A Sequenced Strategy for Improving Outcomes in People With Knee Osteoarthritis Pain

NCT ID: NCT04504812

Last Updated: 2025-04-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 1937 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-02-01
• Study Completion Date: 2025-04-08

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.

Conditions

Knee Osteoarthritis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Phase 1: Best Practices + Duloxetine

Participants will receive Duloxetine and a prescription for guideline-recommended treatments for knee osteoarthritis, i.e., Best Practices. Best Practices can include topical or oral nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen; physical therapy that may include aquatherapy; integrative treatments such as acupuncture, yoga, or a structured exercise program; and other non-invasive treatments.

Phase 1 ended enrollment on April 12, 2024.

Group Type: ACTIVE_COMPARATOR

Duloxetine

Intervention Type: DRUG

Duloxetine is a drug that is used to improve pain and function in people with knee osteoarthritis (KOA). Duloxetine is approved by the Food and Drug Administration (FDA) for the treatment of depression, anxiety disorder, fibromyalgia, and joint pain. It will be titrated up from 20 or 30mg according to a schedule provided by a study provider.

Best Practices

Intervention Type: OTHER

Best Practices can include topical or oral nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen; physical therapy that may include aquatherapy; integrative treatments such as acupuncture, yoga, or a structured exercise program; and other non-invasive treatments.

Phase 1: Best Practices + Duloxetine + Pain coping skills

Participants will receive Duloxetine, pain coping skills training, and a prescription for guideline-recommended treatments for knee osteoarthritis, i.e., Best Practices. Best Practices can include topical or oral nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen; physical therapy that may include aquatherapy; integrative treatments such as acupuncture, yoga, or a structured exercise program; and other non-invasive treatments.

Phase 1 ended enrollment on April 12, 2024.

Group Type: ACTIVE_COMPARATOR

Duloxetine

Intervention Type: DRUG

Duloxetine is a drug that is used to improve pain and function in people with knee osteoarthritis (KOA). Duloxetine is approved by the Food and Drug Administration (FDA) for the treatment of depression, anxiety disorder, fibromyalgia, and joint pain. It will be titrated up from 20 or 30mg according to a schedule provided by a study provider.

Pain Coping Skills Training

Intervention Type: BEHAVIORAL

Participants will be provided with a written manual that includes login information for the pain coping skills training website. The participants will be expected to log into the system weekly, work through the modules, and participate in skills practice. This intervention will be conducted in combination with best practices and duloxetine.

Best Practices

Intervention Type: OTHER

Best Practices can include topical or oral nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen; physical therapy that may include aquatherapy; integrative treatments such as acupuncture, yoga, or a structured exercise program; and other non-invasive treatments.

Phase 2: Intra-Articular Injection (HA+)

Participants will receive an intra-articular injection of hyaluronic acid mixed with steroid and bupivacaine.

Phase 2 ended enrollment on October 24, 2024.

Group Type: ACTIVE_COMPARATOR

Intra-Articular Injection

Intervention Type: COMBINATION_PRODUCT

Intra-Articular Injection is an injection of 3-6 milliliter (mL) hyaluronic acid (HA) mixed with 1 milliliter (mL) depo methylprednisolone (a steroid) and 2 mL 0.5% bupivacaine (an anesthetic) into the knee.

Phase 2: Nerve Procedure: Long Acting Blocks

Participants will receive a nerve blocking procedure, long-acting local anesthetic, and steroid injection.

Phase 2 ended enrollment on October 24, 2024.

Group Type: ACTIVE_COMPARATOR

Nerve Procedure with long acting blocks

Intervention Type: PROCEDURE

People assigned to receive this will have 1 milliliter (mL) of a long-acting local anesthetic (a.k.a. liposomal bupivacaine or EXPAREL) and steroid injected into the knee.

Phase 2: Nerve Procedure: Nerve Ablation

Participants will receive a nerve ablation procedure and steroid injection.

Phase 2 ended enrollment on October 24, 2024.

Group Type: ACTIVE_COMPARATOR

Nerve Procedure with nerve ablation

Intervention Type: PROCEDURE

People assigned to receive this will have heat applied to destroy the nerve signaling pain in the knee. Steroid will be administered after the procedure to reduce the risk of neuritis.

Phase 1: Best Practices

Participants will receive a prescription for guideline-recommended treatments for knee osteoarthritis, i.e., Best Practices. Best Practices can include topical or oral nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen; physical therapy that may include aquatherapy; integrative treatments such as acupuncture, yoga, or a structured exercise program; and other non-invasive treatments.

Based on the pre-specified stopping rules described in Protocol section 13.2, the DSMB advised ceasing enrollment into Arm 1A (Best Practices). This recommendation was accepted by the sponsor and study investigators. Arm 1A (Best Practices) was closed on 11/29/2023.

Group Type: ACTIVE_COMPARATOR

Best Practices

Intervention Type: OTHER

Best Practices can include topical or oral nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen; physical therapy that may include aquatherapy; integrative treatments such as acupuncture, yoga, or a structured exercise program; and other non-invasive treatments.

Interventions

Duloxetine

Duloxetine is a drug that is used to improve pain and function in people with knee osteoarthritis (KOA). Duloxetine is approved by the Food and Drug Administration (FDA) for the treatment of depression, anxiety disorder, fibromyalgia, and joint pain. It will be titrated up from 20 or 30mg according to a schedule provided by a study provider.

Intervention Type: DRUG

Intra-Articular Injection

Intra-Articular Injection is an injection of 3-6 milliliter (mL) hyaluronic acid (HA) mixed with 1 milliliter (mL) depo methylprednisolone (a steroid) and 2 mL 0.5% bupivacaine (an anesthetic) into the knee.

Intervention Type: COMBINATION_PRODUCT

Nerve Procedure with long acting blocks

People assigned to receive this will have 1 milliliter (mL) of a long-acting local anesthetic (a.k.a. liposomal bupivacaine or EXPAREL) and steroid injected into the knee.

Intervention Type: PROCEDURE

Nerve Procedure with nerve ablation

People assigned to receive this will have heat applied to destroy the nerve signaling pain in the knee. Steroid will be administered after the procedure to reduce the risk of neuritis.

Intervention Type: PROCEDURE

Pain Coping Skills Training

Participants will be provided with a written manual that includes login information for the pain coping skills training website. The participants will be expected to log into the system weekly, work through the modules, and participate in skills practice. This intervention will be conducted in combination with best practices and duloxetine.

Intervention Type: BEHAVIORAL

Best Practices

Best Practices can include topical or oral nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen; physical therapy that may include aquatherapy; integrative treatments such as acupuncture, yoga, or a structured exercise program; and other non-invasive treatments.

Intervention Type: OTHER

Other Intervention Names

Cymbalta

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)

• 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)

• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

NIH

Sponsor Role: collaborator

Pacira Pharmaceuticals, Inc

INDUSTRY

Sponsor Role: collaborator

Johns Hopkins University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Steven Cohen, MD

Role: PRINCIPAL_INVESTIGATOR

Johns Hopkins University

Locations

University of California Davis

Sacramento, California, United States

University of California San Diego

San Diego, California, United States

VA Medical Center San Diego

San Diego, California, United States

University of Colorado

Aurora, Colorado, United States

University of Florida

Gainesville, Florida, United States

Emory University

Atlanta, Georgia, United States

Atlanta VA Medical Center

Decatur, Georgia, United States

Northwestern University

Chicago, Illinois, United States

University of Iowa

Iowa City, Iowa, United States

Johns Hopkins

Baltimore, Maryland, United States

Walter Reed Army Medical Center

Bethesda, Maryland, United States

Brigham and Women's Hospital

Boston, Massachusetts, United States

University of Minnesota

Minneapolis, Minnesota, United States

Weill Cornell University

New York, New York, United States

University of Rochester Medical Center

Rochester, New York, United States

University of North Carolina

Chapel Hill, North Carolina, United States

Wake Forest University

Winston-Salem, North Carolina, United States

Cleveland VA Medical Center

Cleveland, Ohio, United States

University Hospitals

Cleveland, Ohio, United States

Oregon Health and Science University

Portland, Oregon, United States

Vanderbilt University

Nashville, Tennessee, United States

University of Utah

Salt Lake City, Utah, United States

University of Virginia

Charlottesville, Virginia, United States

University of Washington

Seattle, Washington, United States

Countries

United States

Provided Documents

Document Type: Informed Consent Form

View Document

Other Identifiers

1UG3AR077360-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

IRB00238678

Identifier Type: -

Identifier Source: org_study_id