Comparative Study of Safety and Efficacy of Two Hyaluronic Acids for the Treatment of Knee Osteoarthritis Pain (DRAGON)

A Multicenter, Randomized, Double-blind, Parallel, Active-controlled Clinical Trial With Non-inferiority Comparison to Evaluate Efficacy and Safety of Intra-articular Injection of DUROLANE® vs. ARTZ® in Treatment of Knee Osteoarthritis

The purpose of this study is to determine the comparative safety and efficacy of intra-articular injection of hyaluronic acid, obtained from two different sources, in the treatment of osteoarthritic pain of the knee.

Study Overview

• Status: Completed
• Conditions: Knee Osteoarthritis
• Intervention / Treatment: Device: ARTZ; Device: DUROLANE

Detailed Description

This is a multicenter, randomized, double blind, parallel-controlled clinical trial using a non-inferiority comparison to evaluate the efficacy and safety of an intra-articular injection of Durolane® vs Artz® in the treatment of knee osteoarthritis. Subjects will be randomized 1:1 to receive either Durolane or Artz. All subjects will be followed up for 26 weeks from the initial treatment.The screening period is expected to be up to 2 weeks in duration before the baseline visit. Each subject will provide a written informed consent and undergo a qualifying screening. Assessment at screening will include postero-anterior view of standing weight-bearing semi-flexed radiographs of the study knee. The osteoarthritis changes of the study knee will be graded 0,1,2,3 or 4 according to the Kellgren-Lawrence radiographic scoring criteria. Radiographic assessment will be made by an assigned and well trained investigator at each study center. The study knee and contralateral knee will use the Likert WOMAC 5-point scoring for pain assessment.

Physical examination of the knees and vital signs will be performed (this examination will be repeated at end).

• Study Type: Interventional
• Enrollment (Actual): 349
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Beijing, China
    • Beijing Frienship Hospital
  • Beijing, China
    • Beijing General Military Hospital
  • Beijing, China
    • Beijing University #3 Hospital
  • Beijing, China
    • Beijing University People's Hospital
  • Hangzhou, China
    • Zhejiang #2 Hospital
  • Shanghai, China
    • Shanghai #6 People's Hospital
  • Shanghai, China
    • Shanghai #9 People's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subject (female or male) 40-80 years of age, inclusive
• Documented diagnosis of mild to moderate osteoarthritis of the study knee that fulfil the ACR(American College of Rheumatology) criteria
• Radiographic evidence of osteoarthritis in the study knee (Kellgren Lawrence radiographic score is 2 or 3)

Exclusion Criteria:

• Clinically apparent tense effusion of the study knee on examination determined by either a positive bulge sign or positive ballottement of the patella
• Kellgren-Lawrence radiographic score 0, 1 or 4 in the study knee
• Symptomatic osteoarthritis of the contralateral knee or of either hip that is not responsive to acetaminophen/paracetamol and/or requires any protocol prohibited therapies

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: ARTZ sodium hyaluronate; The comparator product, ARTZ, is manufactured by Seikagaku Corporation, Japan. Subjects randomized to the ARTZ group were administered five weekly intra-articular injections (2.5 ml, NASHA 25 mg). ARTZ is a sterile, viscoelastic nonpyrogenic solution of purified, high molecular weight (620,000-1,170,000 daltons) sodium hyaluronate having a pH of 6.8-7.8. The sodium hyaluronate is extracted from chicken combs.	Device: ARTZ; Hyaluronic acid (five 2.5 mL injections)
ACTIVE_COMPARATOR: DUROLANE hyaluronic acid; The investigational product was provided in pre-filled syringes containing stabilized non-animal hyaluronic acid (20 mg/mL). Only one injection was given for those subjects randomized to the DUROLANE group, followed by 4 sham injections. DUROLANE is free from products of animal origin and is manufactured by Q-Med AB Corporation.The sham injection procedure was same as the active injection, except that they were subcutaneous and an empty syringe was used.	Device: DUROLANE; Hyaluronic acid stabilized (one 3.0 mL injection + four weekly 0 mL sham injections)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
WOMAC (Western Ontario and McMaster Osteoarthritis Index) Pain Subscale Change From Baseline	Pain assessment is made of 5 items; each has 5 possible values 0=none, 1=mild, 2=moderate, 3=severe, 4=extreme. The items are summed for a total range of 0 to 20. Therefore, the pain change from baseline range is -20 to 20. A negative change is a reduction in pain from the baseline pain score. A mixed-effect repeated measures regression model was used to estimate a least square mean for the entire "Measured Time Frame". Change from baseline was the dependent variable. Subject baseline score was a fixed effect covariate. Enrollment site, treatment, visit, and treatment by visit interaction were fixed class effects. Subject was a random effect. A least square mean single point estimate and 95%CI was calculated for the entire "Measured Time Frame" using all data collected at each time point within the "Measured Time Frame".	over 18 weeks (week timepoints 6, 10, 14, and 18)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
WOMAC (Western Ontario and McMaster Osteoarthritis Index) Pain Subscale Change From Baseline	Pain assessment is made of 5 items; each has 5 possible values 0=none, 1=mild, 2=moderate, 3=severe, 4=extreme. The items are summed for a total range of 0 to 20. Therefore, the pain change from baseline range is -20 to 20. A negative change is a reduction in pain from the baseline pain score. A mixed-effect repeated measures regression model was used to estimate a least square mean for the entire "Measured Time Frame". Change from baseline was the dependent variable. Subject baseline score was a fixed effect covariate. Enrollment site, treatment, visit, and treatment by visit interaction were fixed class effects. Subject was a random effect. A least square mean single point estimate and 95%CI was calculated for the entire "Measured Time Frame" using all data collected at each time point within the "Measured Time Frame".	over 26 weeks (week 6, 10, 14, 18, and 26)
WOMAC (Western Ontario and McMaster Osteoarthritis Index) Physical Function Subscale Change From Baseline	Physical Function assessment is made of 17 items; each has 5 possible values 0=none, 1=mild, 3=moderate, 4=extreme. The items are summed for a total range of 0 to 68. Therefore, the physical function change from baseline range is -68 to 68. A negative change is an improvement in physical function from the baseline physical function score. A mixed-effect repeated measures regression model was used to estimate a least square mean for the entire "Measured Time Frame". Change from baseline was the dependent variable. Subject baseline score was a fixed effect covariate. Enrollment site, treatment, visit, and treatment by visit interaction were fixed class effects. Subject was a random effect. A least square mean single point estimate and 95%CI was calculated for the entire "Measured Time Frame" using all data collected at each time point within the "Measured Time Frame".	over 18 weeks (week timepoints 6, 10, 14, and 18)
WOMAC (Western Ontario and McMaster Osteoarthritis Index) Physical Function Subscale Change From Baseline	Physical Function assessment is made of 17 items; each has 5 possible values 0=none, 1=mild, 3=moderate, 4=extreme. The items are summed for a total range of 0 to 68. Therefore, the physical function change from baseline range is -68 to 68. A negative change is an improvement in physical function from the baseline physical function score. A mixed-effect repeated measures regression model was used to estimate a least square mean for the entire "Measured Time Frame". Change from baseline was the dependent variable. Subject baseline score was a fixed effect covariate. Enrollment site, treatment, visit, and treatment by visit interaction were fixed class effects. Subject was a random effect. A least square mean single point estimate and 95%CI was calculated for the entire "Measured Time Frame" using all data collected at each time point within the "Measured Time Frame".	over 26 weeks (week timepoints 6, 10, 14, 18, and 26)
Subject Global Assessment Change From Baseline	Subject global assessment is one question "Considering all the ways your knee osteoarthritis affects you, how are you doing today?". It has 11 values 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 labeled only at the extremes; 0 = very bad and 10 = very good. The change from baseline range is -10 to 10. A positive change is an improvement from the baseline subject global assessment score. A mixed-effect repeated measures regression model was used to estimate a least square mean for the entire "Measured Time Frame". Change from baseline was the dependent variable. Subject baseline score was a fixed effect covariate. Enrollment site, treatment, visit, and treatment by visit interaction were fixed class effects. Subject was a random effect. A least square mean single point estimate and 95%CI was calculated for the entire "Measured Time Frame" using all data collected at each time point within the "Measured Time Frame".	over 18 weeks (week timepoints 6, 10, 14, and 18)
Subject Global Assessment Change From Baseline	Subject global assessment is one question "Considering all the ways your knee osteoarthritis affects you, how are you doing today?". It has 11 values 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 labeled only at the extremes; 0 = very bad and 10 = very good. The change from baseline range is -10 to 10. A positive change is an improvement from the baseline subject global assessment score. A mixed-effect repeated measures regression model was used to estimate a least square mean for the entire "Measured Time Frame". Change from baseline was the dependent variable. Subject baseline score was a fixed effect covariate. Enrollment site, treatment, visit, and treatment by visit interaction were fixed class effects. Subject was a random effect. A least square mean single point estimate and 95%CI was calculated for the entire "Measured Time Frame" using all data collected at each time point within the "Measured Time Frame".	over 26 weeks (week timepoints 6, 10, 14, 18, and 26)
WOMAC (Western Ontario and McMaster Osteoarthritis Index) Knee Stiffness Subscale Change From Baseline	Knee stiffness assessment is made of 2 items; each has 5 possible values 0=none, 1=mild, 2=moderate, 3=severe, 4=extreme. The items are summed for a total range of 0 to 8. Therefore, the knee stiffness change from baseline range is -8 to 8. A negative change is a reduction in knee stiffness from the baseline knee stiffness score. A mixed-effect repeated measures regression model was used to estimate a least square mean for the entire "Measured Time Frame". Change from baseline was the dependent variable. Subject baseline score was a fixed effect covariate. Enrollment site, treatment, visit, and treatment by visit interaction were fixed class effects. Subject was a random effect. A least square mean single point estimate and 95%CI was calculated for the entire "Measured Time Frame" using all data collected at each time point within the "Measured Time Frame".	over 18 weeks (week timepoints 6, 10, 14, and 18)
WOMAC (Western Ontario and McMaster Osteoarthritis Index) Knee Stiffness Subscale Change From Baseline	Knee stiffness assessment is made of 2 items; each has 5 possible values 0=none, 1=mild, 2=moderate, 3=severe, 4=extreme. The items are summed for a total range of 0 to 8. Therefore, the knee stiffness change from baseline range is -8 to 8. A negative change is a reduction in knee stiffness from the baseline knee stiffness score. A mixed-effect repeated measures regression model was used to estimate a least square mean for the entire "Measured Time Frame". Change from baseline was the dependent variable. Subject baseline score was a fixed effect covariate. Enrollment site, treatment, visit, and treatment by visit interaction were fixed class effects. Subject was a random effect. A least square mean single point estimate and 95%CI was calculated for the entire "Measured Time Frame" using all data collected at each time point within the "Measured Time Frame".	over 26 weeks (week timepoints 6, 10, 14, 18, and 26)

Collaborators and Investigators

• Sponsor: Bioventus LLC
• Collaborators: Smith & Nephew, Inc.
• Investigators: Principal Investigator: Jianhao Lin, MD, People Hospital of Beijing University No. 11 South Ave., Xizhimen, Beijing

Publications and helpful links

General Publications

• Zhang H, Zhang K, Zhang X, Zhu Z, Yan S, Sun T, Guo A, Jones J, Steen RG, Shan B, Zhang J, Lin J. Comparison of two hyaluronic acid formulations for safety and efficacy (CHASE) study in knee osteoarthritis: a multicenter, randomized, double-blind, 26-week non-inferiority trial comparing Durolane to Artz. Arthritis Res Ther. 2015 Mar 10;17(1):51. doi: 10.1186/s13075-015-0557-x.

Study record dates

Study Major Dates

• Study Start: January 1, 2011
• Primary Completion (ACTUAL): August 1, 2011
• Study Completion (ACTUAL): February 1, 2012

Study Registration Dates

• First Submitted: February 11, 2011
• First Submitted That Met QC Criteria: February 11, 2011
• First Posted (ESTIMATE): February 14, 2011

Study Record Updates

• Last Update Posted (ACTUAL): April 9, 2021
• Last Update Submitted That Met QC Criteria: March 16, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Osteoarthritis; Osteoarthritis, Knee
• Other Study ID Numbers: TG1018DLN

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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