Subcutaneous Tirzepatide Once-weekly in Patients With Obesity and Knee Osteoarthritis (STOP KNEE-OA) (STOP KNEE-OA)

Effect of Subcutaneous Tirzepatide Once-weekly in Patients With Obesity and Knee Osteoarthritis (STOP KNEE-OA): A Randomized, Double-Blind, Placebo-Controlled Trial

This is a trial of tirzepatide in people with obesity and knee osteoarthritis. The main purpose of this study is to see if tirzepatide can reduce number of these participants who require a knee replacement. Participants will be randomized to take a weekly injection of tirzepatide or a placebo for a total of 72 weeks.

Study Overview

• Status: Not yet recruiting
• Conditions: Obesity; Knee Osteoarthritis; Osteoarthritis, Knee
• Intervention / Treatment: Drug: Tirzepatide; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 352
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Angela Cochrane; Phone Number: 2364 +61392312364; Email: angela.cochrane@svha.org.au
• Study Contact Backup: Name: Michelle M Dowsey; Phone Number: 3955 +61392313955; Email: mmdowsey@unimelb.edu.au

Study Locations

• Australia
  • Victoria
    • Fitzroy, Victoria, Australia, 3065
      • St Vincent's Hospital Melbourne
      • Contact: Angela Cochrane; Phone Number: 2364 +61392312364; Email: angela.cochrane@svha.org.au
      • Contact: Michelle M Dowsey, PhD; Phone Number: 3955 +61392313955; Email: mmdowsey@unimelb.edu.au

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Have a body mass index of ≥ 30 kg/m2.
• Report one or more previous unsuccessful attempt to lose body weight via lifestyle modification.
• Have been deemed eligible to enter the waiting list for primary knee replacement for the treatment of osteoarthritis in the target joint by an orthopaedic surgeon at one of the participating study sites.
• Have moderate-to-severe knee osteoarthritis in the target joint.
• Be willing to and capable of learning how to self-inject the study drug and follow study procedures for the duration of the trial.
• Provide informed consent to study participation in line with the requirements of the human research ethics committee of the study site.

Female participants must either:

• Not be of reproductive potential, defined as:

• Infertile due to surgical sterilization or congenital anomaly, OR

• Post-menopausal defined as:

  • A woman over the age of 40 years with spontaneous cessation of menses for at least 12 consecutive months (in the absence of medications known to induce amenorrhea), with a follicle-stimulating hormone ≥40mIU/mL, and a negative pregnancy test prior to study entry, OR
  • A woman over the age of 55 years with cessation of menses for at least 12 consecutive months (in the absence of medications known to induce amenorrhea), OR
  • A woman over the age of 55 years that has commenced hormone replacement therapy after a documented diagnosis of menopause.

OR

• Be of reproductive potential, and:

• Test negative for pregnancy on the initial screening visit via a serum pregnancy test, AND
• Use at least two effective forms of contraception, if sexually active, for the duration of the trial and until one month after the last injection of the study drug AND
• Not be breastfeeding.

Exclusion Criteria:

• Have been deemed eligible to enter the waiting list for knee replacement in the contralateral knee by an orthopaedic surgeon at one of the participating study sites.
• Have used any prescription medications intended to promote weight loss (e.g., tirzepatide, liraglutide, semaglutide) in the three months prior to screening.
• Have previously undergone any surgical or endoscopic procedure intended to promote weight loss.
• Have been diagnosed with type 1 diabetes mellitus (T1DM) or T2DM
• Have laboratory evidence indicative of diabetes mellitus during screening.
• Have personal or family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
• Have an active malignancy (excluding basal or squamous cell skin cancer).
• Have had a transplanted organ or awaiting an organ transplant
• Have evidence of a significant, active autoimmune abnormality (e.g., lupus or rheumatoid arthritis)

• Have any other medical conditions, abnormal laboratory tests or concomitant medications that make them unsuitable for participation:

  • Have a clinically significant gastric emptying abnormality.
  • Have had a history of acute or chronic pancreatitis.
  • Have obesity induced by other endocrinologic disorders
  • Have an unstable psychiatric disorder
  • Have uncontrolled hypertension (systolic blood pressure above or equal to 160 mmHg and/or diastolic blood pressure above or equal to 100 mmHg)
  • Have had within the past 6 months prior to randomisation any of the following: acute myocardial infarction, cerebrovascular accident, unstable angina, or hospitalisation due to congestive cardiac failure (are also exclusion criteria for elective knee replacement)
  • Have renal impairment as measured by a serum Creatinine of ≥0.3 mg/dL (≥26.5 μmol/L) at screening visit
  • Have thyroid-stimulating hormone outside of the range of 0.4 to 6.0 mIU/L at screening visit
  • Have acute or chronic hepatitis or abnormal liver function tests as measured by either alanine aminotransferase or alkaline phosphatase >200 IU.
  • Have a calcitonin level at Visit 1 of: ≥20 ng/L with eGFR ≥60 mL/min/1.73 m2, or ≥35 ng/L with eGFR <60 mL/min/1.73 m2.
  • Have any other known contraindication to any glucagon-like peptide-1 receptor agonists.
• Are study site personnel, or immediate family of a member of the study site.
• Have been enrolled in any other study of an investigational product within the past ninety days or are currently enrolled in such a study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tirzepatide; Drug: Tirzepatide is a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1receptor (GLP1R) agonist Dose: Tirzepatide will be initiated at 2.5mg once weekly, with the dose increasing by a further 2.5mg every four weeks until the target weekly dose of 15mg is achieved (or participants reach a lower maximum tolerated dose of 5mg or 10mg). Duration: 72-weeks Mode: subcutaneous	Drug: Tirzepatide; Participants will receive tirzepatide subcutaneously
Placebo Comparator: Placebo; Drug: Placebo Dose: once-weekly Duration: 72 weeks Mode: subcutaneous	Drug: Placebo; Participants will receive placebo subcutaneously

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of patients who undergo knee replacement in the target joint	Percentage of patients who undergo knee replacement in the target joint	within 72 weeks of randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage change in bodyweight	Mean percentage change in body weight at 72 weeks after randomization	Baseline, Week 72
≥5% body weight reduction	Percentage of participants with ≥5% body weight reduction at 72 weeks after randomization	Baseline, Week 72
≥10% body weight reduction	Percentage of participants with ≥10% body weight reduction at 72 weeks after randomization	Baseline, Week 72
≥20% body weight reduction	Percentage of participants with ≥20% body weight reduction at 72 weeks after randomization	Baseline, Week 72
Non-opioid prescription pain medication use	Proportion of participants reporting use of non-opioid prescription analgesics between 68-72 weeks after randomization	Baseline, between 68-72 weeks
Opioid prescription pain medication use	Proportion of participants reporting use of prescription opioid analgesics between 68-72 weeks after randomization	Baseline, between 68-72 weeks
Mean change in use of prescription opioid pain medication	Mean change in prescription opioids dose at 72 weeks after randomization	Baseline, between 68-72 weeks
Participant willingness to undergo knee replacement surgery	Proportion of patients who undergo knee replacement in the target joint within 72 weeks of randomization or re-enter the waiting list within 72 weeks of randomization.	within the 72 weeks since randomization
Long-term (5-year) progression to knee replacement	Percentage of patients who undergo knee replacement in the target joint within 5-years	within 260 weeks of randomization
Long-term (10-year) progression to knee replacement	Percentage of patients who undergo knee replacement in the target joint within 10-years	within 520 weeks of randomization
Osteoarthritis Pain	Change from Baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscale Score. The WOMAC Pain subscale has 5-items, with a possible score range of 0-20, with higher scores indicating worse pain.	Baseline, Week 72
Osteoarthritis Function	Change from Baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Function Subscale Score. The WOMAC Function subscale has 17-items, with a possible range of 0-68, with higher scores indicating worse functional impairment.	Baseline, Week 72
Osteoarthritis Stiffness	Change from Baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Stiffness Subscale Score. The WOMAC Stiffness subscale has 2-items, with a possible range of 0-8, with higher score indicating worse stiffness.	Baseline, Week 72
Physical Health	Mean change in the 12-item Short Form (SF-12) Physical Component Summary at 72 weeks after randomization. The SF-12 Physical Component Summary has a score range of 24.00-56.58, with a lower score indicating poorer physical health.	Baseline, Week 72
Mental Health	Mean change in the 12-item Short Form Survey (SF-12) Mental Component Summary at 72 weeks after randomization. The SF-12 Mental Component Summary has a score range of 19.06-60.76, with a lower score indicating poorer mental health.	Baseline, Week 72
Physical Activity	Mean change in Physical Activity Scale for the Elderly (PASE) score at 72 weeks after randomization. The PASE has 12-items with a total score range from 0-400 or more, with higher scores indicating greater physical activity.	Baseline, Week 72

Collaborators and Investigators

• Sponsor: University of Melbourne
• Collaborators: Eli Lilly and Company
• Investigators: Principal Investigator: Michelle M Dowsey, University of Melbourne

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2024
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): May 1, 2037

Study Registration Dates

• First Submitted: December 18, 2023
• First Submitted That Met QC Criteria: December 18, 2023
• First Posted (Actual): January 5, 2024

Study Record Updates

• Last Update Posted (Estimated): January 15, 2024
• Last Update Submitted That Met QC Criteria: January 11, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Obesity; Osteoarthritis; Total knee replacement
• Additional Relevant MeSH Terms: Overnutrition; Nutrition Disorders; Overweight; Body Weight; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Obesity; Osteoarthritis; Osteoarthritis, Knee; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Tirzepatide
• Other Study ID Numbers: 75430

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Anonymized individual patient level data will be provided in a secure access environment upon approval by the principal investigator of a research proposal and a signed data sharing agreement.
• IPD Sharing Time Frame: Data are available 6 months after the primary results publication. Data will be indefinitely available for requesting
• IPD Sharing Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes