A Study of the Efficacy and Safety of Synvisc® in Chinese Subjects With Symptomatic Osteoarthritis of the Knee(s)

• Sponsor: Sanofi (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01586338
• Collaborator: (none)
• Enrollment: 237
• Location: 1
• Arm: 1
• Duration (Months): 18
• Patients Per Site Per Month: 13.1

Study Details

Study Description

Brief Summary

Primary Objective:

• To evaluate the change of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A1 subscore (walking pain) at 26 weeks compared to the Baseline score

• To evaluate the safety using the incidence, severity, seriousness, relatedness, and frequency of all treatment emergent Adverse Events (AEs)

Secondary Objectives:

• To evaluate the change in WOMAC A1 subscore (walking pain) between baseline and weeks 8, and 12

• To evaluate the change in WOMAC A, B and C score between baseline and weeks 8, 12 and 26

• To evaluate the change in Patient Global Assessment (PTGA) score between baseline and weeks 8, 12 and 26

• To evaluate the change in Clinical Observer Global Assessment (COGA) score between baseline and weeks 8, 12 and 26

• To evaluate the change in concomitant Osteoarthritis (OA) therapy over 26 weeks and between baseline and weeks 1, 2, 8, 12 and 26

Condition or Disease	Intervention/Treatment	Phase
Osteoarthritis	Drug: Hylan G-F 20	Phase 4

Detailed Description

Duration of study period for each participants was 26-28 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 237 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Prospective, Open-label, Single Arm Study of the Efficacy and Safety of Synvisc® (Hylan G-F 20) in Chinese Subjects With Symptomatic Osteoarthritis of the Knee(s)
• Study Start Date: Mar 1, 2012
• Actual Primary Completion Date: Sep 1, 2013
• Actual Study Completion Date: Sep 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Synvisc Three intra-articular (IA) injections of Synvisc (2.25 ml glass syringe containing 16 mg hylan G-F 20) at intervals of one week. The total duration of observation was 26 weeks.	Drug: Hylan G-F 20; Intra-articular injection (pre-filled glass syringe); Other Names: Synvisc®

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A1 Subscore (Walking Pain) at Week 26 [Baseline, Week 26 (missing data imputed by Last Observation Carried Forward [LOCF])]

   WOMAC is health status measure questionnaire of twenty-four questions comprising 3 subscales (pain, stiffness and physical function). WOMAC A1 (walking pain) was measured on a scale of 0-100 mm, where lower score represents lower pain and higher score represents higher pain.

2. Overview of Adverse Events (AE) [Up to Week 26]

   An AE could be any unfavorable and unintended symptom, sign, disease or condition, or test abnormality whether or not considered related to the investigational product. A serious adverse event (SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs (TEAE): AEs that developed/worsened during the 'on treatment period' (from first dose of study drug until the end of study period). Category "AE" included participant with both serious and non-serious AE.

Secondary Outcome Measures

1. Change From Baseline in WOMAC A1 Subscore (Walking Pain) at Week 8 and 12 [Baseline, Week 8 and Week 12 (missing data imputed by LOCF)]

   WOMAC is health status measure questionnaire of twenty-four questions comprising 3 subscales (pain, stiffness and physical function). WOMAC A1 (walking pain) was measured on a scale of 0-100 mm, where lower score represents lower pain and higher score represents higher pain.

2. Change From Baseline in WOMAC A, B and C Score at Weeks 8, 12 and 26 [Baseline, Week 8, 12 and 26 (missing data imputed by LOCF)]

   WOMAC is health status measure questionnaire of twenty-four questions comprising 3 subscales (pain, stiffness and physical function). Each question was measured on a scale of 0-100 mm where lower score represents lower pain (better condition) and higher score represents higher pain. WOMAC A (measure of pain during walking on a flat surface) was sum of first five items with total score ranging from 0-500 mm, Lower score represents lower pain and higher score represents higher pain. WOMAC B (Stiffness) is the sum of the sixth and seventh item, it is in the range of 0-200 mm. WOMAC C (function) is the sum of the eighth to twenty-forth item, the score is in the range of 0-1700 mm.

3. Patient Global Assessment (PTGA) Score [Baseline, Week 8, 12 and 26 (missing data imputed by LOCF)]

   PTGA (self-assessment of target knee osteoarthritis condition) was measured using the 5 point Likert scale (0=very well, 1=well, 2=fair, 3=poor, 4=very poor) by participants to rate the osteoarthritis condition. Percentage of participants with different categories of PTGA score at baseline, Week 8, 12 and 26 are reported.

4. Clinical Observer Global Assessment (COGA) Score [Baseline, Week 8, 12 and 26 (missing data imputed by LOCF)]

   COGA (assessment of target knee osteoarthritis condition) was measured using the 5 point Likert scale (0=very well, 1=well, 2=fair, 3=poor, 4=very poor) by the physician to rate participant's osteoarthritis condition. Percentage of participants with different categories of COGA score at baseline,Week 8, 12 and 26 are reported.

5. Percentage of Participants With Change in Concomitant Medication of Osteoarthritis Therapy at Week 26 [Baseline up to Week 26]

   Participants were asked about their perception regarding any additional Osteoarthritis medications or treatments or any changes in regimen or dosages compared to their baseline (Day 1) state. Any change in the therapy (less use of other therapies, more use of other therapies and no change in use of other therapies) during the study was reported.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 30 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria :

1. The participants had a diagnosis of OA of the Target Knee confirmed by recent X-Ray (mild to moderate joint space narrowing and/or osteophytes predominant in the tibiofemoral compartment)

2. WOMAC A1 baseline 100 mm Visual Analog Score (VAS) between 40-80 mm (moderate or severe walking pain) in the Target knee

3. Participants with bilateral disease included in the study with the below strict conditions:

• Only one knee included in the efficacy assessment and considered the Target Knee (The worst knee by the WOMAC A1 pain scale should be selected). The selected knee must meet the inclusion and exclusion criteria

• The non-target knee might also be treated with Synvisc® and did not need to meet the Kellgren-Lawrence (KL) grade knee specific inclusion criteria described above. The other criteria applied, and included in safety assessment

1. Pre-menopausal female participants had a negative urine pregnancy test and continue to use a medically acceptable form of contraception for the duration of the study. Otherwise, females had been surgically sterile, or postmenopausal (as documented in medical history) for at least 1 year

Exclusion criteria:

1. Significant (requiring surgical correction) valgus or varus deformity of the knee, ligamentous laxity, or meniscal instability

2. Concomitant inflammatory or any other disease/condition which might affect joints (e.g., rheumatoid arthritis, metabolic bone disease, psoriasis, gout, pseudogout, chondrocalcinosis etc)

3. History of sepsis in any joint or any clinical concern for a sub-acute infectious process in the target joint

4. History of surgery in the target knee (if done < 6 months)

5. Planned surgery on any lower extremity joint

6. Presence of clinically significant venous or lymphatic stasis in the leg(s)

7. Clinically apparent tense effusion or inflammation at the target knee

8. Skin disease or infection in the area of the injection site

9. Any musculoskeletal condition that would impede measurement of efficacy at the target knee

10. Pregnant or lactating women

11. Hypersensitivities to avian proteins and/or any components of hyaluronan-based injection

12. Treatment with any Hyaluronic Acid (HA) or derivatives in the previous 6 months.

13. Treatment with Intra-Articular (IA) steroid in the previous 3 months

14. Any contra-indication to IA injection e.g., anticoagulant therapy or clinical concern for potential coagulopathy (e.g. liver disease)

15. Any significant medical condition (e.g., significant psychiatric or neurological disorders, active alcohol/drug abuse, etc), any medical condition that is unstable/poorly controlled or other factor (e.g., planned relocation) that the Investigator felt would interfere with study evaluations and study participation

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	Sanofi-Aventis Administrative Office	Shangai		China

Sponsors and Collaborators

• Sanofi

Investigators

• Study Director: Clinical Sciences & Operations, Sanofi

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT01586338
• Other Study ID Numbers: SYNVIL06244; U1111-1129-3321; EFC13912
• First Posted: Apr 26, 2012
• Last Update Posted: Feb 24, 2016
• Last Verified: Jan 1, 2016

• Additional relevant MeSH terms: Osteoarthritis; Osteoarthritis, Knee; Hylan

Study Results

Participant Flow

Recruitment Details	The study was conducted at 10 centers in China. A total of 237 participants were enrolled between March 09, 2012 and February 28, 2013.
Pre-assignment Detail	Of 237 enrolled participants 232 participants were treated. 5 participants were excluded from total enrolled (3 participant due to informed consent filled by family, and 2 participant due to no efficacy data after treatment).

Arm/Group Title	Synvisc
Arm/Group Description	Three intra-articular (IA) injections of Synvisc (2.25 ml glass syringe containing 16 mg hylan G-F 20) at intervals of one week. The total duration of observation was 26 weeks.
Period Title: Overall Study
STARTED	237
COMPLETED	229
NOT COMPLETED	8

Baseline Characteristics

Arm/Group Title	Synvisc
Arm/Group Description	Three IA injections of Synvisc (2.25 ml glass syringe containing 16 mg hylan G-F 20) at intervals of one week. The total duration of observation was 26 weeks.
Overall Participants	237
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.9 (9.56)
Sex: Female, Male (Count of Participants)
Female	183 77.2%
Male	54 22.8%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A1 Subscore (Walking Pain) at Week 26
Description	WOMAC is health status measure questionnaire of twenty-four questions comprising 3 subscales (pain, stiffness and physical function). WOMAC A1 (walking pain) was measured on a scale of 0-100 mm, where lower score represents lower pain and higher score represents higher pain.
Time Frame	Baseline, Week 26 (missing data imputed by Last Observation Carried Forward [LOCF])

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) included all participants who received at least one injection of Synvisc®. 5 participants were excluded from total enrolled (3 participant due to informed consent filled by family, and 2 participant due to no efficacy data after treatment).

Arm/Group Title	Synvisc
Arm/Group Description	Three IA injections of Synvisc (2.25 ml glass syringe containing 16 mg hylan G-F 20) at intervals of one week. The total duration of observation was 26 weeks.
Measure Participants	232
Mean (Standard Deviation) [mm]	-33.0 (17.71)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Synvisc
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Threshold for significance = 0.05.
	Method	Paired t-test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Synvisc
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Sign Rank Test
	Comments

2. Primary Outcome

Title	Overview of Adverse Events (AE)
Description	An AE could be any unfavorable and unintended symptom, sign, disease or condition, or test abnormality whether or not considered related to the investigational product. A serious adverse event (SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs (TEAE): AEs that developed/worsened during the 'on treatment period' (from first dose of study drug until the end of study period). Category "AE" included participant with both serious and non-serious AE.
Time Frame	Up to Week 26

Outcome Measure Data

Analysis Population Description

Safety Set included all participants who received at least one injection of Synvisc.

Arm/Group Title	Synvisc
Arm/Group Description	Three IA injections of Synvisc (2.25 ml glass syringe containing 16 mg hylan G-F 20) at intervals of one week. The total duration of observation was 26 weeks.
Measure Participants	237
AEs	27.8 11.7%
Treatment-emergent AEs	27.8 11.7%
Treatment-emergent SAEs	1.7 0.7%
Treatment-emergent AEs Lead to Discontinuation	0.4 0.2%

3. Secondary Outcome

Title	Change From Baseline in WOMAC A1 Subscore (Walking Pain) at Week 8 and 12
Description	WOMAC is health status measure questionnaire of twenty-four questions comprising 3 subscales (pain, stiffness and physical function). WOMAC A1 (walking pain) was measured on a scale of 0-100 mm, where lower score represents lower pain and higher score represents higher pain.
Time Frame	Baseline, Week 8 and Week 12 (missing data imputed by LOCF)

Outcome Measure Data

Analysis Population Description

FAS population.

Arm/Group Title	Synvisc
Arm/Group Description	Three IA injections of Synvisc (2.25 ml glass syringe containing 16 mg hylan G-F 20) at intervals of one week. The total duration of observation was 26 weeks.
Measure Participants	232
Change form baseline at Week 8	-26.0 (17.68)
Change form baseline at Week 12	-30.0 (17.43)

4. Secondary Outcome

Title	Change From Baseline in WOMAC A, B and C Score at Weeks 8, 12 and 26
Description	WOMAC is health status measure questionnaire of twenty-four questions comprising 3 subscales (pain, stiffness and physical function). Each question was measured on a scale of 0-100 mm where lower score represents lower pain (better condition) and higher score represents higher pain. WOMAC A (measure of pain during walking on a flat surface) was sum of first five items with total score ranging from 0-500 mm, Lower score represents lower pain and higher score represents higher pain. WOMAC B (Stiffness) is the sum of the sixth and seventh item, it is in the range of 0-200 mm. WOMAC C (function) is the sum of the eighth to twenty-forth item, the score is in the range of 0-1700 mm.
Time Frame	Baseline, Week 8, 12 and 26 (missing data imputed by LOCF)

Outcome Measure Data

Analysis Population Description

FAS population.

Arm/Group Title	Synvisc
Arm/Group Description	Three IA injections of Synvisc (2.25 ml glass syringe containing 16 mg hylan G-F 20) at intervals of one week. The total duration of observation was 26 weeks.
Measure Participants	232
WOMAC A: Change from baseline at Week 8	-92.7 (71.77)
WOMAC A: Change from baseline at Week 12	-109.8 (73.68)
WOMAC A: Change from baseline at Week 26	-121.5 (77.18)
WOMAC B: Change from baseline at Week 8	-28.9 (37.53)
WOMAC B: Change from baseline at Week 12	-34.6 (38.44)
WOMAC B: Change from baseline at Week 26	-36.6 (39.75)
WOMAC C: Change from baseline at Week 8	-270.0 (252.86)
WOMAC C: Change from baseline at Week 12	-325.9 (258.57)
WOMAC C: Change from baseline at Week 26	-358.4 (270.48)

5. Secondary Outcome

Title	Patient Global Assessment (PTGA) Score
Description	PTGA (self-assessment of target knee osteoarthritis condition) was measured using the 5 point Likert scale (0=very well, 1=well, 2=fair, 3=poor, 4=very poor) by participants to rate the osteoarthritis condition. Percentage of participants with different categories of PTGA score at baseline, Week 8, 12 and 26 are reported.
Time Frame	Baseline, Week 8, 12 and 26 (missing data imputed by LOCF)

Outcome Measure Data

Analysis Population Description

FAS population.

Arm/Group Title	Synvisc
Arm/Group Description	Three IA injections of Synvisc (2.25 ml glass syringe containing 16 mg hylan G-F 20) at intervals of one week. The total duration of observation was 26 weeks.
Measure Participants	232
Baseline: Very Well	0.0 0%
Baseline: Well	1.3 0.5%
Baseline: Fair	29.3 12.4%
Baseline: Poor	60.3 25.4%
Baseline: Very Poor	9.1 3.8%
Week 8: Very Well	4.3 1.8%
Week 8: Well	41.8 17.6%
Week 8: Fair	46.1 19.5%
Week 8 : Poor	6.9 2.9%
Week 8: Very Poor	0.9 0.4%
Week 12: Very Well	5.2 2.2%
Week 12: Well	44.4 18.7%
Week 12: Fair	44.0 18.6%
Week 12: Poor	6.0 2.5%
Week 12: Very Poor	0.4 0.2%
Week 26: Very Well	8.2 3.5%
Week 26: Well	46.6 19.7%
Week 26: Fair	37.1 15.7%
Week 26: Poor	7.8 3.3%
Week 26: Very Poor	0.4 0.2%

6. Secondary Outcome

Title	Clinical Observer Global Assessment (COGA) Score
Description	COGA (assessment of target knee osteoarthritis condition) was measured using the 5 point Likert scale (0=very well, 1=well, 2=fair, 3=poor, 4=very poor) by the physician to rate participant's osteoarthritis condition. Percentage of participants with different categories of COGA score at baseline,Week 8, 12 and 26 are reported.
Time Frame	Baseline, Week 8, 12 and 26 (missing data imputed by LOCF)

Outcome Measure Data

Analysis Population Description

FAS population.

Arm/Group Title	Synvisc
Arm/Group Description	Three IA injections of Synvisc (2.25 ml glass syringe containing 16 mg hylan G-F 20) at intervals of one week. The total duration of observation was 26 weeks.
Measure Participants	232
Baseline: Very Well	0.0 0%
Baseline: Well	1.7 0.7%
Baseline: Fair	35.3 14.9%
Baseline: Poor	57.3 24.2%
Baseline: Very Poor	5.6 2.4%
Week 8: Very Well	5.2 2.2%
Week 8: Well	42.7 18%
Week 8: Fair	41.8 17.6%
Week 8: Poor	9.9 4.2%
Week 8: Very Poor	0.4 0.2%
Week 12: Very Well	7.3 3.1%
Week 12: Well	44.4 18.7%
Week 12: Fair	41.8 17.6%
Week 12: Poor	6.0 2.5%
Week 12: Very Poor	0.4 0.2%
Week 26: Very Well	9.5 4%
Week 26: Well	47.4 20%
Week 26: Fair	35.3 14.9%
Week 26: Poor	7.8 3.3%
Week 26: Very Poor	0.0 0%

7. Secondary Outcome

Title	Percentage of Participants With Change in Concomitant Medication of Osteoarthritis Therapy at Week 26
Description	Participants were asked about their perception regarding any additional Osteoarthritis medications or treatments or any changes in regimen or dosages compared to their baseline (Day 1) state. Any change in the therapy (less use of other therapies, more use of other therapies and no change in use of other therapies) during the study was reported.
Time Frame	Baseline up to Week 26

Outcome Measure Data

Analysis Population Description

FAS population.

Arm/Group Title	Synvisc
Arm/Group Description	Three IA injections of Synvisc (2.25 ml glass syringe containing 16 mg hylan G-F 20) at intervals of one week. The total duration of observation was 26 weeks.
Measure Participants	232
Required Less Use of Other Therapies	2.2 0.9%
Required More Use of Other Therapies	3.0 1.3%
Required No Change in Use of Other Therapies	93.1 39.3%
Missing	1.7 0.7%

Adverse Events

Time Frame	All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Week 26) regardless of seriousness or relationship to investigational product.
Adverse Event Reporting Description	Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (from the time of signing the informed consent until completion of the study).
Arm/Group Title	Synvisc
Arm/Group Description	Three IA injections of Synvisc (2.25 ml glass syringe containing 16 mg hylan G-F 20) at intervals of one week. The total duration of observation was 26 weeks.
All Cause Mortality
	Synvisc
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Synvisc
	Affected / at Risk (%)	# Events
Total	4/237 (1.7%)
Injury, poisoning and procedural complications
Meniscal Injury	1/237 (0.4%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	1/237 (0.4%)
Arthropathy	1/237 (0.4%)
Arthralgia	1/237 (0.4%)
Other (Not Including Serious) Adverse Events
	Synvisc
	Affected / at Risk (%)	# Events
Total	66/237 (27.8%)
Cardiac disorders
Atrial Fibrillation	1/237 (0.4%)
Ear and labyrinth disorders
Vertigo	1/237 (0.4%)
Eye disorders
Retinal Hemorrhage	1/237 (0.4%)
Gastrointestinal disorders
Astriction	1/237 (0.4%)
Gingivitis	1/237 (0.4%)
Abdominal Pain	1/237 (0.4%)
Diarrhea	1/237 (0.4%)
Colonic Polyp	1/237 (0.4%)
Atrophic Gastritis	1/237 (0.4%)
Toothache	1/237 (0.4%)
Gastritis	3/237 (1.3%)
General disorders
Pain in the Area of Injection Site	5/237 (2.1%)
Weakness	2/237 (0.8%)
Swelling in the Area of Injection Site	2/237 (0.8%)
Warmth	1/237 (0.4%)
Joint Effusion in the Area of Injection Site	1/237 (0.4%)
Infections and infestations
Upper Respiratory Tract Infection	17/237 (7.2%)
Urinary Tract Infection	3/237 (1.3%)
Herpes Zoster	1/237 (0.4%)
Hand Infection	1/237 (0.4%)
Infectious Pneumonia	1/237 (0.4%)
Injury, poisoning and procedural complications
Ligament Spain	4/237 (1.7%)
Meniscal Injury	1/237 (0.4%)
Extremities Injury	1/237 (0.4%)
Humeral Fracture	1/237 (0.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	22/237 (9.3%)
Back Pain	2/237 (0.8%)
Joint Swelling	2/237 (0.8%)
Osteoarthritis	1/237 (0.4%)
Musculoskeletal Pain	1/237 (0.4%)
Arthropathy	1/237 (0.4%)
Amyasthenia	1/237 (0.4%)
Spondyloarthropathy	1/237 (0.4%)
Gouty Arthritis	1/237 (0.4%)
Extremitiess Pain	1/237 (0.4%)
Vertebral Disc Prolapsed	1/237 (0.4%)
Psychiatric disorders
Migraine	1/237 (0.4%)
Dizziness	1/237 (0.4%)
Cramp	1/237 (0.4%)
Reproductive system and breast disorders
Colporrhagia	1/237 (0.4%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal Pain	1/237 (0.4%)
Skin and subcutaneous tissue disorders
Night Sweat	1/237 (0.4%)
Contact Dermatitis	1/237 (0.4%)
Papule	1/237 (0.4%)
Urticaria	1/237 (0.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.