A Study of the Safety and Efficacy of Hylan G-F 20 (Synvisc) in Patients With Symptomatic Osteoarthritis of the Knee

• Sponsor: Genzyme, a Sanofi Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00131352
• Collaborator: (none)
• Enrollment: 253
• Locations: 21
• Arms: 2
• Duration (Months): 16
• Patients Per Site: 12
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

This clinical study is to evaluate the safety and efficacy of hylan G-F 20 (Synvisc) in patients with symptomatic knee osteoarthritis (OA). Patients will be given 6 mL of hylan G-F 20 (Synvisc) (or a phosphate buffered saline control), with a possible repeat treatment with Synvisc after the week 26 visit.

Condition or Disease	Intervention/Treatment	Phase
Osteoarthritis, Knee; Musculoskeletal Diseases	Device: hylan G-F 20; Other: Phosphate Buffered Saline	Phase 3

Detailed Description

The trial included an initial 26 week treatment with 6 mL of hylan G-F 20 (Synvisc) (or a phosphate buffered saline control) followed by a 4 week repeat treatment of Synvisc.

Study Design

• Study Type: Interventional
• Actual Enrollment: 253 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multi-Centre, Parallel, Double-Blind, Blinded Evaluator, Randomised, Placebo-Controlled Evaluation of the Efficacy and Safety of a Single Dose of 6 mL of Synvisc in Patients With Symptomatic Osteoarthritis of the Knee
• Study Start Date: May 1, 2005
• Actual Primary Completion Date: Sep 1, 2006
• Actual Study Completion Date: Sep 1, 2006

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Synvisc Participants with symptomatic primary osteoarthritis (OA) of the knee received a single injection of 6 mL hylan G-F 20 (Synvisc).	Device: hylan G-F 20; Single injection of 6 mL of hylan G-F 20 (Synvisc).; Other Names: Synvisc-One
Placebo Comparator: Saline Control Participants (control group) with symptomatic primary osteoarthritis (OA) of the knee received a single injection of 6 mL phosphate buffered saline.	Other: Phosphate Buffered Saline; Single injection of 6 mL phosphate buffered saline.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Knee Pain Over the Course of the 26-week Initial Treatment Period As Measured by Participants Using the Western Ontario and McMaster Universities Osteoarthritis Index Likert Scale Version 3.1 (WOMAC LK 3.1) A (Pain) Subscale [Day 0, up to week 26]

   The change from baseline over the course of the 26-week initial treatment period using participants' assessment of pain. Mean scores were used for baseline (day 0) and for all visits up to week 26 (weeks 4, 8, 12, 18 and 26). The WOMAC Pain Subscale has a score range of 0-4, where 0=no pain and 4=extreme pain.

Secondary Outcome Measures

1. Change From Baseline in Knee Pain at Week 26 As Measured by Participants Using the Western Ontario and McMaster Universities Osteoarthritis Index Likert Scale Version 3.1 (WOMAC LK 3.1) A (Pain) Subscale [Day 0, Week 26]

   The change from baseline to week 26 using participants' assessment of pain. The WOMAC Pain Subscale has a score range of 0-4, where 0=no pain and 4=extreme pain.

2. Participants Level of Pain While Walking at Week 26 As Measured by Participants Using the Western Ontario and McMaster Universities Osteoarthritis Index Likert Scale Version 3.1 (WOMAC LK 3.1) A1 (Walking Pain) Subscale [Week 26]

   Participants categorized the pain they felt while walking using the WOMAC LK 3.1) A1 (Walking Pain) Subscale. The scale rates pain as none, mild, moderate, severe and extreme.

3. Change From Baseline Over the Course of the 26-week Initial Treatment Period in Physical Function Measured by Participants Using the Western Ontario and McMaster Universities Osteoarthritis Index Likert Scale (WOMAC LK Version 3.1) C (Function) Subscale [Day 0, up to week 26]

   The change from baseline over the course of the 26-week initial treatment period using participants' assessment of physical function. Mean scores were used for baseline (day 0) and for all visits up to week 26 (weeks 4, 8, 12, 18 and 26). The WOMAC Function Subscale has a score range of 0-4 to assess the degree of difficulty completing tasks within the past 48 hours, where 0=no difficulty and 4=extreme difficulty.

4. Change From Baseline at Week 26 in Physical Function Measured by Participants Using the Western Ontario and McMaster Universities Osteoarthritis Index Likert Scale (WOMAC LK Version 3.1) C (Function) Subscale [Day 0, Week 26]

   The change from baseline to week 26 using participants' assessment of physical function. The WOMAC Function Subscale has a score range of 0-4 to assess the degree of difficulty completing tasks within the past 48 hours, where 0=no difficulty and 4=extreme difficulty.

5. Participant Global Assessment (PTGA) of the Target Knee Osteoarthritis Condition at Week 26 [Week 26]

   The Participant Global Assessment (PTGA) was used by participants to rate their osteoarthritis (OA). PTGA uses 5 scoring levels: Very well=0, Well=1, Fair=2, Poor=3, Very poor=4.

6. Clinical Observer Global Assessment (COGA) of the Target Knee Osteoarthritis (OA) Condition at Week 26 [Week 26]

   The Blinded Clinical Observer gave a global assessment (COGA) of the target knee OA. COGA uses 5 scoring levels: Very well=0, Well=1, Fair=2, Poor=3, Very poor=4.

7. Participants Classified as Responders Per the Outcome Measures in Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) Criteria at Week 26 [Week 26]

   Participants were classified as a positive responder if at least one of the following two conditions were met: A significant improvement in either the pain (WOMAC A) or physical function (WOMAC C) subscales, defined as both a ≥ 50% improvement from Baseline and an absolute change from Baseline of ≥ 20 normalised units (NU), OR Improvement in at least 2 of 3 subscales - pain (WOMAC A), physical function (WOMAC C) or Participant Global Assessment (PTGA). Improvement for all three scales is defined as ≥ 20% improvement from Baseline and an absolute change from Baseline of ≥ 10 NU

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patient with documented diagnosis of primary osteoarthritis (OA) of the target knee made at least 3 months prior to Screening,

• Has radiographic evidence of OA in the tibio-femoral compartment of the target, knee with at least 1 definite osteophyte and a measureable joint space, as diagnosed by standard X-rays taken not longer than 3 months prior to Screening, and before any baseline assessment,

• Has continued target knee pain despite conservative treatment (e.g. weight reduction, physical therapy, analgesics),

• Has pain in the target knee as demonstrated by a score of 2 or 3 on the Western Ontario and McMaster Universities Osteoarthritis Index Likert Scale Version 3.1 (WOMAC LK 3.1) A1 (Walking Pain) Subscale ,

• Has a mean score of 1.5 to 3.5 on the Western Ontario and McMaster Universities Osteoarthritis Index Likert Scale Version 3.1 (WOMAC LK 3.1) A (Pain) Subscale.

• Inclusion Criteria for Repeat Phase: Must have no major safety concerns during the first course of treatment as assessed by the Investigator; Must have a WOMAC LK 3.1 A score of at least 1.

Exclusion criteria:

• Has modified Kellgren-Lawrence Numerical Grading System of grade IV in the patello-femoral compartment of the target knee confirmed by standard X-rays taken not longer than 3 months prior to Screening, and before any baseline assessment,

• Has clinically apparent tense effusion of the target knee,

• Has had viscosupplementation in any joint including the target knee within 9 months prior to Screening,

• Has concomitant inflammatory disease or other condition that affects the joints (e.g. rheumatoid arthritis, metabolic bone disease, psoriasis, gout, symptomatic chondrocalcinosis and active infection, etc.,)

• Symptomatic OA of the contralateral knee or of either hip that is not responsive to paracetamol and requires other therapy,

• Has related hypersensitivities to avian proteins and/or any components of hyaluronan-based injection devices,

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hopital Erasme	Bruxelles		Belgium	1070
2	Universitair Ziekenhuis Gent	Gent		Belgium	9000
3	Universitair Ziekenhuis Gastuisberg Leuven	Leuven		Belgium	3000
4	CHU Liege	Liege		Belgium	4000
5	Faculty Hospital Bohunice	Brno		Czech Republic	62500
6	Institute of Rheumatology	Prague 2		Czech Republic	12850
7	Faculty Thomayer Hospital	Prague 4		Czech Republic	14059
8	Faculty Hospital Motol	Prague		Czech Republic	15006
9	Hopital Henri Mondor	Creteil Cedex		France	94010
10	CHU Dupuytren	Limoges Cedex		France	87042
11	Hopital de la Conception	Marseille		France	13005
12	Hopital Rangueil	Toulouse Cedex 9		France	31059
13	CHU Hopital Trousseau	Tours Cedex		France	37044
14	Johanna-Etienne Krankenhaus	Neuss		Germany	41462
15	AMC/UVA	Amsterdam		Netherlands	1100
16	Academisch Ziekenhuis Maastricht	Maastricht		Netherlands	6202 AZ
17	University Hospital of Wales	Cardiff		United Kingdom	CF14 4XW
18	Kings College Hospital	London		United Kingdom	SE5 9RJ
19	Trafford General Hospital	Manchester		United Kingdom	M41 5SL
20	Freeman Hospital	Newcastle-upon-Tyne		United Kingdom	NE7 7DN
21	Nuffield Orthopaedic Centre	Oxford		United Kingdom	OX3 7LD

Sponsors and Collaborators

• Genzyme, a Sanofi Company

Investigators

• Study Director: Medical Monitor, Genzyme, a Sanofi Company

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00131352
• Other Study ID Numbers: SYNV00704
• First Posted: Aug 18, 2005
• Last Update Posted: Apr 3, 2015
• Last Verified: Mar 1, 2015

• Keywords provided by , ,: Osteoarthritis of the knee; Musculoskeletal
• Additional relevant MeSH terms: Osteoarthritis; Osteoarthritis, Knee; Musculoskeletal Diseases; Hylan

Study Results

Participant Flow

Pre-assignment Detail	329 participants enrolled and 76 screening failures. One participant was randomised to the Synvisc group but received Saline in error; counted in the Saline group for safety analyses (Safety population) and in the Synvisc group for efficacy analyses (Intent-to-treat population) in both study periods.

Arm/Group Title	Synvisc	Saline Control
Arm/Group Description	Participants with symptomatic primary osteoarthritis (OA) of the knee received a single injection of 6 mL hylan G-F 20 (Synvisc) during the Initial Treatment Period. Participants from both treatment arms had the opportunity to receive an additional 6 mL hylan G-F 20 (Synvisc) during the Repeat Treatment Period.	Participants (control group) with symptomatic primary osteoarthritis (OA) of the knee received a single injection of 6 mL phosphate buffered saline during the Initial Treatment Period.
Period Title: Initial Treatment Period
STARTED	123	130
Intent to Treat Population	124	129
COMPLETED	114	118
NOT COMPLETED	9	12
Period Title: Initial Treatment Period
STARTED	160	0
COMPLETED	158	0
NOT COMPLETED	2	0

Baseline Characteristics

Arm/Group Title	Synvisc	Saline Control	Total
Arm/Group Description	Participants with symptomatic primary osteoarthritis (OA) of the knee received a single injection of 6 mL hylan G-F 20 (Synvisc) during the Initial Treatment Period.	Participants (control group) with symptomatic primary osteoarthritis (OA) of the knee received a single injection of 6 mL phosphate buffered saline.	Total of all reporting groups
Overall Participants	124	129	253
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.6 (9.64)	62.5 (9.17)	63.0 (9.40)
Sex: Female, Male (Count of Participants)
Female	92 74.2%	88 68.2%	180 71.1%
Male	32 25.8%	41 31.8%	73 28.9%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	118 95.2%	125 96.9%	243 96%
Black	5 4%	3 2.3%	8 3.2%
Hispanic	0 0%	0 0%	0 0%
Asian	0 0%	1 0.8%	1 0.4%
Other	1 0.8%	0 0%	1 0.4%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Knee Pain Over the Course of the 26-week Initial Treatment Period As Measured by Participants Using the Western Ontario and McMaster Universities Osteoarthritis Index Likert Scale Version 3.1 (WOMAC LK 3.1) A (Pain) Subscale
Description	The change from baseline over the course of the 26-week initial treatment period using participants' assessment of pain. Mean scores were used for baseline (day 0) and for all visits up to week 26 (weeks 4, 8, 12, 18 and 26). The WOMAC Pain Subscale has a score range of 0-4, where 0=no pain and 4=extreme pain.
Time Frame	Day 0, up to week 26

Outcome Measure Data

Analysis Population Description

Intent-To-Treat (ITT) population which included all participants randomized to study treatment on Day 0.

Arm/Group Title	Synvisc	Saline Control
Arm/Group Description	Participants with symptomatic primary osteoarthritis (OA) of the knee received a single injection of 6 mL hylan G-F 20 (Synvisc) during the Initial Treatment Period.	Participants (control group) with symptomatic primary osteoarthritis (OA) of the knee received a single injection of 6 mL phosphate buffered saline.
Measure Participants	124	129
Mean (Standard Error) [units on a scale]	-0.84 (0.060)	-0.69 (0.058)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Synvisc, Saline Control
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.047
	Comments
	Method	ANCOVA
	Comments	The repeated measures ANCOVA model included terms for treatment, site, time and time-by-treatment interaction; the baseline score was a covariate.

2. Secondary Outcome

Title	Change From Baseline in Knee Pain at Week 26 As Measured by Participants Using the Western Ontario and McMaster Universities Osteoarthritis Index Likert Scale Version 3.1 (WOMAC LK 3.1) A (Pain) Subscale
Description	The change from baseline to week 26 using participants' assessment of pain. The WOMAC Pain Subscale has a score range of 0-4, where 0=no pain and 4=extreme pain.
Time Frame	Day 0, Week 26

Outcome Measure Data

Analysis Population Description

Intent-To-Treat (ITT) population.

Arm/Group Title	Synvisc	Saline Control
Arm/Group Description	Participants with symptomatic primary osteoarthritis (OA) of the knee received a single injection of 6 mL hylan G-F 20 (Synvisc) during the Initial Treatment Period.	Participants (control group) with symptomatic primary osteoarthritis (OA) of the knee received a single injection of 6 mL phosphate buffered saline.
Measure Participants	124	129
Mean (Standard Error) [units on a scale]	-0.76 (0.07)	-0.58 (0.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Synvisc, Saline Control
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.064
	Comments
	Method	ANCOVA
	Comments

3. Secondary Outcome

Title	Participants Level of Pain While Walking at Week 26 As Measured by Participants Using the Western Ontario and McMaster Universities Osteoarthritis Index Likert Scale Version 3.1 (WOMAC LK 3.1) A1 (Walking Pain) Subscale
Description	Participants categorized the pain they felt while walking using the WOMAC LK 3.1) A1 (Walking Pain) Subscale. The scale rates pain as none, mild, moderate, severe and extreme.
Time Frame	Week 26

Outcome Measure Data

Analysis Population Description

Intent-To-Treat (ITT) population

Arm/Group Title	Synvisc	Saline Control
Arm/Group Description	Participants with symptomatic primary osteoarthritis (OA) of the knee received a single injection of 6 mL hylan G-F 20 (Synvisc) during the Initial Treatment Period.	Participants (control group) with symptomatic primary osteoarthritis (OA) of the knee received a single injection of 6 mL phosphate buffered saline.
Measure Participants	115	117
None	17 13.7%	13 10.1%
Mild	45 36.3%	39 30.2%
Moderate	41 33.1%	42 32.6%
Severe	11 8.9%	19 14.7%
Extreme	1 0.8%	4 3.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Synvisc, Saline Control
	Comments	Estimate of Odds Ratio (Placebo/Synvisc-One) using WOMAC A1 data at Week 26.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.022
	Comments
	Method	Generalized Estimating Equations (GEE)
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.56
	Confidence Interval	(2-Sided) 95%; 0.35 to 0.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline Over the Course of the 26-week Initial Treatment Period in Physical Function Measured by Participants Using the Western Ontario and McMaster Universities Osteoarthritis Index Likert Scale (WOMAC LK Version 3.1) C (Function) Subscale
Description	The change from baseline over the course of the 26-week initial treatment period using participants' assessment of physical function. Mean scores were used for baseline (day 0) and for all visits up to week 26 (weeks 4, 8, 12, 18 and 26). The WOMAC Function Subscale has a score range of 0-4 to assess the degree of difficulty completing tasks within the past 48 hours, where 0=no difficulty and 4=extreme difficulty.
Time Frame	Day 0, up to week 26

Outcome Measure Data

Analysis Population Description

Intent-To-Treat (ITT) population.

Arm/Group Title	Synvisc	Saline Control
Arm/Group Description	Participants with symptomatic primary osteoarthritis (OA) of the knee received a single injection of 6 mL hylan G-F 20 (Synvisc) during the Initial Treatment Period.	Participants (control group) with symptomatic primary osteoarthritis (OA) of the knee received a single injection of 6 mL phosphate buffered saline.
Measure Participants	124	129
Mean (Standard Error) [units on a scale]	-0.66 (0.061)	-0.63 (0.059)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Synvisc, Saline Control
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.679
	Comments
	Method	ANCOVA
	Comments

5. Secondary Outcome

Title	Change From Baseline at Week 26 in Physical Function Measured by Participants Using the Western Ontario and McMaster Universities Osteoarthritis Index Likert Scale (WOMAC LK Version 3.1) C (Function) Subscale
Description	The change from baseline to week 26 using participants' assessment of physical function. The WOMAC Function Subscale has a score range of 0-4 to assess the degree of difficulty completing tasks within the past 48 hours, where 0=no difficulty and 4=extreme difficulty.
Time Frame	Day 0, Week 26

Outcome Measure Data

Analysis Population Description

Intent-To-Treat (ITT) population.

Arm/Group Title	Synvisc	Saline Control
Arm/Group Description	Participants with symptomatic primary osteoarthritis (OA) of the knee received a single injection of 6 mL hylan G-F 20 (Synvisc) during the Initial Treatment Period.	Participants (control group) with symptomatic primary osteoarthritis (OA) of the knee received a single injection of 6 mL phosphate buffered saline.
Measure Participants	124	129
Mean (Standard Error) [units on a scale]	-0.59 (0.076)	-0.48 (0.074)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Synvisc, Saline Control
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.266
	Comments
	Method	ANCOVA
	Comments

6. Secondary Outcome

Title	Participant Global Assessment (PTGA) of the Target Knee Osteoarthritis Condition at Week 26
Description	The Participant Global Assessment (PTGA) was used by participants to rate their osteoarthritis (OA). PTGA uses 5 scoring levels: Very well=0, Well=1, Fair=2, Poor=3, Very poor=4.
Time Frame	Week 26

Outcome Measure Data

Analysis Population Description

Intent-To-Treat (ITT) population

Arm/Group Title	Synvisc	Saline Control
Arm/Group Description	Participants with symptomatic primary osteoarthritis (OA) of the knee received a single injection of 6 mL hylan G-F 20 (Synvisc) during the Initial Treatment Period.	Participants (control group) with symptomatic primary osteoarthritis (OA) of the knee received a single injection of 6 mL phosphate buffered saline.
Measure Participants	115	117
Very Well	9 7.3%	2 1.6%
Well	33 26.6%	27 20.9%
Fair	50 40.3%	54 41.9%
Poor	21 16.9%	31 24%
Very Poor	2 1.6%	3 2.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Synvisc, Saline Control
	Comments	Model-based estimate of Odds Ratio (Placebo/Synvisc-One) using PTGA data at Week 26.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments
	Method	Generalized Estimating Equations (GEE)
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.51
	Confidence Interval	(2-Sided) 95%; 0.31 to 0.82
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Clinical Observer Global Assessment (COGA) of the Target Knee Osteoarthritis (OA) Condition at Week 26
Description	The Blinded Clinical Observer gave a global assessment (COGA) of the target knee OA. COGA uses 5 scoring levels: Very well=0, Well=1, Fair=2, Poor=3, Very poor=4.
Time Frame	Week 26

Outcome Measure Data

Analysis Population Description

Intent-To-Treat (ITT) population

Arm/Group Title	Synvisc	Saline Control
Arm/Group Description	Participants with symptomatic primary osteoarthritis (OA) of the knee received a single injection of 6 mL hylan G-F 20 (Synvisc) during the Initial Treatment Period.	Participants (control group) with symptomatic primary osteoarthritis (OA) of the knee received a single injection of 6 mL phosphate buffered saline.
Measure Participants	115	117
Very Well	13 10.5%	8 6.2%
Well	37 29.8%	31 24%
Fair	38 30.6%	38 29.5%
Poor	22 17.7%	34 26.4%
Very Poor	5 4%	6 4.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Synvisc, Saline Control
	Comments	Model-based estimate of Odds Ratio (Placebo/Synvisc-One) using COGA data at Week 26.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.025
	Comments
	Method	Generalized Estimating Equations (GEE)
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.56
	Confidence Interval	(2-Sided) 95%; 0.34 to 0.93
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Participants Classified as Responders Per the Outcome Measures in Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) Criteria at Week 26
Description	Participants were classified as a positive responder if at least one of the following two conditions were met: A significant improvement in either the pain (WOMAC A) or physical function (WOMAC C) subscales, defined as both a ≥ 50% improvement from Baseline and an absolute change from Baseline of ≥ 20 normalised units (NU), OR Improvement in at least 2 of 3 subscales - pain (WOMAC A), physical function (WOMAC C) or Participant Global Assessment (PTGA). Improvement for all three scales is defined as ≥ 20% improvement from Baseline and an absolute change from Baseline of ≥ 10 NU
Time Frame	Week 26

Outcome Measure Data

Analysis Population Description

Intent-To-Treat (ITT) population.

Arm/Group Title	Synvisc	Saline Control
Arm/Group Description	Participants with symptomatic primary osteoarthritis (OA) of the knee received a single injection of 6 mL hylan G-F 20 (Synvisc) during the Initial Treatment Period.	Participants (control group) with symptomatic primary osteoarthritis (OA) of the knee received a single injection of 6 mL phosphate buffered saline.
Measure Participants	123	129
Responder - meets OMERACT-OARSI criteria	73 58.9%	66 51.2%
NonResponder -does not meet OMERACT-OARSI criteria	43 34.7%	52 40.3%
NonResponder - Withdrew Before Study Completion	7 5.6%	11 8.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Synvisc, Saline Control
	Comments	Estimate of Odds Ratio (Placebo/Synvisc-One) using Responder classification data at Week 26.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.156
	Comments
	Method	Generalized Estimating Equations (GEE)
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95%; 0.41 to 1.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Initial treatment period: Day 1 to Week 26. Repeat treatment period: Week 26 to Week 30.
Adverse Event Reporting Description	In the event a single participant has experienced both a serious and a non-serious form of the same adverse event term, the individual has been included in the numerator ("number of affected participants") of both adverse event tables. Events are listed independent of relationship to treatment reported.
Arm/Group Title	Synvisc - Initial Treatment Period		Saline Control - Initial Treatment Period		Synvisc - Repeat Treatment Period		Synvisc (From Saline Control) - Repeat Treatment Period
Arm/Group Description	Participants with symptomatic primary osteoarthritis (OA) of the knee received a single injection of 6 mL hylan G-F 20 (Synvisc) during the Initial Treatment Period (up to week 26).		Participants (control group) with symptomatic primary osteoarthritis (OA) of the knee received a single injection of 6 mL phosphate buffered saline during the initial treatment period.		Participants from the Synvisc Initial Treatment Period had the opportunity to receive 6 mL hylan G-F 20 (Synvisc) during the Repeat Treatment Period (weeks 26-30).		Participants from the Saline Control Initial Treatment Period had the opportunity to receive 6 mL hylan G-F 20 (Synvisc) during the Repeat Treatment Period (weeks 26-30).
All Cause Mortality
	Synvisc - Initial Treatment Period		Saline Control - Initial Treatment Period		Synvisc - Repeat Treatment Period		Synvisc (From Saline Control) - Repeat Treatment Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Synvisc - Initial Treatment Period		Saline Control - Initial Treatment Period		Synvisc - Repeat Treatment Period		Synvisc (From Saline Control) - Repeat Treatment Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/123 (4.1%)		3/130 (2.3%)		0/77 (0%)		2/83 (2.4%)
Cardiac disorders
Angina pectoris	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Atrial fibrillation	0/123 (0%)		0/130 (0%)		0/77 (0%)		1/83 (1.2%)
Bradycardia	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Sinus arrest	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Gastrointestinal disorders
Inguinal hernia	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
General disorders
Hernia	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Non-cardiac chest pain	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Injury, poisoning and procedural complications
Femur fracture	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia	0/123 (0%)		0/130 (0%)		0/77 (0%)		1/83 (1.2%)
Prostate cancer	0/123 (0%)		0/130 (0%)		0/77 (0%)		1/83 (1.2%)
Transitional cell carcinoma	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Nervous system disorders
Radial nerve palsy	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Other (Not Including Serious) Adverse Events
	Synvisc - Initial Treatment Period		Saline Control - Initial Treatment Period		Synvisc - Repeat Treatment Period		Synvisc (From Saline Control) - Repeat Treatment Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	70/123 (56.9%)		77/130 (59.2%)		9/77 (11.7%)		11/83 (13.3%)
Cardiac disorders
Arrhythmia	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Sinus arrhythmia	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Gastrointestinal disorders
Abdominal pain	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Constipation	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Diarrhoea	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Gastritis	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Hiatus hernia	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Nausea	0/123 (0%)		2/130 (1.5%)		0/77 (0%)		0/83 (0%)
Toothache	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Vomiting	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
General disorders
Gait disturbance	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Hernia	1/123 (0.8%)		0/130 (0%)		1/77 (1.3%)		0/83 (0%)
Influenza like illness	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Injection site haematoma	0/123 (0%)		0/130 (0%)		1/77 (1.3%)		0/83 (0%)
Injection site pain	1/123 (0.8%)		1/130 (0.8%)		1/77 (1.3%)		2/83 (2.4%)
Malaise	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Oedema peripheral	0/123 (0%)		2/130 (1.5%)		0/77 (0%)		0/83 (0%)
Pyrexia	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Hepatobiliary disorders
Cholecystitis	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Infections and infestations
Bronchitis	2/123 (1.6%)		3/130 (2.3%)		2/77 (2.6%)		0/83 (0%)
Cellulitis	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Cystitis	2/123 (1.6%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Dental caries	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Erysipelas	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Herpes zoster	1/123 (0.8%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Herpes zoster ophthalmic	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Infected insect bite	0/123 (0%)		0/130 (0%)		0/77 (0%)		1/83 (1.2%)
Influenza	4/123 (3.3%)		7/130 (5.4%)		0/77 (0%)		1/83 (1.2%)
Lower respiratory tract infection	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		1/83 (1.2%)
Mastitis	0/123 (0%)		0/130 (0%)		0/77 (0%)		1/83 (1.2%)
Nasopharyngitis	5/123 (4.1%)		7/130 (5.4%)		0/77 (0%)		0/83 (0%)
Oral fungal infection	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Pharyngitis	3/123 (2.4%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Pharyngitis bacterial	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Respiratory tract infection	3/123 (2.4%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Sinusitis	2/123 (1.6%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Upper respiratory tract infection	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Urinary tract infection	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Viral infection	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Injury, poisoning and procedural complications
Contusion	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Fall	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Hand fracture	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Joint dislocation	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Post-traumatic pain	3/123 (2.4%)		3/130 (2.3%)		0/77 (0%)		0/83 (0%)
Procedural pain	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Thermal burn	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Investigations
Heart rate increased	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Helicobacter pylori identification test positive	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	32/123 (26%)		30/130 (23.1%)		4/77 (5.2%)		2/83 (2.4%)
Arthritis	1/123 (0.8%)		0/130 (0%)		1/77 (1.3%)		0/83 (0%)
Arthropathy	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		1/83 (1.2%)
Back pain	8/123 (6.5%)		10/130 (7.7%)		0/77 (0%)		0/83 (0%)
Bone pain	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Bursitis	0/123 (0%)		0/130 (0%)		1/77 (1.3%)		0/83 (0%)
Exostosis	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Joint effusion	7/123 (5.7%)		7/130 (5.4%)		0/77 (0%)		0/83 (0%)
Joint range of motion decreased	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Joint stiffness	10/123 (8.1%)		13/130 (10%)		1/77 (1.3%)		0/83 (0%)
Joint swelling	5/123 (4.1%)		7/130 (5.4%)		0/77 (0%)		1/83 (1.2%)
Joint warmth	2/123 (1.6%)		5/130 (3.8%)		0/77 (0%)		0/83 (0%)
Muscle spasms	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Musculoskeletal chest pain	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Neck pain	1/123 (0.8%)		3/130 (2.3%)		0/77 (0%)		0/83 (0%)
Osteitis	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Osteoarthritis	0/123 (0%)		3/130 (2.3%)		0/77 (0%)		0/83 (0%)
Pain in extremity	1/123 (0.8%)		3/130 (2.3%)		0/77 (0%)		0/83 (0%)
Periarthritis	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Rotator cuff syndrome	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Shoulder pain	4/123 (3.3%)		2/130 (1.5%)		0/77 (0%)		0/83 (0%)
Spinal disorder	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Spinal osteoarthritis	0/123 (0%)		0/130 (0%)		0/77 (0%)		1/83 (1.2%)
Synovial cyst	0/123 (0%)		2/130 (1.5%)		0/77 (0%)		2/83 (2.4%)
Tendon disorder	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Nervous system disorders
Carpal tunnel syndrome	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Cervical root pain	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Dizziness	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Headache	9/123 (7.3%)		15/130 (11.5%)		0/77 (0%)		0/83 (0%)
Hypoaesthesia	0/123 (0%)		0/130 (0%)		0/77 (0%)		1/83 (1.2%)
Migraine	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Nerve compression	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Paraesthesia	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Sciatica	2/123 (1.6%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Syncope vasovagal	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Trigeminal neuralgia	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Psychiatric disorders
Depressed mood	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Depression	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Insomnia	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Panic attack	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Stress	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Respiratory, thoracic and mediastinal disorders
Asthma	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Cough	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Pharyngolaryngeal pain	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Pneumonitis	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Sinus disorder	1/123 (0.8%)		0/130 (0%)		0/77 (0%)		0/83 (0%)
Skin and subcutaneous tissue disorders
Pruritus generalised	0/123 (0%)		1/130 (0.8%)		0/77 (0%)		0/83 (0%)
Vascular disorders
Hypertension	2/123 (1.6%)		0/130 (0%)		0/77 (0%)		0/83 (0%)

Limitations/Caveats

[Not Specified]

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

In multi-site studies, principal investigator (PI) can publish after Genzyme publishes or 18 months after study completion. PI gives Genzyme a draft 60 days before publication. Genzyme can ask that confidential information be removed, and can defer publication another 60 days upon notifying PI that it will file a patent application on inventions contained in the draft.