prestige Clinical Research
state: Ohio
city: Middleburg Heights
country: United States
facility: North Star Medical Research
state: Ohio
city: Oklahoma City
country: United States
facility: Cutting Edge Research Group
state: Oklahoma
city: Oklahoma City
country: United States
facility: Medical Research International
state: Oklahoma
city: Oklahoma City
country: United States
facility: SP Research
state: Oklahoma
city: Downingtown
country: United States
facility: Brandywine Clinical Research
state: Pennsylvania
city: Philadelphia
country: United States
facility: Founders Research Corporation
state: Pennsylvania
city: Spartanburg
country: United States
facility: Carolina Center for Advanced Management of Pain
state: South Carolina
city: Rapid City
country: United States
facility: Healthy Concepts
state: South Dakota
city: Hendersonville
country: United States
facility: Comprehensive Pain Specialists
state: Tennessee
city: Knoxville
country: United States
facility: New Phase Research and Development
state: Tennessee
city: Houston
country: United States
facility: Biopharma Informatic Research Center
state: Texas
city: Houston
country: United States
facility: Coastal Medical Group
state: Texas
city: Salt Lake City
country: United States
facility: Highland Clinical Research
state: Utah
city: Chester
country: United States
facility: Interventional Pain and Spine Specialists
state: Virginia
city: Richmond
country: United States
facility: Healing Hands of Virginia
state: Virginia
Study officials:
References: