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

NCT04504812 | Completed Phase 3 DMC FDA Drug

• 2 other identifiers: IRB002386781UG3AR077360-01
• Study Type: interventional
• Target: 1,937
• Locations: 1 country
• Sites: 24

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.

Conditions

Knee Osteoarthritis

Keywords

osteoarthritis; duloxetine; painTRAINER; hyaluronic acid injection; genicular nerve block; radiofrequency ablation

Outcome Measures

Primary Outcomes (1)

• Change in Pain Intensity as assessed by the Modified 4-item Brief Pain Inventory (BPI) Pain Scale

  The Modified 4-item BPI Pain scale consists of 3 items from BPI Pain Intensity and 1 item from BPI Pain Interference. This is a continuous measure that will be calculated as the average of worst, average, current knee pain, and pain upon walking. Change from baseline (BL) will be used in mITT analyses, and change from treatment will be used in per protocol analyses.

  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 (8)

• Change in Pain Interference as assessed by the BPI

  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

• Change in Physical Functioning as assessed by the Knee Injury and Osteoarthritis Outcome Score (KOOS)

  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

• Patient Global impression of Change (PGIC)

  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

• Change in Pain Intensity as assessed by the BPI

  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

• Compare Morphine Milligram Equivalent (MME) doses

  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

Study Arms (6)

Phase 1: Best Practices + Duloxetine

ACTIVE COMPARATOR

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.

Drug: Duloxetine; Other: Best Practices

Phase 1: Best Practices + Duloxetine + Pain coping skills

ACTIVE COMPARATOR

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.

Drug: Duloxetine; Behavioral: Pain Coping Skills Training; Other: Best Practices

Phase 2: Intra-Articular Injection (HA+)

ACTIVE COMPARATOR

Participants will receive an intra-articular injection of hyaluronic acid mixed with steroid and bupivacaine. Phase 2 ended enrollment on October 24, 2024.

Combination Product: Intra-Articular Injection

Phase 2: Nerve Procedure: Long Acting Blocks

ACTIVE COMPARATOR

Participants will receive a nerve blocking procedure, long-acting local anesthetic, and steroid injection. Phase 2 ended enrollment on October 24, 2024.

Procedure: Nerve Procedure with long acting blocks

Phase 2: Nerve Procedure: Nerve Ablation

ACTIVE COMPARATOR

Participants will receive a nerve ablation procedure and steroid injection. Phase 2 ended enrollment on October 24, 2024.

Procedure: Nerve Procedure with nerve ablation

Phase 1: Best Practices

ACTIVE COMPARATOR

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.

Other: Best Practices

Interventions

Duloxetine 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.

Also known as: Cymbalta

Phase 1: Best Practices + Duloxetine; Phase 1: Best Practices + Duloxetine + Pain coping skills

Intra-Articular Injection 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: Intra-Articular Injection (HA+)

Nerve Procedure with long acting blocks 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: Long Acting Blocks

Nerve Procedure with nerve ablation 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 2: Nerve Procedure: Nerve Ablation

Pain Coping Skills Training 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.

Phase 1: Best Practices + Duloxetine + Pain coping skills

Best Practices 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; Phase 1: Best Practices + Duloxetine; Phase 1: Best Practices + Duloxetine + Pain coping skills

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• 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
• 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
• 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

You may not qualify if:

• \<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
• 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)

Sponsors & Collaborators

• Johns Hopkins University: lead
• Pacira Pharmaceuticals, Inc: collaborator
• National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS): collaborator

Study Sites (24)

University of California Davis

Sacramento, California, 95817, United States

Location

University of California San Diego

San Diego, California, 92037, United States

Location

VA Medical Center San Diego

San Diego, California, 92161, United States

Location

University of Colorado

Aurora, Colorado, 80045, United States

Location

University of Florida

Gainesville, Florida, 32608, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

Atlanta VA Medical Center

Decatur, Georgia, 30033, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

University of Iowa

Iowa City, Iowa, 52242, United States

Location

Johns Hopkins

Baltimore, Maryland, 21287, United States

Location

Walter Reed Army Medical Center

Bethesda, Maryland, 20889, United States

Location

Brigham and Women's Hospital

Boston, Massachusetts, 02199, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Weill Cornell University

New York, New York, 10019, United States

Location

University of Rochester Medical Center

Rochester, New York, 14623, United States

Location

University of North Carolina

Chapel Hill, North Carolina, 27599, United States

Location

Wake Forest University

Winston-Salem, North Carolina, 27517, United States

Location

Cleveland VA Medical Center

Cleveland, Ohio, 44106, United States

Location

University Hospitals

Cleveland, Ohio, 44106, United States

Location

Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

Vanderbilt University

Nashville, Tennessee, 37232, United States

Location

University of Utah

Salt Lake City, Utah, 84108, United States

Location

University of Virginia

Charlottesville, Virginia, 22908, United States

Location

University of Washington

Seattle, Washington, 98185, United States

Location

MeSH Terms

Conditions

Osteoarthritis, Knee; Osteoarthritis

Interventions

Duloxetine Hydrochloride; Injections, Intra-Articular; Practice Guidelines as Topic

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases

Intervention Hierarchy (Ancestors)

Thiophenes; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Injections; Drug Administration Routes; Drug Therapy; Therapeutics; Guidelines as Topic; Quality Assurance, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Study Officials

• Steven Cohen, MD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Individuals randomized to a nerve procedure will be blinded to whether they have a long acting block or nerve ablation.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: August 5, 2020
• First Posted: August 7, 2020
• Study Start: February 1, 2021
• Primary Completion: April 8, 2025
• Study Completion: April 8, 2025
• Last Updated: April 9, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: These policies are expected to focus primarily on the timing of data release. The investigators preliminary plan is to release the database (defined below) and supporting information at the time of publication of the primary manuscript, or within 12 months of last patient's final follow-up, whichever comes first. Implementation of the plan will follow the HEAL Public Access and Data Sharing Policy as outlined at https://heal.nih.gov/about/public-access-data.
• Access Criteria: Access to the releasable database housed in the NIH-assigned repository will be in accordance with procedures and regulations of the NIH or specific institute. The data coordinating center will not provide any support for investigators using the releasable database.

Locations

US (24)