Investigation of 1.2% Sodium Hyaluronate for Treatment of Painful Chronic Osteoarthritis of the Knee

• Sponsor: Ferring Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00988091
• Collaborator: (none)
• Enrollment: 596
• Locations: 34
• Arms: 2
• Duration (Months): 19
• Patients Per Site: 17.5
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

Subjects with chronic osteoarthritis of the knee will be assigned to receive an injection of either 1.2% sodium hyaluronate or buffered saline to evaluate its effectiveness and safety for 26 weeks. After 26 weeks, subjects can elect to receive a second injection of 1.2% sodium hyaluronate and be followed for another 26 weeks.

Condition or Disease	Intervention/Treatment	Phase
Osteoarthritis of the Knee	Device: 1.2% Sodium Hyaluronate; Device: Buffered Saline	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 596 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A 26 Week, Double-Blind, Randomized, Placebo-Controlled Study of the Efficacy and Safety of Single Intra-Articular Injection 1.2% Sodium Hyaluronate for Treatment of Painful Osteoarthritis of the Knee, With Optional 26-Week Open-Label Safety Extension
• Study Start Date: Sep 1, 2009
• Actual Primary Completion Date: Oct 1, 2010
• Actual Study Completion Date: Apr 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: IA-SA Each participant received a single intra-articular (IA) injection of buffered saline (SA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they could receive a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and be followed for an additional 26 weeks.	Device: Buffered Saline; IA-SA is supplied in a disposable 7 ml nominal volume glass syringe containing 5 ml of phosphate buffered saline. Participants are given a single injection in the target knee on Day 1 of the double-blind period.; Other Names: saline
Experimental: IA-BioHA Each participant received a single intra-articular (IA) injection of 1.2% sodium hyaluronate (BioHA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they received a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and were followed for an additional 26 weeks.	Device: 1.2% Sodium Hyaluronate; IA-BioHA is supplied in a disposable 7 ml nominal volume glass syringe containing 60 mg/5 ml of 1.2% sodium hyaluronate. Participants are given a single injection in the target knee on Day 1 of the double-blind period and optionally on the first day of the open-label period (approximately week 27).; Other Names: sodium hyaluronate

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in the Visual Analogue Score (VAS) Pain Score of the 50-foot Walk Test at Week 26 [Day 0 (baseline) through Week 26]

   The level of pain is estimated by the participant following a walk of 50 feet in length which is observed by the investigator. Pain estimates were recorded on a 100 millimeter visual analog scale. A score of 0 millimeters means there was no pain; a score of 100 millimeters means extreme pain. Change from baseline is calculated: week 26 VAS Pain Score - Baseline VAS Pain Score.

Secondary Outcome Measures

1. Change From Baseline in Western Ontario McMaster University Osteoarthritis Index (WOMAC) Disability Scores at Week 26 [Day 0 (baseline), week 26]

   Adjusted mean of all WOMAC pain, stiffness and physical function subscores on Visual Analog Scale (VAS) of 100 mm; 0 mm = no pain, stiffness and difficulty; 100 mm = extreme pain, stiffness and difficulty. Change from baseline calculated as: Week 26 minus baseline.

2. Percentage of Participants With a >=20mm Improvement Between Baseline and Week 26 on the 50 Foot Walk Visual Analogue Scale (VAS) Pain Score. [Day 0 (baseline), Week 26]

   The level of pain is estimated by the participant following a walk of 50 feet in length which is observed by the investigator. Pain estimates were recorded on a 100 millimeter visual analog scale. A score of 0 millimeters means there was no pain; a score of 100 millimeters means extreme pain. Change from baseline is calculated: week 26 VAS Pain Score - Baseline VAS Pain Score. The percent of participants who showed a 20mm or greater improvement in the pain scores at week 26 compared to baseline are reported.

3. Subjective Patient Assessment of Treatment at Week 26 [Week 26]

   At the end of the double-blind period (week 26), participants were asked: "Are you satisfied with the results of the injection?" Answers could be: 1=dissatisfied; 2=slightly satisfied; 3=satisfied; or 4=very satisfied.

4. Number of Tablets of Rescue Medication Used Between Visits [Day 1 to week 26]

   Acetaminophen (500-mg tablets) was provided to study participants as a rescue medication in case they needed a pain medication during the study. The mean number of tablets of rescue medication should have been summarized, however the data was not captured in a reliable way and is therefore not reported.

5. Change From Baseline in Patient Global Assessment at Week 26 [Day 0 (baseline), Week 26]

   Participants were asked to mark along a 100mm visual analog scale (VAS) indicating the point best representing the severity of the knee pain that day. The left side of the VAS was 0=no pain and the right side was 100 = extreme pain. Change from baseline was calculated as Week 26 - Baseline.

6. Percentage of Observed Osteoarthritis Research Society International (OARSI30) Responders Using the Visual Analogue Scale (VAS) to Assess Pain Following a 50-foot Walk at Week 26 [Day 0 (baseline), week 26]

   Responders are identified based on a calculation of three scales: 50-foot walk test for pain, function (WOMAC Disability score) and global assessment (Patient Global Assessment Score) scales. Each of the individual scales was completed by the participant. A responder showed considerable improvement in pain or function (>=50 percent and absolute change of >=20 millimeters), or improvement in at least two of three categories: Pain and/or Function and/or Patient Global Assessment scales of >=20 percent and absolute change >=10 millimeter. Response at Week 26 is compared to baseline.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Chronic osteoarthritis (OA) of target knee confirmed by American College of Rheumatology (ACR) Criteria.

• Pain due to OA in target knee present for at least 6 months.

• During Screening and Baseline visits, subjects will require a visual analog scale (VAS) score (100 mm) of ≥ 41 mm and ≤ 90 mm, recorded immediately following a 50-foot walk, AND at Baseline, cannot have decreased >10mm (improvement) from Screening.

• A bilateral standing anteroposterior (AP) X-ray confirming OA of the target knee.

• Ability and willingness to use only acetaminophen as the analgesic (rescue) study medication

• Ability to perform procedures required of the pain index evaluations (unassisted walking 50 feet on a flat surface and going up and down stairs).

• Willingness and ability to complete efficacy and safety questionnaires and ability to read and understand study instructions.

• Signed Subject Informed Consent Form

Exclusion Criteria:

• Any major injury (including sports injuries) to the target knee within the prior 12 months.

• Any surgery to the target knee, hip and contralateral hip within the prior 12 months.

• Major and minor articular procedures

• Inflammatory arthropathies such as rheumatoid arthritis, lupus arthropathy, or psoriatic arthritis.

• Gout or calcium pyrophosphate (pseudogout) diseases of the target knee that have flared within the previous 6 months.

• X-ray findings of acute fractures, severe loss of bone density, avascular necrosis, and/or severe bone or joint deformity in the target knee.

• Osteonecrosis of either knee.

• Fibromyalgia, pes anserine bursitis, lumbar radiculopathy, and/or neurogenic or vascular claudication.

• Significant anterior knee pain due to diagnosed isolated patella-femoral syndrome or chondromalacia in the target knee.

• Significant target knee joint infection or skin disorder/infection within the previous 6 months prior to study enrollment.

• Symptomatic OA of the hips, spine, or ankle, if it would interfere with the evaluation of the target knee.

• Known hypersensitivity to acetaminophen, sodium hyaluronate, or phosphate buffered saline solution.

• Women of childbearing potential who are pregnant, nursing, or planning to become pregnant, and those who do not agree to remain on an acceptable method of birth control throughout the entire study period.

• Recurrent medical history of severe allergic or immune-mediated reactions or other immune disorders.

• Vascular insufficiency of lower limbs or peripheral neuropathy severe enough to interfere with the study evaluation.

• Current treatment or treatment within the previous 2 years prior to Screening for any malignancy unless specific written permission is provided by the Sponsor (excluding basal cell or squamous cell carcinoma of the skin).

• Chronic liver disease and active liver disease based on liver profile of aspartate aminotransferase (AST), alanine transaminase (ALT), and conjugated bilirubin >2 times the upper limit of normal.

• Renal insufficiency based on serum creatinine >2.0 mg/dL.

• Any clinically significant laboratory value based on clinical history that the Investigator feels may affect the study evaluation.

• Any intercurrent chronic disease or condition that may interfere with the completion of the 6-month (or 12-month) follow-up of the study, such as liver disease, severe coronary disease, drug abuse, disordered mental state, or other clinically significant condition.

• Current alcoholism, and/or any known current addiction to pain medications.

• Any clinically significant finding that would place the patient at health risk, impact the study, or affect the completion of the study.

• Any psychiatric illness that would prevent comprehension of the details and nature of the study.

• Participation in any experimental device study within 6 months prior to the Screening, or an experimental drug study within 1 month prior to the Screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Apex Clinical Trials, LLC	Homewood	Alabama	United States
2	Tucson Orthopaedic Institute	Tucson	Arizona	United States
3	St. Joseph's Mercy Clinic	Hot Springs	Arkansas	United States
4	Rx Medical Research of Arkansas, Inc	Little Rock	Arkansas	United States
5	Southbay Pharma Research	Buena Park	California	United States
6	Providence Clinical Research	Burbank	California	United States
7	Triwest Research Associates	La Mesa	California	United States
8	UCLA-Division of Rheumatology	Los Angeles	California	United States
9	Investigational Site	Santa Barbara	California	United States
10	Colorado Arthritis Center, PC	Englewood	Colorado	United States
11	Front Range Clinical Research	Wheatridge	Colorado	United States
12	New England Research Associates, LLC	Trumball	Connecticut	United States
13	International Physicians Research	Aventura	Florida	United States
14	Investigational Site	Ft. Lauderdale	Florida	United States
15	Sunrise Medical Research	Lauderdale Lakes	Florida	United States
16	Tri-County Orthopaedic Center	Leesburg	Florida	United States
17	Clinical Research Center LLC	Wellington	Florida	United States
18	National Pain Research Institute, LLC	Winter Park	Florida	United States
19	Georgia Institute for Clinical Research	Marietta	Georgia	United States
20	Pinnacle Orthopaedics and Sports Medicine	Marietta	Georgia	United States
21	Lee Research Institute	Shawnee	Kansas	United States
22	Professional Research Network of Kansas	Wichita	Kansas	United States
23	New Jersey Physicians, LLC	Passaic	New Jersey	United States
24	Research Department, Bone & Joint Hospital at St. Anthony	Oklahoma City	Oklahoma	United States
25	Omega Medical Research	Warwick	Rhode Island	United States
26	Palmetto Medical Research	Mt. Pleasant	South Carolina	United States
27	Palmetto Clinical Trial Services, LLC	Simpsonville	South Carolina	United States
28	Black Hills Orthopedic & Spine Center	Rapid City	South Dakota	United States
29	Holston Medical Group	Kingsport	Tennessee	United States
30	McKenzie Medical Center	McKenzie	Tennessee	United States
31	Texas Orthopedic Specialists, PA	Grapevine	Texas	United States
32	Memorial Bone & Joint Research Foundation	Houston	Texas	United States
33	Discovery Clinical Trials (DCT) - Stone Oak, LLC	San Antonio	Texas	United States
34	Northwest Clinical Research Center	Bellevue	Washington	United States

Sponsors and Collaborators

• Ferring Pharmaceuticals

Investigators

• Study Director: Clinical Development Support, Ferring Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ferring Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00988091
• Other Study ID Numbers: 2009-03
• First Posted: Oct 1, 2009
• Last Update Posted: Jun 15, 2012
• Last Verified: Jun 1, 2012

• Additional relevant MeSH terms: Osteoarthritis; Osteoarthritis, Knee; Hyaluronic Acid

Study Results

Participant Flow

Recruitment Details	A total of 1007 subjects were screened for the double-blind period of the study, and 596 subjects were randomized and treated (safety population).

Arm/Group Title	IA-SA	IA-BioHA
Arm/Group Description	Each participant received a single intra-articular (IA) injection of buffered saline (SA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they could receive a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and be followed for an additional 26 weeks.	Each participant received a single intra-articular (IA) injection of 1.2% sodium hyaluronate (BioHA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they received a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and were followed for an additional 26 weeks.
Period Title: Double-blind Period
STARTED	298	298
Intent to Treat Population	294	295
COMPLETED	255	251
NOT COMPLETED	43	47
Period Title: Double-blind Period
STARTED	229	225
COMPLETED	208	192
NOT COMPLETED	21	33

Baseline Characteristics

Arm/Group Title	IA-SA	IA-BioHA	Total
Arm/Group Description	Each participant received a single intra-articular (IA) injection of buffered saline (SA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they could receive a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and be followed for an additional 26 weeks.	Each participant received a single intra-articular (IA) injection of 1.2% sodium hyaluronate (BioHA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they received a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and were followed for an additional 26 weeks.	Total of all reporting groups
Overall Participants	298	298	596
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.30 (11.180)	60.70 (10.228)	60.50 (10.708)
Sex: Female, Male (Count of Participants)
Female	193 64.8%	168 56.4%	361 60.6%
Male	105 35.2%	130 43.6%	235 39.4%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in the Visual Analogue Score (VAS) Pain Score of the 50-foot Walk Test at Week 26
Description	The level of pain is estimated by the participant following a walk of 50 feet in length which is observed by the investigator. Pain estimates were recorded on a 100 millimeter visual analog scale. A score of 0 millimeters means there was no pain; a score of 100 millimeters means extreme pain. Change from baseline is calculated: week 26 VAS Pain Score - Baseline VAS Pain Score.
Time Frame	Day 0 (baseline) through Week 26

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	IA-SA	IA-BioHA
Arm/Group Description	Each participant received a single intra-articular (IA) injection of buffered saline (SA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they could receive a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and be followed for an additional 26 weeks.	Each participant received a single intra-articular (IA) injection of 1.2% sodium hyaluronate (BioHA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they received a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and were followed for an additional 26 weeks.
Measure Participants	294	295
Least Squares Mean (Standard Error) [units on a scale]	-33.48 (1.81)	-28.15 (1.82)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IA-SA, IA-BioHA
	Comments	A treatment difference of >=7.0 mm and a pooled SD of 27.6 mm, requires a sample size of 244 subjects/treatment to complete the trial at 80% power at a two-sided significance level of 5%. To account for 18% dropout rate, the sample size was increased to 298/arm (total of 596). The primary null hypothesis (Ho) is that the effect of the two treatment groups at 26 weeks is equal and the corresponding alternative hypothesis (HA) is that the effect of the two treatment groups at 26 weeks is unequal.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.034
	Comments	The p-value was not adjusted for multiple comparisons because there was a single treatment comparison for the primary endpoint. The a priori threshold for statistical significance was p <0.05.
	Method	Mixed Models Repeated Measures ANCOVA
	Comments	The analysis included baseline score as a covariate and study center as a stratification variable.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	5.33
	Confidence Interval	(2-Sided) 95%; 0.41 to 10.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Western Ontario McMaster University Osteoarthritis Index (WOMAC) Disability Scores at Week 26
Description	Adjusted mean of all WOMAC pain, stiffness and physical function subscores on Visual Analog Scale (VAS) of 100 mm; 0 mm = no pain, stiffness and difficulty; 100 mm = extreme pain, stiffness and difficulty. Change from baseline calculated as: Week 26 minus baseline.
Time Frame	Day 0 (baseline), week 26

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	IA-SA	IA-BioHA
Arm/Group Description	Each participant received a single intra-articular (IA) injection of buffered saline (SA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they could receive a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and be followed for an additional 26 weeks.	Each participant received a single intra-articular (IA) injection of 1.2% sodium hyaluronate (BioHA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they received a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and were followed for an additional 26 weeks.
Measure Participants	294	295
Least Squares Mean (Standard Error) [units on a scale]	-21.72 (1.55)	-18.82 (1.57)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IA-SA, IA-BioHA
	Comments	The null hypothesis (Ho) is that the effect of the two treatment groups at 26 weeks is equal and the corresponding alternative hypothesis (HA) is that the effect of the two treatment groups at 26 weeks is unequal.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.175
	Comments	For secondary outcome measures, fixed-sequence testing was used in a sequentially rejective fashion. The a priori threshold for statistical significance was p <0.05.
	Method	Mixed Models Repeated Measures ANCOVA
	Comments	The analysis included baseline score as a covariate and study center as a stratification variable.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	2.89
	Confidence Interval	(2-Sided) 95%; -1.29 to 7.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Participants With a >=20mm Improvement Between Baseline and Week 26 on the 50 Foot Walk Visual Analogue Scale (VAS) Pain Score.
Description	The level of pain is estimated by the participant following a walk of 50 feet in length which is observed by the investigator. Pain estimates were recorded on a 100 millimeter visual analog scale. A score of 0 millimeters means there was no pain; a score of 100 millimeters means extreme pain. Change from baseline is calculated: week 26 VAS Pain Score - Baseline VAS Pain Score. The percent of participants who showed a 20mm or greater improvement in the pain scores at week 26 compared to baseline are reported.
Time Frame	Day 0 (baseline), Week 26

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	IA-SA	IA-BioHA
Arm/Group Description	Each participant received a single intra-articular (IA) injection of buffered saline (SA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they could receive a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and be followed for an additional 26 weeks.	Each participant received a single intra-articular (IA) injection of 1.2% sodium hyaluronate (BioHA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they received a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and were followed for an additional 26 weeks.
Measure Participants	256	253
Number [percentage of participants]	66.8 22.4%	60.9 20.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IA-SA, IA-BioHA
	Comments	The null hypothesis (Ho) is that the effect of the two treatment groups at 26 weeks is equal and the corresponding alternative hypothesis (HA) is that the effect of the two treatment groups at 26 weeks is unequal.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.193
	Comments	For secondary outcome measures, fixed-sequence testing was used in a sequentially rejective fashion. The a priori threshold for statistical significance was p <0.05.
	Method	Regression, Logistic
	Comments	The analysis included study center as a stratification variable.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.777
	Confidence Interval	(2-Sided) 95%; 0.532 to 1.136
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Subjective Patient Assessment of Treatment at Week 26
Description	At the end of the double-blind period (week 26), participants were asked: "Are you satisfied with the results of the injection?" Answers could be: 1=dissatisfied; 2=slightly satisfied; 3=satisfied; or 4=very satisfied.
Time Frame	Week 26

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	IA-SA	IA-BioHA
Arm/Group Description	Each participant received a single intra-articular (IA) injection of buffered saline (SA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they could receive a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and be followed for an additional 26 weeks.	Each participant received a single intra-articular (IA) injection of 1.2% sodium hyaluronate (BioHA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they received a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and were followed for an additional 26 weeks.
Measure Participants	266	269
Mean (Standard Deviation) [units on a scale]	2.71 (1.096)	2.70 (1.115)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IA-SA, IA-BioHA
	Comments	The null hypothesis (Ho) is that the effect of the two treatment groups at 26 weeks is equal and the corresponding alternative hypothesis (HA) is that the effect of the two treatment groups at 26 weeks is unequal.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.887
	Comments	For secondary outcome measures, fixed-sequence testing was used in a sequentially rejective fashion. The a priori threshold for statistical significance was p <0.05.
	Method	Cochran-Mantel-Haenszel
	Comments	The analysis included study center as a stratification variable.

5. Secondary Outcome

Title	Number of Tablets of Rescue Medication Used Between Visits
Description	Acetaminophen (500-mg tablets) was provided to study participants as a rescue medication in case they needed a pain medication during the study. The mean number of tablets of rescue medication should have been summarized, however the data was not captured in a reliable way and is therefore not reported.
Time Frame	Day 1 to week 26

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	IA-SA	IA-BioHA
Arm/Group Description	Each participant received a single intra-articular (IA) injection of buffered saline (SA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they could receive a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and be followed for an additional 26 weeks.	Each participant received a single intra-articular (IA) injection of 1.2% sodium hyaluronate (BioHA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they received a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and were followed for an additional 26 weeks.
Measure Participants	0	0

6. Secondary Outcome

Title	Change From Baseline in Patient Global Assessment at Week 26
Description	Participants were asked to mark along a 100mm visual analog scale (VAS) indicating the point best representing the severity of the knee pain that day. The left side of the VAS was 0=no pain and the right side was 100 = extreme pain. Change from baseline was calculated as Week 26 - Baseline.
Time Frame	Day 0 (baseline), Week 26

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	IA-SA	IA-BioHA
Arm/Group Description	Each participant received a single intra-articular (IA) injection of buffered saline (SA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they could receive a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and be followed for an additional 26 weeks.	Each participant received a single intra-articular (IA) injection of 1.2% sodium hyaluronate (BioHA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they received a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and were followed for an additional 26 weeks.
Measure Participants	294	295
Least Squares Mean (Standard Error) [units on a scale]	-27.41 (1.83)	-23.41 (1.85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IA-SA, IA-BioHA
	Comments	The null hypothesis (Ho) is that the effect of the two treatment groups at 26 weeks is equal and the corresponding alternative hypothesis (HA) is that the effect of the two treatment groups at 26 weeks is unequal.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.116
	Comments	For secondary outcome measures, fixed-sequence testing was used in a sequentially rejective fashion. The a priori threshold for statistical significance was p <0.05.
	Method	Mixed Models Repeated Measures ANCOVA
	Comments	The analysis included baseline score as a covariate and study center as a stratification variable.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	4.00
	Confidence Interval	(2-Sided) 95%; -0.99 to 8.98
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Percentage of Observed Osteoarthritis Research Society International (OARSI30) Responders Using the Visual Analogue Scale (VAS) to Assess Pain Following a 50-foot Walk at Week 26
Description	Responders are identified based on a calculation of three scales: 50-foot walk test for pain, function (WOMAC Disability score) and global assessment (Patient Global Assessment Score) scales. Each of the individual scales was completed by the participant. A responder showed considerable improvement in pain or function (>=50 percent and absolute change of >=20 millimeters), or improvement in at least two of three categories: Pain and/or Function and/or Patient Global Assessment scales of >=20 percent and absolute change >=10 millimeter. Response at Week 26 is compared to baseline.
Time Frame	Day 0 (baseline), week 26

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	IA-SA	IA-BioHA
Arm/Group Description	Each participant received a single intra-articular (IA) injection of buffered saline (SA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they could receive a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and be followed for an additional 26 weeks.	Each participant received a single intra-articular (IA) injection of 1.2% sodium hyaluronate (BioHA) into the target knee, and was followed for a total of 26 weeks in the double-blind period. Participants had the option of continuing into the open-label period in which they received a single intra-articular injection of 1.2% sodium hyaluronate (IA-BioHA) into the target knee and were followed for an additional 26 weeks.
Measure Participants	253	249
Number [percentage of participants]	70.0 23.5%	62.2 20.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IA-SA, IA-BioHA
	Comments	The null hypothesis (Ho) is that the effect of the two treatment groups at 26 weeks is equal and the corresponding alternative hypothesis (HA) is that the effect of the two treatment groups at 26 weeks is unequal.[
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.081
	Comments	For secondary outcome measures, fixed-sequence testing was used in a sequentially rejective fashion. The a priori threshold for statistical significance was p <0.05.
	Method	Regression, Logistic
	Comments	The analysis included study center as a stratification variable.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.710
	Confidence Interval	(2-Sided) 95%; 0.483 to 1.044
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Double-blind period is day 1 to week 26. The open-label period is week 27 to week 52.
Arm/Group Title	IA-SA: Double-blind Period		IA-BioHA: Double-blind Period		IA-BioHA: Open-label Period
Arm/Group Description	Each participant received a single intra-articular (IA) injection of buffered saline (SA) into the target knee, and was followed for a total of 26 weeks in the double-blind period.		Each participant received a single intra-articular (IA) injection of 1.2% sodium hyaluronate (BioHA) into the target knee, and was followed for a total of 26 weeks in the double-blind period.		Participants had the option of continuing into the open-label period in which their target knee received a single intra-articular (IA) injection of 1.2% sodium hyaluronate (BioHA) and they were followed for an additional 26 weeks.
All Cause Mortality
	IA-SA: Double-blind Period		IA-BioHA: Double-blind Period		IA-BioHA: Open-label Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	IA-SA: Double-blind Period		IA-BioHA: Double-blind Period		IA-BioHA: Open-label Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/298 (2%)		13/298 (4.4%)		12/454 (2.6%)
Cardiac disorders
Bradycardia	0/298 (0%)		1/298 (0.3%)		0/454 (0%)
Cardiac failure congestive	0/298 (0%)		1/298 (0.3%)		0/454 (0%)
Myopericarditis	0/298 (0%)		1/298 (0.3%)		0/454 (0%)
Angina pectoris	1/298 (0.3%)		0/298 (0%)		1/454 (0.2%)
Atrial fibrillation	2/298 (0.7%)		0/298 (0%)		0/454 (0%)
Myocardial infarction	0/298 (0%)		0/298 (0%)		1/454 (0.2%)
Congenital, familial and genetic disorders
Urethral intrinsic sphincter deficiency	0/298 (0%)		1/298 (0.3%)		0/454 (0%)
General disorders
Chest pain	0/298 (0%)		1/298 (0.3%)		0/454 (0%)
Death	0/298 (0%)		1/298 (0.3%)		0/454 (0%)
Hepatobiliary disorders
Cholecystitis	0/298 (0%)		0/298 (0%)		1/454 (0.2%)
Infections and infestations
Intraspinal abscess	0/298 (0%)		1/298 (0.3%)		0/454 (0%)
Pneumonia	0/298 (0%)		1/298 (0.3%)		1/454 (0.2%)
Diverticulitis	0/298 (0%)		0/298 (0%)		1/454 (0.2%)
Urosepsis	0/298 (0%)		0/298 (0%)		1/454 (0.2%)
Injury, poisoning and procedural complications
Femur fracture	0/298 (0%)		1/298 (0.3%)		0/454 (0%)
Upper limb fracture	1/298 (0.3%)		0/298 (0%)		0/454 (0%)
Joint injury	0/298 (0%)		0/298 (0%)		1/454 (0.2%)
Investigations
Heart rate irregular	1/298 (0.3%)		0/298 (0%)		0/454 (0%)
Metabolism and nutrition disorders
Hyponatraemia	0/298 (0%)		0/298 (0%)		1/454 (0.2%)
Obesity	0/298 (0%)		0/298 (0%)		1/454 (0.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/298 (0%)		1/298 (0.3%)		1/454 (0.2%)
Osteoarthritis	0/298 (0%)		1/298 (0.3%)		0/454 (0%)
Back pain	1/298 (0.3%)		0/298 (0%)		0/454 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Uterine leiomyoma	1/298 (0.3%)		0/298 (0%)		0/454 (0%)
Nervous system disorders
Headache	0/298 (0%)		1/298 (0.3%)		0/454 (0%)
Syncope	1/298 (0.3%)		0/298 (0%)		0/454 (0%)
Transient ischaemic attack	0/298 (0%)		0/298 (0%)		1/454 (0.2%)
Psychiatric disorders
Psychotic disorder	0/298 (0%)		0/298 (0%)		1/454 (0.2%)
Renal and urinary disorders
Urinary incontinence	0/298 (0%)		1/298 (0.3%)		0/454 (0%)
Renal failure acute	0/298 (0%)		0/298 (0%)		1/454 (0.2%)
Reproductive system and breast disorders
Pelvic prolapse	0/298 (0%)		1/298 (0.3%)		0/454 (0%)
Surgical and medical procedures
Nephrectomy	0/298 (0%)		1/298 (0.3%)		0/454 (0%)
Spinal fusion surgery	0/298 (0%)		1/298 (0.3%)		0/454 (0%)
Knee arthroplasty	0/298 (0%)		0/298 (0%)		1/454 (0.2%)
Other (Not Including Serious) Adverse Events
	IA-SA: Double-blind Period		IA-BioHA: Double-blind Period		IA-BioHA: Open-label Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/298 (8.4%)		29/298 (9.7%)		32/454 (7%)
Musculoskeletal and connective tissue disorders
Arthralgia	25/298 (8.4%)		29/298 (9.7%)		32/454 (7%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review the draft manuscript prior to publication and can request delay of publication where any contents are deemed patentable by the sponsor or confidential to the sponsor. Comments will be given within four weeks from receipt of the draft manuscript. Additional time may be required to allow Ferring to seek patent protection of the invention.