Safety and Effectiveness of Monovisc® Injection for Osteoarthritis of the Knee

• Sponsor: Anika Therapeutics, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00653432
• Collaborator: (none)
• Enrollment: 369
• Locations: 31
• Arms: 2
• Duration (Months): 25
• Patients Per Site: 11.9
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether intra-articular injection of Monovisc® hyaluronic acid provides symptomatic relief of osteoarthritis of the knee.

Condition or Disease	Intervention/Treatment	Phase
Osteoarthritis	Device: Monovisc®; Other: Saline	N/A

Detailed Description

This randomized, double-blind, placebo controlled prospective study will assess the safety and effectiveness of a single intra-articular injection of Monovisc® in providing symptomatic relief of pain caused by idiopathic osteoarthritis (OA) of the knee as compared to a placebo comparator injection of sterile saline.

Study Design

• Study Type: Interventional
• Actual Enrollment: 369 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo Controlled, Multi-Center Study of a Single Injection Cross-Linked Sodium Hyaluronate to Provide Symptomatic Relief of Osteoarthritis of the Knee
• Study Start Date: Jan 1, 2008
• Actual Primary Completion Date: Dec 1, 2009
• Actual Study Completion Date: Feb 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Monovisc® Injectable Hyaluronic Acid Gel	Device: Monovisc®; Intra-articular injection; Other Names: Sodium Hyaluronate Hyaluronic Acid Gel
Placebo Comparator: Saline 0.9% Sterile Saline	Other: Saline; 0.9% Sterile Saline

Outcome Measures

Primary Outcome Measures

1. Proportion Subjects Achieving Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Score (ITT) >=40% and 15 mm From Baseline Through 12 Weeks [12 Weeks]

   The primary endpoint measures the proportion of subjects (Monovisc vs. saline) who achieved >= a 40% improvement (reduction) in the WOMAC Pain Score and show at least 15 mm improvement (reduction) in the WOMAC Pain Score from baseline through 12 weeks. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Score is a validated scale from 0 to 100 mm, where a higher score is equal to a higher pain level. The primary endpoint uses the ITT population that has data available for both baseline and 12 week time points.

Secondary Outcome Measures

1. Evaluator Global Assessment Change From Baseline Through Week 12 (ITT) [12 Weeks]

   Comparison of the change of the Evaluator Global Assessment from baseline through Week 12 between Monovisc and saline arms (ITT Population). The Evaluator Global Assessment is done by the Blinded Evaluator, and answers the question "Considering all the ways the osteoarthritis in the patient's index knee affect him/her, what is your assessment of how much the patient's knee is bothering him/her today?" The Evaluator Global Assessment is scored on a 0 to 100 mm Visual Analog Scale (VAS Scale), where a higher number means the patient is bothered to a higher degree. A negative number for the change from baseline indicates a reduction (improvement) in the assessment. The endpoint uses the ITT population that has data available for both baseline and 12 week time points.

2. Patient Global Assessment Change From Baseline Through Week 12 (ITT) [12 Weeks]

   Comparison of the change of the Patient Global Assessment from baseline through Week 12 between Monovisc and saline arms (ITT Population). The Patient Global Assessment is done by the patient, and answers the question "Considering all the ways the osteoarthritis in your study knee affects you, what is your assessment of how much your study knee is bothering you today?" The Patient Global Assessment is scored on a 0 to 100 mm Visual Analog Scale (VAS Scale), where a higher number means the patient is bothered to a higher degree. A negative number for the change from baseline indicates a reduction (improvement) in the assessment. The endpoint uses the ITT population that has data available for both baseline and 12 week time points.

3. Range of Motion Change From Baseline Through Week 12 (ITT) [12 Weeks]

   Comparison of the change of Range of Motion from baseline through Week 12 between Monovisc and saline arms (ITT Population). Range of motion is defined as the difference between flexion and extension in degrees where full extension range is 180 degrees. The endpoint uses the ITT population that has data available for both baseline and 12 week time points.

4. WOMAC Physical Function Score Change From Baseline Through Week 12 (ITT) [12 Weeks]

   This endpoint compares the change of the WOMAC Physical Function Score from baseline through Week 12 between Monovisc and saline arms (ITT Population). The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Physical Function Score is a validated scale from 0 to 100 mm, where a higher score is equal to a higher degree of functional limitation. A negative number for the change from baseline indicates improvement in physical function. The ITT population includes subjects with data at baseline and 12 Week time points.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 35 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Main Inclusion Criteria:

• Male or Female

• Age 35 to 75 years

• Body Mass Index (BMI) 20 to 40 kg/m2

• Willing and able to provide informed consent

• Willing to limit analgesic use to acetaminophen 7 days prior to and 12 weeks after injection

• Not pregnant or lactating

• Previous conservative treatment regimen for osteoarthritis (OA)

• Diagnosis of idiopathic OA of the index knee

• OA symptoms for >= 6 months

• Index knee Kellgren-Lawrence (K-L) grade of II or III

• Index knee Baseline Summed WOMAC Pain Score >= 200mm and < 400mm after NSAID washout

• Contralateral Knee K-L grade 0, I or II

• Contralateral Knee Baseline WOMAC Pain Score < 150mm after NSAID washout

Main Exclusion Criteria:

• Joint disorders which could interfere with treatment effectiveness

• Joint disorders which could interfere with study assessments

• Arthroscopy of either knee within 3 months of screening

• Open surgery of index knee within 12 months of screening

• Open surgery of contralateral knee within 3 months of screening

• Injection of Hyaluronic Acid (HA) in either knee within 6 months of screening

• Injection of steroid in index knee within 3 months of screening

• Any pre-treatment contraindication for injection or aspiration of the index knee, including cutaneous infection, intra-articular infection, knee deformity or condition which may jeopardize sterility or delivery of injection

• Synovial fluid aspirate volume > 20 milliliters (mL)

• Visual appearance of synovial fluid that contraindicates injection

• Index knee range of motion < 90 degrees

• Subject participation in other research study within 30 days of screening

• Subject unwilling to maintain active lifestyle, exercise program and body weight similar to that during 3 months prior to screening for duration of study

• Unwilling to maintain constant dosage of oral glucosamine or chondroitin sulfate for duration of study, if applicable

• Other medication or treatments that could interfere with study injection or assessments

• Allergy to gram positive bacterial products or intolerance of acetaminophen

• Active fibromyalgia

• Peripheral neuropathy severe enough to interfere with evaluation of either knee

• Vascular insufficiency severe enough to interfere with evaluation of the subject

• Hemiparesis involving either lower extremity

• Systemic bleeding disorder

• Other conditions which may adversely affect the success of the procedure

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Clinical Research Consultants	Hoover	Alabama	United States	35216
2	Novara Clinical Research	Mesa	Arizona	United States	85206
3	Arizona Research Center	Phoenix	Arizona	United States	85023
4	Tuscon Orthopaedic Institute	Tucson	Arizona	United States	85712
5	Providence Clinical Research	Burbank	California	United States	91505
6	San Diego Arthritis Medical Clinic	San Diego	California	United States	92108
7	Summit Clinical Research	Aurora	Colorado	United States	80013
8	Boulder Medical Center	Boulder	Colorado	United States	80304
9	Colorado Orthopedic Consultants	Englewood	Colorado	United States	80110
10	Plancher Orthopaedic and Sports Medicine	Cos Cob	Connecticut	United States	06807
11	Community Research Foundation	Miami	Florida	United States	33155
12	Tampa Medical Clinic	Tampa	Florida	United States	33614
13	Resurgens Orthopedics	Cumming	Georgia	United States	30041
14	Intermountain Research Center	Boise	Idaho	United States	83702
15	Rush University Medical Center	Chicago	Illinois	United States	60612
16	Illinois Bone & Joint Institute	Morton Grove	Illinois	United States	60053
17	Wellborn Clinic	Evansville	Indiana	United States	47713
18	David Neustadt PSC	Louisville	Kentucky	United States	40202
19	Center for Rheumatology and Bone Research	Wheaton	Maryland	United States	20902
20	Great Lakes Research Group	Bay City	Michigan	United States	48706
21	Western Montana Clinic	Missoula	Montana	United States	59802
22	Physician Research Collaboration	Lincoln	Nebraska	United States	68516
23	Arthritis Center of Reno	Reno	Nevada	United States	89502
24	Arthritis, Rheumatic & Back Disease Associates	Voorhees	New Jersey	United States	08043
25	Altoona Center for Clinical Research	Duncansville	Pennsylvania	United States	16635
26	Brian Gunnlaugson, MD	Johnstown	Pennsylvania	United States	15901
27	The Arthritis Group	Philadelphia	Pennsylvania	United States	19152
28	Clinical Research Center of Reading	West Reading	Pennsylvania	United States	19611
29	SCRI	Germantown	Tennessee	United States	38138
30	Valley Orthopedic Clinic	Harlingen	Texas	United States	78550
31	Sunnybrook Health Sciences Centre	Toronto	Ontario	Canada	M4N 3M5

Sponsors and Collaborators

• Anika Therapeutics, Inc.

Investigators

• Study Director: Stephen Schmitz, MD, Prometrika, LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Anika Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT00653432
• Other Study ID Numbers: Monovisc-0702
• First Posted: Apr 7, 2008
• Last Update Posted: Sep 1, 2020
• Last Verified: Aug 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Anika Therapeutics, Inc.: Monovisc®; Hyaluronic Acid Gel; Injection; Knee
• Additional relevant MeSH terms: Osteoarthritis; Osteoarthritis, Knee; Hyaluronic Acid

Study Results

Participant Flow

Arm/Group Title	Monovisc®	Saline
Arm/Group Description	Injectable Hyaluronic Acid Gel Monovisc®: Intra-articular injection	0.9% Sterile Saline Saline: 0.9% Sterile Saline
Period Title: Overall Study
STARTED	184	185
Intend-to-treat ITT	181	184
COMPLETED	162	169
NOT COMPLETED	22	16

Baseline Characteristics

Arm/Group Title	Monovisc®	Saline	Total
Arm/Group Description	Injectable Hyaluronic Acid Gel Monovisc®: Intra-articular injection	0.9% Sterile Saline Saline: 0.9% Sterile Saline	Total of all reporting groups
Overall Participants	181	184	365
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.7 (7.9)	58.7 (9.2)	59.2 (8.6)
Sex: Female, Male (Count of Participants)
Female	107 59.1%	106 57.6%	213 58.4%
Male	74 40.9%	78 42.4%	152 41.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 1.1%	1 0.5%	3 0.8%
Asian	3 1.7%	0 0%	3 0.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	21 11.6%	16 8.7%	37 10.1%
White	154 85.1%	163 88.6%	317 86.8%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 0.6%	4 2.2%	5 1.4%

Outcome Measures

1. Primary Outcome

Title	Proportion Subjects Achieving Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Score (ITT) >=40% and 15 mm From Baseline Through 12 Weeks
Description	The primary endpoint measures the proportion of subjects (Monovisc vs. saline) who achieved >= a 40% improvement (reduction) in the WOMAC Pain Score and show at least 15 mm improvement (reduction) in the WOMAC Pain Score from baseline through 12 weeks. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Score is a validated scale from 0 to 100 mm, where a higher score is equal to a higher pain level. The primary endpoint uses the ITT population that has data available for both baseline and 12 week time points.
Time Frame	12 Weeks

Outcome Measure Data

Analysis Population Description

Intent to Treat population includes all subjects who received a study injection and who had data for both baseline and 12 week time points.

Arm/Group Title	Monovisc®	Saline
Arm/Group Description	Injectable Hyaluronic Acid Gel Monovisc®: Intra-articular injection	0.9% Sterile Saline Saline: 0.9% Sterile Saline
Measure Participants	173	173
Number [Proportion of subjects]	62.57	56.14

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Monovisc®, Saline
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1450
	Comments
	Method	Ordinal GEE Model
	Comments

2. Secondary Outcome

Title	Evaluator Global Assessment Change From Baseline Through Week 12 (ITT)
Description	Comparison of the change of the Evaluator Global Assessment from baseline through Week 12 between Monovisc and saline arms (ITT Population). The Evaluator Global Assessment is done by the Blinded Evaluator, and answers the question "Considering all the ways the osteoarthritis in the patient's index knee affect him/her, what is your assessment of how much the patient's knee is bothering him/her today?" The Evaluator Global Assessment is scored on a 0 to 100 mm Visual Analog Scale (VAS Scale), where a higher number means the patient is bothered to a higher degree. A negative number for the change from baseline indicates a reduction (improvement) in the assessment. The endpoint uses the ITT population that has data available for both baseline and 12 week time points.
Time Frame	12 Weeks

Outcome Measure Data

Analysis Population Description

Intent to Treat population includes all subjects who received a study injection and who had data for both baseline and 12 week time points.

Arm/Group Title	Monovisc®	Saline
Arm/Group Description	Injectable Hyaluronic Acid Gel Monovisc®: Intra-articular injection	0.9% Sterile Saline Saline: 0.9% Sterile Saline
Measure Participants	171	171
Mean (Standard Deviation) [units in mm on a 0 -100 mm scale]	-28.6 (26.4)	-26.4 (26.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Monovisc®, Saline
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5824
	Comments
	Method	Ordinal GEE Model
	Comments

3. Secondary Outcome

Title	Patient Global Assessment Change From Baseline Through Week 12 (ITT)
Description	Comparison of the change of the Patient Global Assessment from baseline through Week 12 between Monovisc and saline arms (ITT Population). The Patient Global Assessment is done by the patient, and answers the question "Considering all the ways the osteoarthritis in your study knee affects you, what is your assessment of how much your study knee is bothering you today?" The Patient Global Assessment is scored on a 0 to 100 mm Visual Analog Scale (VAS Scale), where a higher number means the patient is bothered to a higher degree. A negative number for the change from baseline indicates a reduction (improvement) in the assessment. The endpoint uses the ITT population that has data available for both baseline and 12 week time points.
Time Frame	12 Weeks

Outcome Measure Data

Analysis Population Description

Intent to Treat population includes all subjects who received a study injection and who had data for both baseline and 12 week time points.

Arm/Group Title	Monovisc®	Saline
Arm/Group Description	Injectable Hyaluronic Acid Gel Monovisc®: Intra-articular injection	0.9% Sterile Saline Saline: 0.9% Sterile Saline
Measure Participants	171	171
Mean (Standard Deviation) [units in mm on a 0 -100 mm scale]	-28.8 (30.8)	-28.9 (27.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Monovisc®, Saline
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9136
	Comments
	Method	Ordinal GEE Model
	Comments

4. Secondary Outcome

Title	Range of Motion Change From Baseline Through Week 12 (ITT)
Description	Comparison of the change of Range of Motion from baseline through Week 12 between Monovisc and saline arms (ITT Population). Range of motion is defined as the difference between flexion and extension in degrees where full extension range is 180 degrees. The endpoint uses the ITT population that has data available for both baseline and 12 week time points.
Time Frame	12 Weeks

Outcome Measure Data

Analysis Population Description

Intent to Treat population includes all subjects who received a study injection and who had data for both baseline and 12 week time points.

Arm/Group Title	Monovisc®	Saline
Arm/Group Description	Injectable Hyaluronic Acid Gel Monovisc®: Intra-articular injection	0.9% Sterile Saline Saline: 0.9% Sterile Saline
Measure Participants	171	171
Mean (Standard Deviation) [degrees flexion - extension]	1.5 (14.9)	4.6 (14.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Monovisc®, Saline
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1699
	Comments
	Method	Ordinal GEE Model
	Comments

5. Secondary Outcome

Title	WOMAC Physical Function Score Change From Baseline Through Week 12 (ITT)
Description	This endpoint compares the change of the WOMAC Physical Function Score from baseline through Week 12 between Monovisc and saline arms (ITT Population). The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Physical Function Score is a validated scale from 0 to 100 mm, where a higher score is equal to a higher degree of functional limitation. A negative number for the change from baseline indicates improvement in physical function. The ITT population includes subjects with data at baseline and 12 Week time points.
Time Frame	12 Weeks

Outcome Measure Data

Analysis Population Description

Intent to Treat population includes all subjects who received a study injection and who had data for both baseline and 12 week time points.

Arm/Group Title	Monovisc®	Saline
Arm/Group Description	Injectable Hyaluronic Acid Gel Monovisc®: Intra-articular injection	0.9% Sterile Saline Saline: 0.9% Sterile Saline
Measure Participants	171	171
Mean (Standard Deviation) [units in mm on a 0 -100 mm scale]	-24.1 (26.1)	-22.3 (25.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Monovisc®, Saline
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3238
	Comments
	Method	Ordinal GEE Model
	Comments

6. Post-Hoc Outcome

Title	Proportion Subjects Achieving Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Score (ITT) >=50% and 20 mm From Baseline Through 26 Weeks
Description	This post-hoc endpoint measures the proportion of subjects (Monovisc vs. saline) who achieved >= a 50% improvement (reduction) in the WOMAC Pain Score and show at least 20 mm improvement (reduction) in the WOMAC Pain Score from baseline through 26 weeks. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Score is a validated scale from 0 to 100 mm, where a higher score is equal to a higher pain level. Reduction in the WOMAC Pain Score from baseline (e.g. a negative number) indicates improvement in pain. The primary endpoint uses the ITT population that has data available for both baseline and 26 week timepoints.
Time Frame	Baseline and 26

Outcome Measure Data

Analysis Population Description

Intent-To-Treat population was defined as all randomized patients who received the study injection and had at least one post-injection visit; i.e: at least one visit after the Week 0 visit.

Arm/Group Title	Monovisc®	Saline
Arm/Group Description	Injectable Hyaluronic Acid Gel Monovisc®: Intra-articular injection	0.9% Sterile Saline Saline: 0.9% Sterile Saline
Measure Participants	171	171
Number [Percentage of Participants]	44.38 24.5%	34.12 18.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Monovisc®, Saline
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0427
	Comments
	Method	Ordinal GEE Model
	Comments

7. Post-Hoc Outcome

Title	Evaluator Global Assessment Change From Baseline Through Week 26 (ITT)
Description	Comparison of the change of the Evaluator Global Assessment from baseline through Week 26 between Monovisc and saline arms (ITT Population). The Evaluator Global Assessment is done by the Blinded Evaluator, and answers the question "Considering all the ways the osteoarthritis in the patient's index knee affect him/her, what is your assessment of how much the patient's knee is bothering him/her today?" The Evaluator Global Assessment is scored on a 0 to 100 mm Visual Analog Scale, where a higher number means the patient is bothered to a higher degree. A negative number for the change from baseline indicates a reduction (improvement) in the assessment. The endpoint uses the ITT population that has data available for both baseline and 26 week time points.
Time Frame	26 Weeks

Outcome Measure Data

Analysis Population Description

Intent to Treat population includes all subjects who received a study injection and who had data for both baseline and 26 week time points.

Arm/Group Title	Monovisc®	Saline
Arm/Group Description	Injectable Hyaluronic Acid Gel Monovisc®: Intra-articular injection	0.9% Sterile Saline Saline: 0.9% Sterile Saline
Measure Participants	162	168
Mean (Standard Deviation) [units in mm on a 0 -100 mm scale]	-27.9 (24.2)	-27.5 (27.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Monovisc®, Saline
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8206
	Comments
	Method	Ordinal GEE Model
	Comments

8. Post-Hoc Outcome

Title	Patient Global Assessment Change From Baseline Through Week 26 (ITT)
Description	Comparison of the change of the Patient Global Assessment from baseline through Week 26 between Monovisc and saline arms (ITT Population). The Patient Global Assessment is done by the patient, and answers the question "Considering all the ways the osteoarthritis in your study knee affects you, what is your assessment of how much your study knee is bothering you today?" The Patient Global Assessment is scored on a 0 to 100 mm Visual analog Scale, where a higher number means the patient is bothered to a higher degree. A negative number for the change from baseline indicates a reduction (improvement) in the assessment. The endpoint uses the ITT population that has data available for both baseline and 26 week time points.
Time Frame	26 Weeks

Outcome Measure Data

Analysis Population Description

Intent to Treat population includes all subjects who received a study injection and who had data for both baseline and 26 week time points.

Arm/Group Title	Monovisc®	Saline
Arm/Group Description	Injectable Hyaluronic Acid Gel Monovisc®: Intra-articular injection	0.9% Sterile Saline Saline: 0.9% Sterile Saline
Measure Participants	162	168
Mean (Standard Deviation) [units in mm on a 0 -100 mm scale]	-28.5 (27.9)	-28.6 (27.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Monovisc®, Saline
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9818
	Comments
	Method	Ordinal GEE Model
	Comments

9. Post-Hoc Outcome

Title	Range of Motion Change From Baseline Through Week 26 (ITT)
Description	Comparison of the change of Range of Motion from baseline through Week 26 between Monovisc and saline arms (ITT Population). Range of motion is defined as the difference between flexion and extension in degrees where full extension range is 180 degrees. The endpoint uses the ITT population that has data available for both baseline and 26 week time points.
Time Frame	26 Weeks

Outcome Measure Data

Analysis Population Description

Intent to Treat population includes all subjects who received a study injection and who had data for both baseline and 26 week time points.

Arm/Group Title	Monovisc®	Saline
Arm/Group Description	Injectable Hyaluronic Acid Gel Monovisc®: Intra-articular injection	0.9% Sterile Saline Saline: 0.9% Sterile Saline
Measure Participants	162	168
Mean (Standard Deviation) [degrees flexion - extension]	1.0 (14.9)	4.2 (14.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Monovisc®, Saline
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0542
	Comments
	Method	Ordinal GEE Model
	Comments

10. Post-Hoc Outcome

Title	WOMAC Physical Function Score Change From Baseline Through Week 26 (ITT)
Description	This endpoint compares the change of the WOMAC Physical Function Score from baseline through Week 26 between Monovisc and saline arms (ITT Population). The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Physical Function Score is a validated scale from 0 to 100 mm, where a higher score is equal to a higher degree of functional limitation. A negative number for the change from baseline indicates improvement in physical function. The ITT population includes subjects with data at baseline and 26 Week time points.
Time Frame	26 Weeks

Outcome Measure Data

Analysis Population Description

Intent to Treat population includes all subjects who received a study injection and who had data for both baseline and 26 week time points.

Arm/Group Title	Monovisc®	Saline
Arm/Group Description	Injectable Hyaluronic Acid Gel Monovisc®: Intra-articular injection	0.9% Sterile Saline Saline: 0.9% Sterile Saline
Measure Participants	162	168
Mean (Standard Deviation) [units in mm on a 0 -100 mm scale]	-23.3 (26.0)	-21.4 (24.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Monovisc®, Saline
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3230
	Comments
	Method	Ordinal GEE Model
	Comments

Adverse Events

Time Frame	26 Weeks
Arm/Group Title	Monovisc®		Saline
Arm/Group Description	Injectable Hyaluronic Acid Gel Monovisc®: Intra-articular injection		0.9% Sterile Saline Saline: 0.9% Sterile Saline
All Cause Mortality
	Monovisc®		Saline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Monovisc®		Saline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/184 (4.9%)		5/185 (2.7%)
Cardiac disorders
Angina Unstable	1/184 (0.5%)	1	1/185 (0.5%)	1
General disorders
Chest Pain	0/184 (0%)	0	1/185 (0.5%)	1
Infections and infestations
Bronchitis	2/184 (1.1%)	2	0/185 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/184 (0.5%)	1	0/185 (0%)	0
Synovitis	1/184 (0.5%)	1	0/185 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal Cell Carcinoma	1/184 (0.5%)	1	0/185 (0%)	0
Prostate Cancer	0/184 (0%)	0	1/185 (0.5%)	1
Nervous system disorders
Carotid Artery Stenosis	1/184 (0.5%)	1	0/185 (0%)	0
Pregnancy, puerperium and perinatal conditions
Abortion Spontaneous	1/184 (0.5%)	1	0/185 (0%)	0
Psychiatric disorders
Suicide Attempt	0/184 (0%)	0	1/185 (0.5%)	1
Reproductive system and breast disorders
Rectocele	1/184 (0.5%)	1	0/185 (0%)	0
Respiratory, thoracic and mediastinal disorders
Epistaxis	0/184 (0%)	0	1/185 (0.5%)	1
Other (Not Including Serious) Adverse Events
	Monovisc®		Saline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	121/184 (65.8%)		123/185 (66.5%)
Ear and labyrinth disorders
Vertigo	2/184 (1.1%)	2	1/185 (0.5%)	1
Gastrointestinal disorders
Diarrhea	1/184 (0.5%)	1	3/185 (1.6%)	3
Gastritis	0/184 (0%)	0	2/185 (1.1%)	2
Stomach Discomfort	2/184 (1.1%)	2	1/185 (0.5%)	1
Toothache	5/184 (2.7%)	6	4/185 (2.2%)	7
General disorders
Influenza Like Illness	2/184 (1.1%)	2	1/185 (0.5%)	1
Injection Site Pain	3/184 (1.6%)	3	1/185 (0.5%)	1
Malaise	1/184 (0.5%)	1	3/185 (1.6%)	3
Oedema Peripheral	2/184 (1.1%)	2	2/185 (1.1%)	2
Pain	3/184 (1.6%)	4	2/185 (1.1%)	2
Pyrexia	0/184 (0%)	0	3/185 (1.6%)	3
Immune system disorders
Hypersensitivity	0/184 (0%)	0	2/185 (1.1%)	2
Infections and infestations
Bronchitis	4/184 (2.2%)	5	2/185 (1.1%)	2
Cystitis	3/184 (1.6%)	3	0/185 (0%)	0
Gastroenteritis Viral	3/184 (1.6%)	3	2/185 (1.1%)	2
Influenza	5/184 (2.7%)	5	8/185 (4.3%)	8
Lower Respiratory Tract Infection	1/184 (0.5%)	1	2/185 (1.1%)	2
Nasopharyngitis	9/184 (4.9%)	9	11/185 (5.9%)	11
Sinusitis	6/184 (3.3%)	7	5/185 (2.7%)	5
Tooth Abscess	1/184 (0.5%)	1	2/185 (1.1%)	2
Tooth Infection	0/184 (0%)	0	2/185 (1.1%)	2
Upper Respiratory Tract Infection	11/184 (6%)	14	14/185 (7.6%)	16
Urinary Tract Infection	1/184 (0.5%)	1	5/185 (2.7%)	6
Injury, poisoning and procedural complications
Back Injury	1/184 (0.5%)	1	2/185 (1.1%)	2
Contusion	6/184 (3.3%)	9	9/185 (4.9%)	11
Excoriation	3/184 (1.6%)	3	2/185 (1.1%)	2
Joint Sprain	1/184 (0.5%)	1	8/185 (4.3%)	8
Muscle Strain	4/184 (2.2%)	4	2/185 (1.1%)	2
Skin Laceration	2/184 (1.1%)	2	0/185 (0%)	0
Thermal Burn	2/184 (1.1%)	2	0/185 (0%)	0
Metabolism and nutrition disorders
Hypercholesterolaemia	2/184 (1.1%)	2	3/185 (1.6%)	3
Musculoskeletal and connective tissue disorders
Arthralgia	31/184 (16.8%)	59	27/185 (14.6%)	44
Back Pain	16/184 (8.7%)	26	16/185 (8.6%)	25
Joint Effusion	5/184 (2.7%)	6	0/185 (0%)	0
Joint Stiffness	2/184 (1.1%)	2	1/185 (0.5%)	2
Joint Swelling	2/184 (1.1%)	2	4/185 (2.2%)	5
Muscle Spasms	4/184 (2.2%)	4	2/185 (1.1%)	3
Musculoskeletal Pain	9/184 (4.9%)	20	7/185 (3.8%)	7
Musculoskeletal Stiffness	0/184 (0%)	0	3/185 (1.6%)	3
Myalgia	1/184 (0.5%)	1	2/185 (1.1%)	3
Neck Pain	1/184 (0.5%)	2	5/185 (2.7%)	5
Osteoarthritis	2/184 (1.1%)	3	3/185 (1.6%)	3
Pain in Extremity	15/184 (8.2%)	24	13/185 (7%)	14
Synovial Cyst	2/184 (1.1%)	2	0/185 (0%)	0
Tendonitis	3/184 (1.6%)	3	0/185 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal Cell Carcinoma	2/184 (1.1%)	2	0/185 (0%)	0
Nervous system disorders
Headache	24/184 (13%)	39	28/185 (15.1%)	56
Hypoaesthesia	2/184 (1.1%)	2	0/185 (0%)	0
Migrane	3/184 (1.6%)	3	0/185 (0%)	0
Sciatica	2/184 (1.1%)	2	4/185 (2.2%)	4
Sinus Headache	4/184 (2.2%)	5	9/185 (4.9%)	14
Psychiatric disorders
Depression	2/184 (1.1%)	2	0/185 (0%)	0
Insomnia	3/184 (1.6%)	3	0/185 (0%)	0
Respiratory, thoracic and mediastinal disorders
Nasal Congestion	2/184 (1.1%)	3	1/185 (0.5%)	2
Pharyngolaryngeal Pain	4/184 (2.2%)	4	4/185 (2.2%)	4
Rhinorrhoea	1/184 (0.5%)	1	2/185 (1.1%)	2
Rhonchi	2/184 (1.1%)	2	0/185 (0%)	0
Skin and subcutaneous tissue disorders
Erythema	2/184 (1.1%)	2	1/185 (0.5%)	1
Vascular disorders
Hypertension	2/184 (1.1%)	2	3/185 (1.6%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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