Clinical trial NCT04504812: A Sequenced Strategy for Improving Outcomes in People With Knee Osteoarthritis Pain
Official title: A Sequenced Strategy for Improving Outcomes in People With Knee Osteoarthritis Pain
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Knee Osteoarthritis
Keywords: osteoarthritis
duloxetine
painTRAINER
hyaluronic acid injection
genicular nerve block
radiofrequency ablation
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
Collaborators: name: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
name: Pacira Pharmaceuticals, Inc
First posted: 2020-08-07
Enrollment: 1937
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Using a stepped care model, Phase 1 participants will be randomly assigned to minimally invasive treatments, including best practices, best practices plus duloxetine, and best practices plus duloxetine combined with a web-based pain coping skills training program. Those who note interest in additional treatment following completion of Phase 1, as well as those that are not eligible for Phase 1 treatment, will be randomly assigned to more aggressive procedures: intra-articular hyaluronic acid, steroid and local anesthetic injection, or a nerve procedure that would either include a long acting block or nerve ablation. Interim analyses will be completed for both phases, and pre-specified stopping rules will determine if all study arms will continue. Modified Intention to Treat (mITT) and per protocol analyses will be conducted.
Primary purpose: TREATMENT

Brief summary: There is an urgent public health need to reduce reliance on opioids for effective long-term pain management, particularly in knee osteoarthritis (KOA). This effectiveness trial will compare commonly recommended treatments to reduce pain and functional limitations in KOA.These results will lead to improved patient selection for treatment and inform evidence based guidelines by offering well-tested, effective, non-surgical alternatives.

Detailed description: Knee osteoarthritis (KOA) is one of the leading causes of chronic pain and disability worldwide, affecting over 30% of older adults. It represents a major global health and economic burden to individuals and society. The rates of KOA have more than doubled in the past 70 years and continue to grow sharply, given increases in life expectancy and population body mass index (BMI). Surgery is often employed to treat KOA, but it is associated with a high rate of persistent pain, and is not a permanent solution. Numerous nonsurgical therapies have been advocated to treat pain in patients with KOA yet are not often used in clinical care. The limited pain relief and functional improvement seen in a subset of knee OA sufferers has led to a high rate of opioid use and disability in this population. The overarching goal of this study is to conduct a sequential parallel group randomized controlled trial (RCT) to evaluate the comparative effectiveness of conservative behavioral and non-opioid pharmacological treatments (Phase 1) and, among those that indicate interest in obtaining further treatment and those not eligible for conservative treatment, the benefits of procedural interventions (Phase 2). This study will also evaluate whether clinical and psychosocial phenotypes predict short- and longer-term treatment response. The results of this study will examine the effectiveness of each tested intervention and provide meaningful information regarding effectiveness across key subgroups of participants.

Eligibility criteria: Inclusion Criteria:

* Knee pain score of ≥4 and ≤ 9 on the Modified 4-Item BPI Pain Scale at pre-intervention screening
* Meets at least 1 of the 3 American College of Rheumatology (ACR) Classification criteria for knee osteoarthritis.

ACR criteria are:

1. At least three of the following using history and physical examination: age \>50 years old; morning stiffness \<30 minutes; crepitus on knee motion; bony tenderness; bony enlargement; no palpable warmth
2. At least one of the following using history, physical examination, and radiographic findings + the presence of osteophytes: age \>50 years old; morning stiffness \<30 minutes; crepitus on active motion and osteophytes
3. At least 5 of the following using history, physical examination, and laboratory findings: age \>50 years old; morning stiffness \<30 minutes; crepitus on knee motion; bony tenderness; bony enlargement; no palpable warmth; erythrocyte sedimentation rate (ESR) \<40 mm/hour; Rheumatoid Factor (RF) \<1:40; synovial fluid signs of osteoarthritis

Exclusion Criteria:

* \<18 years of age
* Any inability to complete study procedures, including, but not limited to inadequate resources to mitigate low English language literacy
* Refusal of randomization
* Knee pain exclusions: Pain during an average of \< 4 days per week over the past 3 months; pain in the index knee from a joint disease other than OA (e.g., infectious arthritis, rheumatoid arthritis, spondyloarthropathy)
* Medication exclusions: Report changes in analgesic medication dose within 2 weeks of baseline; oral morphine equivalent dose of \> 90 mg/d at baseline
* Medical condition exclusions: Severe vision or hearing impairment or any signs of cognitive impairment that would prevent comprehension of consent procedures, study measures, or procedures; unstable medical condition that presents an absolute or relative contraindication for participation in both arms (e.g., unstable angina, congestive heart failure); poorly controlled serious psychiatric condition that could prevent full participation or affect outcomes (e.g., suicidal ideation, active psychosis, poorly controlled depression, active substance abuse \[excluding tobacco, caffeine or moderate alcohol use\])
* Knee-specific medical condition exclusions: History of bilateral knee joint replacement arthroplasty total knee arthroplasty (TKA) or TKA in the affected knee; partial replacements may be eligible depending on physician judgment; scheduled joint replacement; history of unilateral TKA and complaints of KOA pain limited to the operated knee; Intra-articular viscosupplementation, steroid injection or arthroscopic surgery in the index knee within 12 weeks of baseline
* Pregnancy by self-report, report of intention to become pregnant (Phase 1), or as determined by urine pregnancy screening (if Standard of Care at site) (Phase 2). Due to the unknown effects of duloxetine on the developing fetus and newborn, and the potential harms of fluoroscopy in pregnancy, women who are pregnant or lactating or intend to get pregnant will not be included in this study. Those of childbearing potential will be asked to use reliable contraception during the course of their participation in the study and to notify the study team if they become pregnant during participation. Definition of reliable birth control will be defined as: Female and male sterilization (female tubal ligation or occlusion, male vasectomy); long-acting reversible contraceptives (LARC) methods (intrauterine devices, hormonal implants); short-acting hormonal methods (pill, mini pills, patch, shot, vaginal ring); barrier methods (condoms, diaphragms, sponge, cervical cap)

Phase 1 specific Exclusion Criteria- An individual who meets any of the following criteria will be excluded from participation in Phase 1 of this study and will be enrolled and randomized directly into Phase 2:

* Known allergic reaction or medical condition that renders an individual unsuitable for Phase 1 study interventions, including closed-angle glaucoma, kidney disease (creatinine clearance \< 30 mL/ min), severe liver disease, known adverse reaction to duloxetine or another selective serotonin-norepinephrine reuptake inhibitor (SNRI), bipolar disorder or mania, high likelihood of drug interactions that could lead to side effects (e.g., serotonin syndrome in people on multiple drugs that inhibit serotonin reuptake including monoamine oxidase (MAO) inhibitors).
* Report failed trial of an adequate dose of duloxetine to relieve KOA symptoms over a 1-month period
* Have tried and failed two of the following: NSAIDS, physical therapy (there are many physical therapies so clinicians should exercise their judgment as to what constitutes 'failed' therapy), or weight loss (need determined by clinician) and refuses participation in Phase 1
* End-stage renal disease
* Unreliable access to the internet on a daily basis, i.e., sufficient access to participate in the study and may include public library access, cafe/coffee shop spaces, access to a friend or neighbor's wifi or hotspot, etc. (reliability determined on a site-by-site basis)

Phase 2 specific exclusion criteria- An individual who meets any of the following is excluded from sequential participation in Phase 1 and then Phase 2, and will instead be randomized as a "solo" recruit into Phase 1:

* Inability to pay for interventions (insurance or otherwise)
* Medical condition exclusions: Untreated coagulopathy that could interfere with Phase 2 interventions; for automated implantable cardioverter-defibrillator that cannot be disabled before radiofrequency ablation (RFA), the investigator can consult cardiology, bioengineering or the device manufacturer before enrolling in phase 2 (i.e. not a definite exclusion criterion)
* Knee specific medical condition exclusions: Current local infection in the knee; ulcers or an open wound in the region of the index knee; underwent an adequate trial of any Phase 2 procedural study intervention in the study knee; severe needle phobia that cannot be addressed pharmacologically

Primary outcomes:
measure: Change in Pain Intensity as assessed by the Modified 4-item Brief Pain Inventory (BPI) Pain Scale
timeFrame: Change from Baseline to 8 weeks post-randomization (mITT) and to 8 weeks post-treatment (per protocol) in Phase 1; Change from Baseline to 12 weeks post-randomization (mITT) and to 12 weeks post-treatment (per protocol) in Phase 2
Secondary outcomes:
measure: Change in Pain Interference as assessed by the BPI
timeFrame: Change from Baseline to 8 weeks post-randomization (mITT) and to 8 weeks post-treatment (per protocol) in Phase 1; Change from Baseline to 12 weeks post-randomization (mITT) and to 12 weeks post-treatment (per protocol) in Phase 2
measure: Change in Physical Functioning as assessed by the Knee Injury and Osteoarthritis Outcome Score (KOOS)
timeFrame: Change from baseline to 8 weeks post-randomization (mITT) and to 8 weeks post-treatment (per protocol) in Phase 1; Change from Baseline to 12 weeks post-randomization (mITT) and to 12 weeks post-treatment (per protocol) in Phase 2
measure: Patient Global impression of Change (PGIC)
timeFrame: 8 weeks post-randomization (mITT) and 8 weeks post-treatment (per protocol) in Phase 1; 12 weeks post-randomization (mITT) and 12 weeks post-treatment (per protocol) in Phase 2
measure: Change in Pain Intensity as assessed by the BPI
timeFrame: Change from baseline to 8 weeks post-randomization (mITT) and to 8 weeks post-treatment (per protocol) in Phase 1; Change from baseline to 12 weeks post-randomization (mITT) and to 12 weeks post-treatment (per protocol) in Phase 2
measure: Compare Morphine Milligram Equivalent (MME) doses
timeFrame: Change from baseline to 8 weeks post-randomization (mITT) and to 8 weeks post-treatment (per protocol) in Phase 1; Change from baseline to 12 weeks post-randomization (mITT) and to 12 weeks post-treatment (per protocol) in Phase 2
measure: Time to receipt of additional treatment for to KOA
timeFrame: Up to 2 years
measure: Treatment response as a binary outcome for Phase 1 and 2 intervention arms using the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) guidelines
timeFrame: Opioid use and pain are measured at all follow-up time points and will be used through Phase1: 8 weeks post-rand. and 8 weeks post-treatment; Phase 2: 12 weeks post-rand. and 8 weeks post-treatment
measure: Treatment response as a binary outcome for Phase 1 and 2 intervention arms based on OARSI-OMERACT guidelines, incorporating changes in opioid dose.
timeFrame: Opioid use and pain assessed up to 2 years. PGIC assessed at main outcome visit (8 and 12 weeks for Phase 1 and Phase 2, respectively). The treatment response categorical outcome will be analyzed separately for mITT and per- protocol analyses.
Other outcomes:
Locations:
city: Sacramento
country: United States
facility: University of California Davis
state: California
city: San Diego
country: United States
facility: University of California San Diego
state: California
city: San Diego
country: United States
facility: VA Medical Center San Diego
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Decatur
country: United States
facility: Atlanta VA Medical Center
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Baltimore
country: United States
facility: Johns Hopkins
state: Maryland
city: Bethesda
country: United States
facility: Walter Reed Army Medical Center
state: Maryland
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: New York
country: United States
facility: Weill Cornell University
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland VA Medical Center
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Seattle
country: United States
facility: University of Washington
state: Washington
Study officials:
affiliation: Johns Hopkins University
name: Steven Cohen, MD
role: PRINCIPAL_INVESTIGATOR
References: