The Osteoarthritis Prevention Study (TOPS)

The goal of this study is to establish the efficacy of an intervention of dietary weight loss, exercise, and weight-loss maintenance for knee Osteoarthritis (OA) prevention in adult females aged ≥ 50 years with obesity and no or infrequent knee pain. The primary aim is to compare the effects of a dietary weight loss, exercise, and weight-loss maintenance to an attention control group in preventing the development of structural Magnetic Resonance Imaging (MRI) knee OA. Secondary aims will determine the intervention effects on pain, mobility, health-related quality of life, knee joint compressive forces, inflammatory measures, weight loss, exercise self-efficacy, and cost-effectiveness of this intervention.

Study Overview

• Status: Recruiting
• Conditions: Osteoarthritis, Knee
• Intervention / Treatment: Behavioral: Diet and Exercise

Detailed Description

Osteoarthritis (OA), the leading cause of disability among adults, is without a cure and is associated with significant comorbidities. OA ranks as the third most common diagnosis for hospital inpatient stays with 1.25 M per year, with the knee the most commonly affected weight-bearing joint. This study will address knee OA disease prevention in adult females because prevention of OA is preferable to treatment, females are affected at nearly twice the rate as males, and to date interventions designed to slow or stop knee OA progression have failed. Dietary weight loss, with and without exercise, has level 1 evidence of effective treatment for adults with knee OA and overweight and obesity. Reduced degenerative cartilage changes are also associated with weight loss, making it a possible preventive therapy for people at risk for knee OA. The objective of this Phase III, multi-site (Boston, MA, Chapel Hill, NC, Sydney, Australia, and Winston-Salem, NC) randomized clinical trial is to establish the efficacy of an intervention of dietary weight loss, exercise, and weight-loss maintenance for knee OA prevention. We will establish efficacy in structural, symptomatic, and mechanistic outcomes compared to attention control, and determine the cost-effectiveness of this non-pharmacologic, non-surgical intervention in preventing incident knee OA in adult females aged ≥ 50 years with obesity and no or infrequent knee pain, a cohort at high risk for knee OA.

Participants will be 1,230 ambulatory, community dwelling females with obesity (BMI ≥ 30 kg/m2), and aged ≥ 50 years. Structural and symptomatic eligibility will be determined at the individual knee level. The eligible knee will have no radiographic (Kellgren Lawrence (KL) score ≤ 1) and no MRI knee OA with no or infrequent knee pain (< 15 days/month) in the same knee. The primary aim is to compare the effects of a 48-month intervention of dietary weight loss, exercise, and weight-loss maintenance to an attention control group in preventing the development of structural (MRI) knee OA using the MRI OA Knee Score (MOAKS). Secondary aims will determine the intervention effects on the Knee Injury and Osteoarthritis Outcome Score (KOOS) pain, mobility (6 minute walk distance), and health-related quality of life (SF-36). Mechanistic secondary outcomes include knee joint compressive forces as a measure of joint loading, IL-6 as an inflammatory measure, and weight loss and exercise self-efficacy. A cost-effectiveness analysis will establish the value of the 48-month D+E (diet and exercise) intervention.

This study is significant in that it will test a critically needed primary prevention intervention of dietary weight loss, exercise, and weight-loss maintenance for females at risk for the development of knee OA designed to reduce incident structural knee OA compared to an attention control group, and intended to maximize health benefits at a reasonable cost.

• Study Type: Interventional
• Enrollment (Estimated): 1230
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jovita Newman; Phone Number: 336-758-3969; Email: jollajk@wfu.edu

Study Locations

• Australia
  • Sydney, Australia
    • Not yet recruiting
    • University of Sydney
    • Contact: Vicky Duong; Phone Number: +61 2 9926 4928; Email: vicky.duong@sydney.edu.au
    • Contact: Karen Bracken; Phone Number: +61 2 9926 4928; Email: karen.bracken@sydney.edu.au
    • Principal Investigator: David Hunter, MBBS, Ph.D., MSc
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Brigham and Women's Hospital
      • Principal Investigator: Elena Losina, Ph.D.
      • Contact: Annie Holleman; Phone Number: 617-525-9727; Email: aholleman@bwh.harvard.edu
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27516
      • Recruiting
      • University of North Carolina at Chapel Hill
      • Principal Investigator: Leigh Callahan, Ph.D.
      • Contact: Cortney Armitano-Lago; Phone Number: 919-962-2025; Email: Cortney_Lago@med.unc.edu
    • Winston-Salem, North Carolina, United States, 27109
      • Recruiting
      • Wake Forest University
      • Contact: Jovita Newman; Phone Number: 336-758-3969; Email: jollajk@wfu.edu
      • Principal Investigator: Shannon Mihalko, Ph.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Female
• BMI ≥ 30 kg/m2
• An eligible knee will have no OA by xray and MRI
• No or infrequent knee pain (< 15 days/month) in the same knee

Exclusion Criteria:

• symptomatic or severe coronary artery disease
• unable to walk without a device
• blindness
• type 1 diabetes
• active treatment for cancer
• during the past 12 months knee fracture, anterior cruciate ligament (ACL), medial collateral ligament (MCL), or meniscus injury with or without surgical repair
• knee injection during the past 6 months
• bilateral knee OA by x-ray Kellgren-Lawrence (KL) ≥ 2
• bilateral knee OA by MRI
• bilateral symptomatic knee OA (frequent bilateral knee pain > 15 days per month)
• BMI< 30.0 kg/m2
• male sex
• claustrophobia
• contraindication to MRI including body weight > 300 lbs or knee coil does not fit
• unwillingness or inability to change eating and physical activity habits due to environment
• cannot speak and read English
• planning to leave area > 2 months during the 48-month intervention period

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Diet and Exercise; The dietary component of the weight loss intervention is characterized by the frequency of contacts, methods to induce dietary restriction, and behavioral therapy strategies. The first 6 months of the diet program is an energy-restricted diet with the option of using partial meal replacements and nutritious snacks (Rapid Nutrition, PLC). The weight loss goal for the diet and exercise group is a minimum of 10% of baseline body weight by the end of year 1. The weight loss phase is followed by 3 years of a weight-loss maintenance program, with the goal of sustaining the achieved weight loss. The exercise component includes 60-minute sessions 2 days per week for 48 months.	Behavioral: Diet and Exercise; Group and individual weight loss and weight maintenance sessions combined with exercise throughout the 48 months.
No Intervention: Attention Control; This comparison group provides attention, social interaction, and healthy lifestyle classes. There will be 4, 1-hour face-to-face group meetings per year featuring community health professionals, quarterly newsletters, and quarterly text messages.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Structural knee Osteoarthritis (OA) MRI change Scores	Compare the effects of a 48-month intervention of dietary weight loss, exercise, and weight-loss maintenance to an attention control group in preventing the development of structural (MRI) knee OA. Assessed using the MRI Osteoarthritis Knee Score (MOAKS). The MOAKS evaluates degenerative changes in the knee, including the location and severity of osteophyte formation, bone marrow lesions, and cartilage loss. The MOAKS classification system of osteophytes has grades ranging from 0 (none) to 3 (large).	Month 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Knee Pain Scores	Compare the effects of a 48-month intervention of dietary weight loss, exercise and weight-loss maintenance to an attention control group on the Knee Injury and Osteoarthritis Outcome Score (KOOS pain). Standardized answer options are given (5 Likert boxes) and each question is assigned a score from 0 to 4. A normalized score is calculated for the pain subscale. We will transform the score to a 0-100 scale, with 100 representing the most pain and 0 representing no pain.	Month 48
Mobility Scores	Compare the effects of a 48-month intervention of dietary weight loss, exercise and weight-loss maintenance to an attention control group on 6-minute walk distance. Assessment of 6 minute walk distance (measured in meters). Greater distance indicates better mobility.	Month 48
Health-Related Quality of Life Scores	Compare the effects of a 48-month intervention of dietary weight loss, exercise and weight-loss maintenance to an attention control group on health-related quality of life (SF-36). Questions from the SF-36 yield 2 broad summary scores: physical health and mental health. Scores for each domain range from 0 to 100, with a higher score defining a more favorable health state.	Month 48

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Knee Joint Loading Number	Compare the effects of a 48-month intervention of dietary weight loss, exercise, and weight-loss maintenance to an attention control group on knee joint compressive loads (Newtons). Higher numbers indicate greater loads.	Month 48
Inflammation Value	Compare the effects of a 48-month intervention of dietary weight loss, exercise, and weight-loss maintenance to an attention control group on plasma Interleukin-6 (IL-6). Higher values indicate more inflammation.	Month 48
Self-Efficacy Scores - exercise	Compare the effects of a 48-month intervention of dietary weight loss, exercise, and weight-loss maintenance to an attention control group on exercise self-efficacy. Exercise self efficacy will be measured using the walking efficacy for duration scale measures one's ability to walk/jog at a moderately fast pace for various durations. Range 0-100. A higher score indicates a higher self-efficacy. indicate better self-efficacy.	Month 48
Cost-Effectiveness Ratios	To establish the cost-effectiveness of this multimodal weight loss, exercise, and weight-loss maintenance program by conducting cost-effectiveness and budgetary impact analyses using data from the current trial in a validated computer-simulation model of knee OA. The cost-effectiveness ratio provides a measure of value for money. The cost-effectiveness of a specific prevention or treatment strategy is measured in dollars per quality-adjusted life-year gained ($/QALY). a budget impact analysis (BIA) of the weight loss program quantifies the financial consequences of adopting the weight loss program by various payer models.	Month 48
Self-Efficacy Scores - weight loss	Compare the effects of a 48-month intervention of dietary weight loss, exercise, and weight-loss maintenance to an attention control group on weight loss self-efficacy. Weight-loss self efficacy will be measured by the weight efficacy lifestyle questionnaire. A 20-item measure developed to assess self-efficacy for weight management. Participants are asked to rate their confidence to resist the desire to eat using a 10-point scale ranging from 0 not confident to 9 very confident. Total scores range from 0-180. Higher scores indicate better self-efficacy.	Month 48

Collaborators and Investigators

• Sponsor: Wake Forest University
• Collaborators: University of Missouri-Columbia; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Center for Complementary and Integrative Health (NCCIH); Centers for Disease Control and Prevention; Office of Behavioral and Social Sciences Research (OBSSR); Office of Research on Women's Health (ORWH); Arthritis Foundation; Office of Disease Prevention; Rapid Nutrition PLC
• Investigators: Principal Investigator: Stephen P Messier, Ph.D., Wake Forest University

Study record dates

Study Major Dates

• Study Start (Actual): March 21, 2024
• Primary Completion (Estimated): April 1, 2029
• Study Completion (Estimated): April 1, 2029

Study Registration Dates

• First Submitted: July 6, 2023
• First Submitted That Met QC Criteria: July 6, 2023
• First Posted (Actual): July 14, 2023

Study Record Updates

• Last Update Posted (Actual): April 12, 2024
• Last Update Submitted That Met QC Criteria: April 11, 2024
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Obesity; Knee Pain
• Additional Relevant MeSH Terms: Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Osteoarthritis; Osteoarthritis, Knee
• Other Study ID Numbers: IRB00080136; U01AR082121-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All of the individual participant data collected during the trial after deidentification.
• IPD Sharing Time Frame: Immediately following publication. No end date.
• IPD Sharing Access Criteria: Investigators whose proposed use of the data has been approved by the study P&P committee. Proposals should be directed to the study PI, Stephen Messier at messier@wfu.edu or the central contact.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No