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

• Sponsor: Bioventus LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01295580
• Collaborator: Smith & Nephew, Inc. (Industry)
• Enrollment: 349
• Locations: 7
• Arms: 2
• Duration (Months): 13
• Patients Per Site: 49.9
• Patients Per Site Per Month: 3.8

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Knee Osteoarthritis	Device: ARTZ; Device: DUROLANE	N/A

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 Design

• Study Type: Interventional
• Actual Enrollment: 349 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Investigational product was masked from study staff and participants with the exception of the unblinded treating investigator conducting the intra-articular injections.
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Jan 1, 2011
• Actual Primary Completion Date: Aug 1, 2011
• Actual Study Completion Date: Feb 1, 2012

Arms and Interventions

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)

Outcome Measures

Primary Outcome Measures

1. WOMAC (Western Ontario and McMaster Osteoarthritis Index) Pain Subscale Change From Baseline [over 18 weeks (week timepoints 6, 10, 14, and 18)]

   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".

Secondary Outcome Measures

1. WOMAC (Western Ontario and McMaster Osteoarthritis Index) Pain Subscale Change From Baseline [over 26 weeks (week 6, 10, 14, 18, and 26)]

   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".

2. WOMAC (Western Ontario and McMaster Osteoarthritis Index) Physical Function Subscale Change From Baseline [over 18 weeks (week timepoints 6, 10, 14, and 18)]

   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".

3. WOMAC (Western Ontario and McMaster Osteoarthritis Index) Physical Function Subscale Change From Baseline [over 26 weeks (week timepoints 6, 10, 14, 18, and 26)]

   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".

4. Subject Global Assessment Change From Baseline [over 18 weeks (week timepoints 6, 10, 14, and 18)]

   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".

5. Subject Global Assessment Change From Baseline [over 26 weeks (week timepoints 6, 10, 14, 18, and 26)]

   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".

6. WOMAC (Western Ontario and McMaster Osteoarthritis Index) Knee Stiffness Subscale Change From Baseline [over 18 weeks (week timepoints 6, 10, 14, and 18)]

   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".

7. WOMAC (Western Ontario and McMaster Osteoarthritis Index) Knee Stiffness Subscale Change From Baseline [over 26 weeks (week timepoints 6, 10, 14, 18, and 26)]

   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".

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Beijing Frienship Hospital	Beijing		China
2	Beijing General Military Hospital	Beijing		China
3	Beijing University #3 Hospital	Beijing		China
4	Beijing University People's Hospital	Beijing		China
5	Zhejiang #2 Hospital	Hangzhou		China
6	Shanghai #6 People's Hospital	Shanghai		China
7	Shanghai #9 People's Hospital	Shanghai		China

Sponsors and Collaborators

• Bioventus LLC
• Smith & Nephew, Inc.

Investigators

• Principal Investigator: Jianhao Lin, MD, People Hospital of Beijing University No. 11 South Ave., Xizhimen, Beijing

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Bioventus LLC
• ClinicalTrials.gov Identifier: NCT01295580
• Other Study ID Numbers: TG1018DLN
• First Posted: Feb 14, 2011
• Last Update Posted: Apr 9, 2021
• Last Verified: Mar 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Osteoarthritis; Osteoarthritis, Knee

Study Results

Participant Flow

Arm/Group Title	ARTZ	DUROLANE
Arm/Group Description	ARTZ: Hyaluronic acid (five 2.5 mL injections)	DUROLANE: Hyaluronic acid stabilized (one 3.0 mL injection + four weekly 0 mL sham injections)
Period Title: Overall Study
STARTED	174	175
COMPLETED	164	167
NOT COMPLETED	10	8

Baseline Characteristics

Arm/Group Title	ARTZ	DUROLANE	Total
Arm/Group Description	ARTZ: Hyaluronic acid (five 2.5 mL injections)	DUROLANE: Hyaluronic acid stabilized (one 3.0 mL injection + four weekly 0 mL sham injections)	Total of all reporting groups
Overall Participants	174	175	349
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.6 (8.16)	60.3 (8.11)	60.4 (8.13)
Sex: Female, Male (Count of Participants)
Female	139 79.9%	132 75.4%	271 77.7%
Male	35 20.1%	43 24.6%	78 22.3%
Race/Ethnicity, Customized (participants) [Number]
Nationality: Han	173 99.4%	168 96%	341 97.7%
Nationality: Other	1 0.6%	7 4%	8 2.3%
Region of Enrollment (participants) [Number]
China	174 100%	175 100%	349 100%

Outcome Measures

1. Primary Outcome

Title	WOMAC (Western Ontario and McMaster Osteoarthritis Index) Pain Subscale Change From Baseline
Description	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".
Time Frame	over 18 weeks (week timepoints 6, 10, 14, and 18)

Outcome Measure Data

Analysis Population Description

per protocol: all subjects randomized and treated with no important protocol deviation(s), which were established at a blinded data review meeting. An important deviation is any deviation that has the potential to bias the primary outcome.

Arm/Group Title	ARTZ	DUROLANE
Arm/Group Description	ARTZ: Hyaluronic acid (five 2.5 mL injections)	DUROLANE: Hyaluronic acid stabilized (one 3.0 mL injection + four weekly 0 mL sham injections)
Measure Participants	158	161
Least Squares Mean (95% Confidence Interval) [units on a scale]	-5.87	-5.97

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ARTZ, DUROLANE
	Comments	Primary Hypothesis: Ho: μDUR[18] - μArtz[18] ≥ +1.6 units Ha: μDUR[18] - μArtz[18] < +1.6 units Power Calculations: Assume the over 18 weeks difference is 0mm, SD 20mm (5 on the Likert scale), 90% power, 2-sided test alpha 5%, and a 8mm non-inferiority margin (1.6 on the Likert scale), the sample size required is 132 subjects per group adjusted to 175 to hold power constant due to loss to follow-up and dropout.
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	This is a non-inferiority test. The non-inferiority margin of +1.6 units corresponds to an 8% margin on the pain subscale (range 0-20) Alpha inflation was controlled using pre-planned stepwise hypotheses testing (1) WOMAC Pain over 18 weeks then (2) over 26 weeks, (3) WOMAC Physical Function over 18 weeks then (4) over 26 weeks, (5) Subject Global Assessment over 18 weeks then (6) over 26 weeks, (7) WOMAC Knee Stiffness over 18 weeks then (8) over 26 weeks.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 95%; -0.58 to 0.39
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	WOMAC (Western Ontario and McMaster Osteoarthritis Index) Pain Subscale Change From Baseline
Description	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".
Time Frame	over 26 weeks (week 6, 10, 14, 18, and 26)

Outcome Measure Data

Analysis Population Description

per protocol: all subjects randomized and treated with no important protocol deviation(s), which were established at a blinded data review meeting. An important deviation is any deviation that has the potential to bias the primary outcome.

Arm/Group Title	ARTZ	DUROLANE
Arm/Group Description	ARTZ: Hyaluronic acid (five 2.5 mL injections)	DUROLANE: Hyaluronic acid stabilized (one 3.0 mL injection + four weekly 0 mL sham injections)
Measure Participants	158	161
Least Squares Mean (95% Confidence Interval) [units on a scale]	-6.05	-6.15

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ARTZ, DUROLANE
	Comments	Ho: μDUR[26] - μArtz[26] ≥ +1.6 units Ha: μDUR[26] - μArtz[26] < +1.6 units
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	This is a non-inferiority test. The non-inferiority margin of +1.6 units corresponds to an 8% margin on the pain subscale (range 0-20)
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.56 to 0.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	WOMAC (Western Ontario and McMaster Osteoarthritis Index) Physical Function Subscale Change From Baseline
Description	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".
Time Frame	over 18 weeks (week timepoints 6, 10, 14, and 18)

Outcome Measure Data

Analysis Population Description

per protocol: all subjects randomized and treated with no important protocol deviation(s), which were established at a blinded data review meeting. An important deviation is any deviation that has the potential to bias the primary outcome.

Arm/Group Title	ARTZ	DUROLANE
Arm/Group Description	ARTZ: Hyaluronic acid (five 2.5 mL injections)	DUROLANE: Hyaluronic acid stabilized (one 3.0 mL injection + four weekly 0 mL sham injections)
Measure Participants	158	161
Least Squares Mean (95% Confidence Interval) [units on a scale]	-12.10	-12.75

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ARTZ, DUROLANE
	Comments	Ho: μDUR[18] - μArtz[18] ≥ +5.44 units Ha: μDUR[18] - μArtz[18] < +5.44 units
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	This is a non-inferiority test. The non-inferiority margin of +5.44 units corresponds to an 8% margin on the physical function subscale (range 0-68).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.65
	Confidence Interval	(2-Sided) 95%; -1.81 to 0.51
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	WOMAC (Western Ontario and McMaster Osteoarthritis Index) Physical Function Subscale Change From Baseline
Description	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".
Time Frame	over 26 weeks (week timepoints 6, 10, 14, 18, and 26)

Outcome Measure Data

Analysis Population Description

per protocol: all subjects randomized and treated with no important protocol deviation(s), which were established at a blinded data review meeting. An important deviation is any deviation that has the potential to bias the primary outcome.

Arm/Group Title	ARTZ	DUROLANE
Arm/Group Description	ARTZ: Hyaluronic acid (five 2.5 mL injections)	DUROLANE: Hyaluronic acid stabilized (one 3.0 mL injection + four weekly 0 mL sham injections)
Measure Participants	158	161
Least Squares Mean (95% Confidence Interval) [units on a scale]	-12.58	-13.16

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ARTZ, DUROLANE
	Comments	Ho: μDUR[26] - μArtz[26] ≥ +5.44 units Ha: μDUR[26] - μArtz[26] < +5.44 units
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	This is a non-inferiority test. The non-inferiority margin of +5.44 units corresponds to an 8% margin on the physical function subscale (range 0-68).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.58
	Confidence Interval	(2-Sided) 95%; -1.69 to 0.53
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Subject Global Assessment Change From Baseline
Description	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".
Time Frame	over 18 weeks (week timepoints 6, 10, 14, and 18)

Outcome Measure Data

Analysis Population Description

per protocol: all subjects randomized and treated with no important protocol deviation(s), which were established at a blinded data review meeting. An important deviation is any deviation that has the potential to bias the primary outcome.

Arm/Group Title	ARTZ	DUROLANE
Arm/Group Description	ARTZ: Hyaluronic acid (five 2.5 mL injections)	DUROLANE: Hyaluronic acid stabilized (one 3.0 mL injection + four weekly 0 mL sham injections)
Measure Participants	158	161
Least Squares Mean (95% Confidence Interval) [units on a scale]	2.55	2.70

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ARTZ, DUROLANE
	Comments	Ho: μDUR[18] - μArtz[18] ≤ -0.8 units Ha: μDUR[18] - μArtz[18] > -0.8 units
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	This is a non-inferiority test. The non-inferiority margin of -0.8 units corresponds to an 8% margin on the subject global assessment (range 0-10). Note that because the assessment interpretation is reversed as compared to the WOMAC assessments the lower bound of the 95%CI is compared to the -0.8 non-inferiority margin.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.15
	Confidence Interval	(2-Sided) 95%; -0.15 to 0.45
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Subject Global Assessment Change From Baseline
Description	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".
Time Frame	over 26 weeks (week timepoints 6, 10, 14, 18, and 26)

Outcome Measure Data

Analysis Population Description

per protocol: all subjects randomized and treated with no important protocol deviation(s), which were established at a blinded data review meeting. An important deviation is any deviation that has the potential to bias the primary outcome.

Arm/Group Title	ARTZ	DUROLANE
Arm/Group Description	ARTZ: Hyaluronic acid (five 2.5 mL injections)	DUROLANE: Hyaluronic acid stabilized (one 3.0 mL injection + four weekly 0 mL sham injections)
Measure Participants	158	161
Least Squares Mean (95% Confidence Interval) [units on a scale]	2.67	2.81

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ARTZ, DUROLANE
	Comments	Ho: μDUR[18] - μArtz[18] ≤ -0.8 units Ha: μDUR[18] - μArtz[18] > -0.8 units
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	This is a non-inferiority test. The non-inferiority margin of -0.8 units corresponds to an 8% margin on the subject global assessment (range 0-10). Note that because the assessment interpretation is reversed as compared to the WOMAC assessments the lower bound of the 95%CI is compared to the -0.8 non-inferiority margin.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.14
	Confidence Interval	(2-Sided) 95%; -0.16 to 0.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	WOMAC (Western Ontario and McMaster Osteoarthritis Index) Knee Stiffness Subscale Change From Baseline
Description	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".
Time Frame	over 18 weeks (week timepoints 6, 10, 14, and 18)

Outcome Measure Data

Analysis Population Description

per protocol: all subjects randomized and treated with no important protocol deviation(s), which were established at a blinded data review meeting. An important deviation is any deviation that has the potential to bias the primary outcome.

Arm/Group Title	ARTZ	DUROLANE
Arm/Group Description	ARTZ: Hyaluronic acid (five 2.5 mL injections)	DUROLANE: Hyaluronic acid stabilized (one 3.0 mL injection + four weekly 0 mL sham injections)
Measure Participants	158	161
Least Squares Mean (95% Confidence Interval) [units on a scale]	-1.73	-1.87

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ARTZ, DUROLANE
	Comments	Ho: μDUR[18] - μArtz[18] ≥ +0.64 units Ha: μDUR[18] - μArtz[18] < +0.64 units
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	This is a non-inferiority test. The non-inferiority margin of +0.64 units corresponds to an 8% margin on the knee stiffness subscale (range 0-8).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 95%; -0.33 to 0.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	WOMAC (Western Ontario and McMaster Osteoarthritis Index) Knee Stiffness Subscale Change From Baseline
Description	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".
Time Frame	over 26 weeks (week timepoints 6, 10, 14, 18, and 26)

Outcome Measure Data

Analysis Population Description

per protocol: all subjects randomized and treated with no important protocol deviation(s), which were established at a blinded data review meeting. An important deviation is any deviation that has the potential to bias the primary outcome.

Arm/Group Title	ARTZ	DUROLANE
Arm/Group Description	ARTZ: Hyaluronic acid (five 2.5 mL injections)	DUROLANE: Hyaluronic acid stabilized (one 3.0 mL injection + four weekly 0 mL sham injections)
Measure Participants	158	161
Least Squares Mean (95% Confidence Interval) [units on a scale]	-1.80	-1.95

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ARTZ, DUROLANE
	Comments	Ho: μDUR[26] - μArtz[26] ≥ +0.64 units Ha: μDUR[26] - μArtz[26] < +0.64 units
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	This is a non-inferiority test. The non-inferiority margin of 0.64 units corresponds to an 8% margin on the knee stiffness subscale (range 0-8).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 95%; -0.33 to 0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	26 weeks
Arm/Group Title	ARTZ		DUROLANE
Arm/Group Description	ARTZ: Hyaluronic acid (five 2.5 mL injections)		DUROLANE: Hyaluronic acid stabilized (one 3.0 mL injection + four weekly 0 mL sham injections)
All Cause Mortality
	ARTZ		DUROLANE
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	ARTZ		DUROLANE
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/174 (3.4%)		3/175 (1.7%)
Cardiac disorders
Coronary artery disease	0/174 (0%)		1/175 (0.6%)
Ear and labyrinth disorders
Otitis media	1/174 (0.6%)		0/175 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/174 (0.6%)		0/175 (0%)
Joint swelling	1/174 (0.6%)		0/175 (0%)
Meniscus lesion	1/174 (0.6%)		0/175 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung neoplasm malignant	1/174 (0.6%)		0/175 (0%)
Renal and urinary disorders
Calculus ureteric	0/174 (0%)		1/175 (0.6%)
Surgical and medical procedures
Colon polypectomy	0/174 (0%)		1/175 (0.6%)
Vascular disorders
Cerebral infarction	2/174 (1.1%)		0/175 (0%)
Other (Not Including Serious) Adverse Events
	ARTZ		DUROLANE
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	37/174 (21.3%)		39/175 (22.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	29/174 (16.7%)		26/175 (14.9%)
Respiratory, thoracic and mediastinal disorders
Upper respiratory tract infection	8/174 (4.6%)		13/175 (7.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.