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

• ClinicalTrials.gov Identifier: NCT03190369
• Recruitment Status: Completed
• First Posted: June 16, 2017
• Results First Posted: February 5, 2020
• Last Update Posted: February 6, 2020
• Sponsor: Genzyme, a Sanofi Company
• Information provided by (Responsible Party): Sanofi ( Genzyme, a Sanofi Company )

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Osteoarthritis
• Interventions: Device: Hylan G-F 20 (GZ402662/SAR402662); Drug: Placebo
• Enrollment: 440

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 Details	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
Reason Not Completed
Poor compliance to protocol	0	1
Withdraw before treatment	1	5
Randomized but not treated	0	2

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 Number of Baseline Participants		220	220	440
Baseline Analysis Population Description		Analysis was performed on randomized population which consisted of all participants with a treatment kit number allocated and recorded in IVRS/IWRS database, and regardless of whether the treatment kit was used or not.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	220 participants	220 participants	440 participants
		61.6 (7.8)	61.5 (7.9)	61.5 (7.9)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	220 participants	220 participants	440 participants
	Female	172 78.2%	170 77.3%	342 77.7%
	Male	48 21.8%	50 22.7%	98 22.3%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	220 participants	220 participants	440 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	220 100.0%	220 100.0%	440 100.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	0 0.0%	0 0.0%	0 0.0%
	White	0 0.0%	0 0.0%	0 0.0%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	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.
Overall Number of Participants Analyzed	220	218
Least Squares Mean (Standard Error); Unit of Measure: 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	[Not Specified]
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	[Not Specified]

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.
Overall Number of Participants Analyzed	220	218
Least Squares Mean (Standard Error); Unit of Measure: 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.
Overall Number of Participants Analyzed	220	218
Least Squares Mean (Standard Error); Unit of Measure: 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.
Overall Number of Participants Analyzed	220	218
Least Squares Mean (Standard Error); Unit of Measure: 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.
Overall Number of Participants Analyzed	220	218
Least Squares Mean (Standard Error); Unit of Measure: 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.
Overall Number of Participants Analyzed	220	218
Measure Type: Number; Unit of Measure: percentage of participants
Week 4	58.6	53.2
Week 8	65.0	62.4
Week 12	66.4	62.8
Week 16	69.1	63.3
Week 20	65.0	66.5
Week 26	68.2	67.0

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.
Overall Number of Participants Analyzed	220	218
Measure Type: Count of Participants; Unit of Measure: Participants
	142 64.5%	134 61.5%

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 (%)		Affected / at Risk (%)
Total	0/220 (0.00%)		0/218 (0.00%)
Serious Adverse Events
	Placebo		Hylan G-F 20
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/220 (4.55%)		14/218 (6.42%)
Cardiac disorders
Arteriosclerosis Coronary Artery † 1	0/220 (0.00%)	0	1/218 (0.46%)	1
Gastrointestinal disorders
Abdominal Adhesions † 1	0/220 (0.00%)	0	1/218 (0.46%)	1
Infections and infestations
Bronchitis † 1	0/220 (0.00%)	0	1/218 (0.46%)	1
Hepatitis B † 1	1/220 (0.45%)	1	0/218 (0.00%)	0
Pneumonia † 1	2/220 (0.91%)	2	2/218 (0.92%)	2
Injury, poisoning and procedural complications
Joint Injury † 1	1/220 (0.45%)	1	0/218 (0.00%)	0
Ligament Sprain † 1	0/220 (0.00%)	0	1/218 (0.46%)	1
Radius Fracture † 1	1/220 (0.45%)	1	0/218 (0.00%)	0
Metabolism and nutrition disorders
Type 2 Diabetes Mellitus † 1	1/220 (0.45%)	1	0/218 (0.00%)	0
Musculoskeletal and connective tissue disorders
Intervertebral Disc Protrusion † 1	1/220 (0.45%)	1	0/218 (0.00%)	0
Lumbar Spinal Stenosis † 1	0/220 (0.00%)	0	1/218 (0.46%)	1
Spinal Osteoarthritis † 1	1/220 (0.45%)	1	1/218 (0.46%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon Cancer † 1	0/220 (0.00%)	0	1/218 (0.46%)	1
Lung Adenocarcinoma † 1	0/220 (0.00%)	0	1/218 (0.46%)	1
Ovarian Fibroma † 1	0/220 (0.00%)	0	1/218 (0.46%)	1
Rectal Cancer † 1	0/220 (0.00%)	0	1/218 (0.46%)	1
Renal Cell Carcinoma † 1	0/220 (0.00%)	0	1/218 (0.46%)	1
Nervous system disorders
Cerebral Infarction † 1	1/220 (0.45%)	1	1/218 (0.46%)	1
Lacunar Infarction † 1	0/220 (0.00%)	0	1/218 (0.46%)	1
Reproductive system and breast disorders
Uterine Polyp † 1	1/220 (0.45%)	1	0/218 (0.00%)	0
Vascular disorders
Hypertension † 1	1/220 (0.45%)	1	2/218 (0.92%)	2
1 Term from vocabulary, MedDRA 21.1; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo		Hylan G-F 20
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	66/220 (30.00%)		75/218 (34.40%)
Gastrointestinal disorders
Toothache † 1	8/220 (3.64%)	9	11/218 (5.05%)	16
Infections and infestations
Nasopharyngitis † 1	12/220 (5.45%)	18	13/218 (5.96%)	14
Upper Respiratory Tract Infection † 1	30/220 (13.64%)	40	28/218 (12.84%)	31
Musculoskeletal and connective tissue disorders
Arthralgia † 1	24/220 (10.91%)	29	26/218 (11.93%)	35
Joint Swelling † 1	4/220 (1.82%)	5	16/218 (7.34%)	18
1 Term from vocabulary, MedDRA 21.1; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS 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.

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.

Results Point of Contact

• Name/Title: Trial Transparency Team
• Organization: Sanofi aventis recherche & développement
• Phone: 800-633-1610 ext 1#
• EMail: Contact-US@sanofi.com

• Responsible Party: Sanofi ( Genzyme, a Sanofi Company )
• ClinicalTrials.gov Identifier: NCT03190369
• Other Study ID Numbers: EFC12723; U1111-1131-0507 ( Other Identifier: UTN )
• First Submitted: June 14, 2017
• First Posted: June 16, 2017
• Results First Submitted: January 19, 2020
• Results First Posted: February 5, 2020
• Last Update Posted: February 6, 2020