C-SOUND: Randomized Study of the Efficacy and Safety of a Single Dose of Synvisc-One® in Chinese Patients With Symptomatic Osteoarthritis of the Knee

• Sponsor: Genzyme, a Sanofi Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03190369
• Collaborator: (none)
• Enrollment: 440
• Locations: 21
• Arms: 2
• Actual Duration (Months): 17.2
• Patients Per Site: 21
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

Primary Objective:

-To evaluate the efficacy of a single 6-milliliter (mL) intra-articular (IA) injection of Hylan G-F 20 measured by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Numerical Rating Scale (NRS) 3.1 A1 score, in comparison to an IA placebo injection over 26 weeks, in Chinese participants with symptomatic Osteoarthritis (OA) of the knee.

Secondary Objectives:

• To evaluate the efficacy of a single 6-mL IA injection of Hylan G-F 20 measured by 7-day average score of WOMAC A1 pain sub-score in comparison to an IA placebo injection over 26 weeks.

• To evaluate the efficacy of a single 6-mL IA injection of Hylan G-F 20 measured by WOMAC A, patient global assessment (PTGA) and clinical observer global assessment (COGA) in comparison to an IA placebo injection over 26 weeks.

• To evaluate the response rate of a single 6-mL IA injection of Hylan G-F 20 in comparison to an IA placebo injection over 26 weeks. Response was defined as WOMAC A1 greater than or equal to (>=) 2-point improvement from baseline on NRS.

• To evaluate the safety of a single 6-mL IA injection of Hylan G-F 20, in comparison to an IA placebo injection over 26 weeks.

Condition or Disease	Intervention/Treatment	Phase
Osteoarthritis	Device: Hylan G-F 20 (GZ402662/SAR402662); Drug: Placebo	Phase 3

Detailed Description

The duration of the study was 29 weeks at maximum. The screening and wash-out period lasted for up to 14 days, depending on the half-life of the medications followed by an 8-day baseline period including the treatment day. Overall, there were up to 21 days between signing informed consent (at screening visit) and the randomization (Day 1). Treatment was administered on Day 1, and follow-up period was 26 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 440 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A 26-week, Multicenter, Double-blind, Randomized, Placebo-controlled Parallel Group Study to Evaluate the Efficacy and Safety of a Single Dose of 6 mL of Hylan G-F 20 (Synvisc-One®) in Chinese Patients With Symptomatic Osteoarthritis of the Knee
• Actual Study Start Date: Aug 21, 2017
• Actual Primary Completion Date: Jan 28, 2019
• Actual Study Completion Date: Jan 28, 2019

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Participants received a single IA injection of phosphate buffered saline on Day 1 and were observed for 26 weeks.	Drug: Placebo; Pharmaceutical form: Solution for injection Route of administration: Intra articular
Experimental: Hylan G-F 20 Participants received a single IA injection of 6 mL Hylan G-F 20 (Synvisc-One) on Day 1 and were observed for 26 weeks.	Device: Hylan G-F 20 (GZ402662/SAR402662); Pharmaceutical form: Solution for injection Route of administration: Intra articular; Other Names: Synvisc-One

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A1 Pain (Walking Pain) Subscale Score Over 26 Weeks [From Baseline up to Week 26]

   The WOMAC Numerical Rating Scale (NRS) version 3.1 questionnaire was a self-administered, health status measure questionnaire of 24 questions comprising 3 subscales (joint pain, stiffness and physical function) for participants with Osteoarthritis (OA) of the knee. WOMAC A1 pain subscale (measure of pain during walking on a flat surface) was measured on 11-point (NRS) ranging from 0 (none) to 10 (extreme), where lower score represented no pain and higher score represented extreme pain.

Secondary Outcome Measures

1. Change From Baseline in 7-day Average WOMAC A1 Pain (Walking Pain) Subscale Score Over 26 Weeks [From Baseline up to Week 26]

   The WOMAC NRS version 3.1 questionnaire was a self-administered, health status measure questionnaire of 24 questions comprising 3 subscales (joint pain, stiffness and physical function) for participants with OA of the knee. WOMAC A1 pain subscale (measure of pain during walking on a flat surface) was measured on 11-point (NRS) ranging from 0 (none) to 10 (extreme), where lower score represented no pain and higher score represented extreme pain. For 7-day average WOMAC A1, the baseline value was defined as the average of the WOMAC A1 scores recorded 7 days prior to the first investigational medicinal product (IMP) administration (WOMAC A1 score recorded on Day 1 included). The 7-day average WOMAC A1 was set as missing if 3 or more of the 7 WOMAC A1 scores were missing.

2. Change From Baseline in WOMAC A Score Over 26 Weeks [From Baseline up to Week 26]

   The WOMAC NRS version 3.1 questionnaire was a self-administered, health status measure questionnaire of 24 questions comprising 3 subscales (joint pain, stiffness and physical function) for participants with OA of the knee. WOMAC A (5 items: measure of pain while walking, using stairs, at night while in bed, sitting or lying, and standing); each item was measured on 11-point (NRS) ranging from 0 (none) to 10 (extreme), where lower score represented no pain and higher score represented extreme pain. Total WOMAC A score was the sum of 5 item scores and ranges from 0 (none) to 50 (extreme); where lower score represented no pain and higher score represented extreme pain.

3. Change From Baseline in Patient Global Self-Assessment (PTGA) Score of Osteoarthritis Over 26 Weeks [From Baseline up to Week 26]

   PTGA (self-assessment of target knee OA condition) was measured using an 11-point NRS ranging from 0 (best possible) to 10 (worst possible), where lower score represented best possible condition and higher score represented worst possible condition.

4. Change From Baseline in Clinical Observer Global Assessment (COGA) Score of Osteoarthritis Over 26 Weeks [From Baseline up to Week 26]

   COGA was used by the physicians to perform a global assessment of the participant's target knee OA condition. The response was captured using the 11-point NRS pain intensity rating scale ranging from 0 (best possible) to 10 (worst possible) at the specified time points, where lower score represented best possible condition and higher score represented worst possible condition.

5. Percentage of Positive WOMAC A1 Responder Over 26 Weeks [Week 4, Week 8, Week 12, Week 16, Week 20 and Week 26]

   WOMAC A1 responder were defined as >=2-point improvement from baseline in the WOMAC A1 NRS. The WOMAC NRS version 3.1 questionnaire was a self-administered, health status measure questionnaire of 24 questions comprising 3 subscales (joint pain, stiffness and physical function) for participants with OA of the knee. WOMAC A1 pain subscale (measure of pain during walking on a flat surface) was measured on 11-point (NRS) ranging from 0 (none) to 10 (extreme), where lower score represented no pain and higher score represented extreme pain.

6. Number of Participants With Treatment Emergent Adverse Events (TEAEs) [From Baseline up to Week 26]

   Adverse Event (AE) was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily had a causal relationship with the treatment. TEAEs were defined as AEs that developed, worsened (according to the Investigator opinion), or became serious during the on-treatment period (time from the injection of IMP up to Week 26 follow-up visit).

Eligibility Criteria

Criteria

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

Inclusion criteria :

• Symptomatic OA of the target knee joint with WOMAC A1 NRS score of >=4.0 and less than or equal to (<=) 8.0 as recorded in the baseline period.

• Confirmed by standard X-rays performed within 3 months prior to screening visit: modified Kellgren-Lawrence Numerical Grading System of Grade I-III in the target knee joint.

• According to the American College of Rheumatology (ACR) Criteria.

• With failure to respond adequately to conservative non-pharmacologic therapy and/or simple analgesics, such as acetaminophen.

• Participant was willing and was able to provide signed informed consent prior to any study related procedures being performed.

Exclusion criteria:

• The score of contralateral knee pain (if present) >3.0 NRS at screening visit.

• Ipsilateral hip OA.

• Participant with systemic corticosteroids within 12 weeks prior to screening visit.

• Participant with injection of IA corticosteroids in the target knee joint within 26 weeks prior to screening visit.

• Concurrent chronic pain conditions with pain score >3.0 NRS at screening, or peripheral or central neuropathy that may affect sensation of the target knee area, including but not limited to back pain, hip pain, disc herniation, sciatica, diabetic neuropathy, post-stroke pain or fibromyalgia.

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigational Site Number 1560001	Beijing		China	100044
2	Investigational Site Number 1560005	Beijing		China	100050
3	Investigational Site Number 1560020	Beijing		China	100191
4	Investigational Site Number 1560009	Beijing		China	100730
5	Investigational Site Number 1560012	Changchun		China	130021
6	Investigational Site Number 1560013	Changsha		China	410008
7	Investigational Site Number 1560023	Chengdu		China	610041
8	Investigational Site Number 1560016	Guangzhou		China	510080
9	Investigational Site Number 1560011	Hohhot		China	010017
10	Investigational Site Number 1560017	Kunming		China	650032
11	Investigational Site Number 1560019	Nanjing		China	210009
12	Investigational Site Number 1560021	Nanjing		China	210029
13	Investigational Site Number 1560007	Qingdao		China	266003
14	Investigational Site Number 1560002	Shanghai		China	200011
15	Investigational Site Number 1560003	Shanghai		China	200032
16	Investigational Site Number 1560022	Shanghai		China	200072
17	Investigational Site Number 1560018	Taiyuan		China	030001
18	Investigational Site Number 1560010	Tianjin		China	300052
19	Investigational Site Number 1560015	Tianjin		China	300192
20	Investigational Site Number 1560006	Wuhan		China	430033
21	Investigational Site Number 1560008	Wuxi		China	214023

Sponsors and Collaborators

• Genzyme, a Sanofi Company

Investigators

• Study Director: Clinical Sciences & Operations, Sanofi

Study Documents (Full-Text)

• Study Protocol - Feb 17, 2017
• Statistical Analysis Plan - Jan 28, 2019

More Information

Publications

None provided.

• Responsible Party: Genzyme, a Sanofi Company
• ClinicalTrials.gov Identifier: NCT03190369
• Other Study ID Numbers: EFC12723; U1111-1131-0507
• First Posted: Jun 16, 2017
• Last Update Posted: Mar 25, 2022
• Last Verified: Mar 1, 2022

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

Study Results

Participant Flow

Recruitment Details	The study was conducted at 21 sites in China from 21 August 2017 to 28 January 2019. A total of 524 participants were screened, of which, 84 participants were screen failures. Screen failures were mainly due to inclusion criteria not met.
Pre-assignment Detail	A total of 440 participants were enrolled and randomized in the study. Assignment to arms was done centrally using an interactive voice response system/interactive web response system (IVRS/IWRS) in 1:1 ratio (Placebo: Hylan G-F 20).

Arm/Group Title	Placebo	Hylan G-F 20
Arm/Group Description	Participants received a single intra-articular (IA) injection of phosphate buffered saline on Day 1 and were observed for 26 weeks.	Participants received a single IA injection of 6 mL Hylan G-F 20 (Synvisc-One) on Day 1 and were observed for 26 weeks.
Period Title: Overall Study
STARTED	220	220
Treated	220	218
COMPLETED	219	212
NOT COMPLETED	1	8

Baseline Characteristics

Arm/Group Title	Placebo	Hylan G-F 20	Total
Arm/Group Description	Participants received a single IA injection of phosphate buffered saline on Day 1 and were observed for 26 weeks.	Participants received a single IA injection of 6 mL Hylan G-F 20 (Synvisc-One) on Day 1 and were observed for 26 weeks.	Total of all reporting groups
Overall Participants	220	220	440
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.6 (7.8)	61.5 (7.9)	61.5 (7.9)
Sex: Female, Male (Count of Participants)
Female	172 78.2%	170 77.3%	342 77.7%
Male	48 21.8%	50 22.7%	98 22.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	220 100%	220 100%	440 100%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A1 Pain (Walking Pain) Subscale Score Over 26 Weeks
Description	The WOMAC Numerical Rating Scale (NRS) version 3.1 questionnaire was a self-administered, health status measure questionnaire of 24 questions comprising 3 subscales (joint pain, stiffness and physical function) for participants with Osteoarthritis (OA) of the knee. WOMAC A1 pain subscale (measure of pain during walking on a flat surface) was measured on 11-point (NRS) ranging from 0 (none) to 10 (extreme), where lower score represented no pain and higher score represented extreme pain.
Time Frame	From Baseline up to Week 26

Outcome Measure Data

Analysis Population Description

Analysis was performed on modified Intent-To-Treat (mITT) population which included all randomized and treated participants. Participants were analyzed in the treatment group to which they were randomized.

Arm/Group Title	Placebo	Hylan G-F 20
Arm/Group Description	Participants received a single IA injection of phosphate buffered saline on Day 1 and were observed for 26 weeks.	Participants received a single IA injection of 6 mL Hylan G-F 20 (Synvisc-One) on Day 1 and were observed for 26 weeks.
Measure Participants	220	218
Least Squares Mean (Standard Error) [score on a scale]	-2.271 (0.110)	-2.146 (0.108)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Hylan G-F 20
	Comments	Least-square (LS) means, standard errors (SE) were analyzed from repeated measures analysis of covariance (ANCOVA). The model included treatment groups (Hylan G-F 20 and placebo), site, visit and visit by treatment interaction, as well as the baseline WOMAC A1 score as a covariate).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3610
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments	Least-square (LS) means, standard errors (SE) were analyzed from repeated measures ANCOVA.
Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	0.125
	Confidence Interval	(2-Sided) 95%; -0.144 to 0.395
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.137
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in 7-day Average WOMAC A1 Pain (Walking Pain) Subscale Score Over 26 Weeks
Description	The WOMAC NRS version 3.1 questionnaire was a self-administered, health status measure questionnaire of 24 questions comprising 3 subscales (joint pain, stiffness and physical function) for participants with OA of the knee. WOMAC A1 pain subscale (measure of pain during walking on a flat surface) was measured on 11-point (NRS) ranging from 0 (none) to 10 (extreme), where lower score represented no pain and higher score represented extreme pain. For 7-day average WOMAC A1, the baseline value was defined as the average of the WOMAC A1 scores recorded 7 days prior to the first investigational medicinal product (IMP) administration (WOMAC A1 score recorded on Day 1 included). The 7-day average WOMAC A1 was set as missing if 3 or more of the 7 WOMAC A1 scores were missing.
Time Frame	From Baseline up to Week 26

Outcome Measure Data

Analysis Population Description

Analysis was performed on mITT population.

Arm/Group Title	Placebo	Hylan G-F 20
Arm/Group Description	Participants received a single IA injection of phosphate buffered saline on Day 1 and were observed for 26 weeks.	Participants received a single IA injection of 6 mL Hylan G-F 20 (Synvisc-One) on Day 1 and were observed for 26 weeks.
Measure Participants	220	218
Least Squares Mean (Standard Error) [score on a scale]	-2.275 (0.108)	-2.176 (0.106)

3. Secondary Outcome

Title	Change From Baseline in WOMAC A Score Over 26 Weeks
Description	The WOMAC NRS version 3.1 questionnaire was a self-administered, health status measure questionnaire of 24 questions comprising 3 subscales (joint pain, stiffness and physical function) for participants with OA of the knee. WOMAC A (5 items: measure of pain while walking, using stairs, at night while in bed, sitting or lying, and standing); each item was measured on 11-point (NRS) ranging from 0 (none) to 10 (extreme), where lower score represented no pain and higher score represented extreme pain. Total WOMAC A score was the sum of 5 item scores and ranges from 0 (none) to 50 (extreme); where lower score represented no pain and higher score represented extreme pain.
Time Frame	From Baseline up to Week 26

Outcome Measure Data

Analysis Population Description

Analysis was performed on mITT population.

Arm/Group Title	Placebo	Hylan G-F 20
Arm/Group Description	Participants received a single IA injection of phosphate buffered saline on Day 1 and were observed for 26 weeks.	Participants received a single IA injection of 6 mL Hylan G-F 20 (Synvisc-One) on Day 1 and were observed for 26 weeks.
Measure Participants	220	218
Least Squares Mean (Standard Error) [score on a scale]	-8.747 (0.491)	-8.621 (0.486)

4. Secondary Outcome

Title	Change From Baseline in Patient Global Self-Assessment (PTGA) Score of Osteoarthritis Over 26 Weeks
Description	PTGA (self-assessment of target knee OA condition) was measured using an 11-point NRS ranging from 0 (best possible) to 10 (worst possible), where lower score represented best possible condition and higher score represented worst possible condition.
Time Frame	From Baseline up to Week 26

Outcome Measure Data

Analysis Population Description

Analysis was performed on mITT population.

Arm/Group Title	Placebo	Hylan G-F 20
Arm/Group Description	Participants received a single IA injection of phosphate buffered saline on Day 1 and were observed for 26 weeks.	Participants received a single IA injection of 6 mL Hylan G-F 20 (Synvisc-One) on Day 1 and were observed for 26 weeks.
Measure Participants	220	218
Least Squares Mean (Standard Error) [score on a scale]	-2.138 (0.104)	-2.144 (0.102)

5. Secondary Outcome

Title	Change From Baseline in Clinical Observer Global Assessment (COGA) Score of Osteoarthritis Over 26 Weeks
Description	COGA was used by the physicians to perform a global assessment of the participant's target knee OA condition. The response was captured using the 11-point NRS pain intensity rating scale ranging from 0 (best possible) to 10 (worst possible) at the specified time points, where lower score represented best possible condition and higher score represented worst possible condition.
Time Frame	From Baseline up to Week 26

Outcome Measure Data

Analysis Population Description

Analysis was performed on mITT population.

Arm/Group Title	Placebo	Hylan G-F 20
Arm/Group Description	Participants received a single IA injection of phosphate buffered saline on Day 1 and were observed for 26 weeks.	Participants received a single IA injection of 6 mL Hylan G-F 20 (Synvisc-One) on Day 1 and were observed for 26 weeks.
Measure Participants	220	218
Least Squares Mean (Standard Error) [score on a scale]	-2.145 (0.095)	-2.225 (0.094)

6. Secondary Outcome

Title	Percentage of Positive WOMAC A1 Responder Over 26 Weeks
Description	WOMAC A1 responder were defined as >=2-point improvement from baseline in the WOMAC A1 NRS. The WOMAC NRS version 3.1 questionnaire was a self-administered, health status measure questionnaire of 24 questions comprising 3 subscales (joint pain, stiffness and physical function) for participants with OA of the knee. WOMAC A1 pain subscale (measure of pain during walking on a flat surface) was measured on 11-point (NRS) ranging from 0 (none) to 10 (extreme), where lower score represented no pain and higher score represented extreme pain.
Time Frame	Week 4, Week 8, Week 12, Week 16, Week 20 and Week 26

Outcome Measure Data

Analysis Population Description

Analysis was performed on mITT population.

Arm/Group Title	Placebo	Hylan G-F 20
Arm/Group Description	Participants received a single IA injection of phosphate buffered saline on Day 1 and were observed for 26 weeks.	Participants received a single IA injection of 6 mL Hylan G-F 20 (Synvisc-One) on Day 1 and were observed for 26 weeks.
Measure Participants	220	218
Week 4	58.6 26.6%	53.2 24.2%
Week 8	65.0 29.5%	62.4 28.4%
Week 12	66.4 30.2%	62.8 28.5%
Week 16	69.1 31.4%	63.3 28.8%
Week 20	65.0 29.5%	66.5 30.2%
Week 26	68.2 31%	67.0 30.5%

7. Secondary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (TEAEs)
Description	Adverse Event (AE) was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily had a causal relationship with the treatment. TEAEs were defined as AEs that developed, worsened (according to the Investigator opinion), or became serious during the on-treatment period (time from the injection of IMP up to Week 26 follow-up visit).
Time Frame	From Baseline up to Week 26

Outcome Measure Data

Analysis Population Description

Analysis was performed on safety population which included randomized participants who received at least 1 injection or part of an injection of Hylan G-F 20 or placebo.

Arm/Group Title	Placebo	Hylan G-F 20
Arm/Group Description	Participants received a single IA injection of phosphate buffered saline on Day 1 and were observed for 26 weeks.	Participants received a single IA injection of 6 mL Hylan G-F 20 (Synvisc-One) on Day 1 and were observed for 26 weeks.
Measure Participants	220	218
Count of Participants [Participants]	142 64.5%	134 60.9%

Adverse Events

Time Frame	AE data was collected from the time of the injection of IMP up to Week 26 follow-up visit.
Adverse Event Reporting Description	Reported AEs are TEAEs that developed, worsened, or became serious during the treatment period (time from the injection of IMP up to Week 26 follow-up visit). Analysis was performed on safety population.
Arm/Group Title	Placebo		Hylan G-F 20
Arm/Group Description	Participants received a single IA injection of phosphate buffered saline on Day 1 and were observed for 26 weeks.		Participants received a single IA injection of 6 mL Hylan G-F 20 (Synvisc-One) on Day 1 and were observed for 26 weeks.
All Cause Mortality
	Placebo		Hylan G-F 20
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/220 (0%)		0/218 (0%)
Serious Adverse Events
	Placebo		Hylan G-F 20
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/220 (4.5%)		14/218 (6.4%)
Cardiac disorders
Arteriosclerosis Coronary Artery	0/220 (0%)	0	1/218 (0.5%)	1
Gastrointestinal disorders
Abdominal Adhesions	0/220 (0%)	0	1/218 (0.5%)	1
Infections and infestations
Bronchitis	0/220 (0%)	0	1/218 (0.5%)	1
Hepatitis B	1/220 (0.5%)	1	0/218 (0%)	0
Pneumonia	2/220 (0.9%)	2	2/218 (0.9%)	2
Injury, poisoning and procedural complications
Joint Injury	1/220 (0.5%)	1	0/218 (0%)	0
Ligament Sprain	0/220 (0%)	0	1/218 (0.5%)	1
Radius Fracture	1/220 (0.5%)	1	0/218 (0%)	0
Metabolism and nutrition disorders
Type 2 Diabetes Mellitus	1/220 (0.5%)	1	0/218 (0%)	0
Musculoskeletal and connective tissue disorders
Intervertebral Disc Protrusion	1/220 (0.5%)	1	0/218 (0%)	0
Lumbar Spinal Stenosis	0/220 (0%)	0	1/218 (0.5%)	1
Spinal Osteoarthritis	1/220 (0.5%)	1	1/218 (0.5%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon Cancer	0/220 (0%)	0	1/218 (0.5%)	1
Lung Adenocarcinoma	0/220 (0%)	0	1/218 (0.5%)	1
Ovarian Fibroma	0/220 (0%)	0	1/218 (0.5%)	1
Rectal Cancer	0/220 (0%)	0	1/218 (0.5%)	1
Renal Cell Carcinoma	0/220 (0%)	0	1/218 (0.5%)	1
Nervous system disorders
Cerebral Infarction	1/220 (0.5%)	1	1/218 (0.5%)	1
Lacunar Infarction	0/220 (0%)	0	1/218 (0.5%)	1
Reproductive system and breast disorders
Uterine Polyp	1/220 (0.5%)	1	0/218 (0%)	0
Vascular disorders
Hypertension	1/220 (0.5%)	1	2/218 (0.9%)	2
Other (Not Including Serious) Adverse Events
	Placebo		Hylan G-F 20
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	66/220 (30%)		75/218 (34.4%)
Gastrointestinal disorders
Toothache	8/220 (3.6%)	9	11/218 (5%)	16
Infections and infestations
Nasopharyngitis	12/220 (5.5%)	18	13/218 (6%)	14
Upper Respiratory Tract Infection	30/220 (13.6%)	40	28/218 (12.8%)	31
Musculoskeletal and connective tissue disorders
Arthralgia	24/220 (10.9%)	29	26/218 (11.9%)	35
Joint Swelling	4/220 (1.8%)	5	16/218 (7.3%)	18

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The Sponsor supports publication of clinical trial results but may request that investigators temporarily delay or alter publications in order to protect proprietary information. The Sponsor may also require that the results of multicenter studies be published only in their entirety and not as individual site data.