A Study of the Efficacy and Safety of EUFLEXXA™ for Treatment of Painful Osteoarthritis of the Knee

• Sponsor: Ferring Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00379236
• Collaborator: (none)
• Enrollment: 588
• Location: 1
• Arms: 3
• Duration (Months): 19
• Patients Per Site Per Month: 31

Study Details

Study Description

Brief Summary

This multicenter, randomized, double-blind study will be performed in approximately 600 subjects with chronic idiopathic osteoarthritis (OA) of the knee. An open-label safety extension will follow.

Condition or Disease	Intervention/Treatment	Phase
Osteoarthritis, Knee	Device: EUFLEXXA™; Device: placebo	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 588 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Double-Blind, Randomized, Placebo-Controlled Study of the Efficacy and Safety of EUFLEXXA™ for Treatment of Painful Osteoarthritis of the Knee, With an Open-Label Safety Extension
• Study Start Date: Oct 1, 2006
• Actual Primary Completion Date: Dec 1, 2007
• Actual Study Completion Date: May 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: EUFLEXXA™ Double-blind Each subject received 3 single-dose injections of EUFLEXXA™ into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.	Device: EUFLEXXA™; EUFLEXXA™ is supplied in a single-dose syringe containing 20 mg/2 ml of 1% sodium hyaluronate (molecular weight 2.4-3.6 MD); sodium chloride, 17 mg; disodium hydrogen phosphate dodecahydrate, 1.12 mg; sodium dihydrogen phosphate dihydrate, 0.1 mg; enough water for injection to make 2.0 ml. EUFLEXXA™ is supplied in 2.25 ml nominal volume, disposable prefilled glass syringes containing 2 mL of EUFLEXXA™. Only the contents of the syringe are sterile. EUFLEXXA™ is nonpyrogenic. See package insert for further details.
Placebo Comparator: Placebo Double-blind Each subject received 3 single-dose injections of placebo into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.	Device: placebo; Placebo is supplied in a disposable prefilled glass syringe. Each single-dose syringe will contain 2 mL of phosphate buffered saline. Only the contents of the syringe are sterile.
Experimental: EUFLEXXA™ Open Label All patients who participated in the 26 week double-blind study (including participants randomized to the placebo treatment group) and elected to participate in the open label extension, received three injections of EUFLEXXA™ in the target knee. Injections were given once a week on weeks 26, 27 and 28.	Device: EUFLEXXA™; EUFLEXXA™ is supplied in a single-dose syringe containing 20 mg/2 ml of 1% sodium hyaluronate (molecular weight 2.4-3.6 MD); sodium chloride, 17 mg; disodium hydrogen phosphate dodecahydrate, 1.12 mg; sodium dihydrogen phosphate dihydrate, 0.1 mg; enough water for injection to make 2.0 ml. EUFLEXXA™ is supplied in 2.25 ml nominal volume, disposable prefilled glass syringes containing 2 mL of EUFLEXXA™. Only the contents of the syringe are sterile. EUFLEXXA™ is nonpyrogenic. See package insert for further details.

Outcome Measures

Primary Outcome Measures

1. Observed Pain Scores on 50-foot Walk Test During the Double-blind Study [Weeks 0, 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 evaluated on a 100 millimeter visual analog scale. A score of 0 millimeters means there was no pain observed; a score of 100 millimeters means extreme pain was observed.

2. Percent Change From Baseline in Observed Pain Scores on 50-foot Walk Test During the Double-blind Study [Weeks 0 and 26]

   The percent difference in participant pain recorded by the participant during a walk of 50 feet in length between the baseline (week 0) and week 26 scores. Scores are measured on a visual analog scale of 100 millimeters; a score of 0 millimeters meaning no pain was observed; a score of 100 millimeters meaning extreme pain was observed.

3. Shifts From Extension Study Baseline (Week 26) in Range of Motion Findings at Week 52 [weeks 26 and 52]

   Number of participants in various categories of target knee joint examination findings from baseline (week 26 pre-injection) to week 52. Range of motion indicates the flexibility of the knee, and is measured by the number of degrees between when the knee is hyper-extended and when the knee is flexed.

4. Shifts From Extension Study Baseline (Week 26) in Ratings of Knee Tenderness at Week 52 [weeks 26 and 52]

   Number of participants in various categories of target knee joint examination findings from baseline (week 26 pre-injection) to week 52. Tenderness of the knee was subjectively rated by participants as none, mild, moderate or severe.

5. Shifts From Extension Study Baseline (Week 26) in Ratings of Knee Local Warmth at Week 52 [weeks 26 and 52]

   Number of participants in various categories of target knee joint examination findings from baseline (week 26 pre-injection) to week 52. Local warmth of the target knee was recorded as Yes (warmth present) or No (knee was not warmer than expected).

6. Shifts From Extension Study Baseline (Week 26) in Ratings of Knee Redness at Week 52 [weeks 26 and 52]

   Number of participants in various categories of target knee joint examination findings from baseline (week 26 pre-injection) to week 52. Redness of the knee was subjectively rated as Yes (knee was red) and No (knee was not red).

Secondary Outcome Measures

1. Percent Change From Screening in Observed Pain Scores on 50-foot Walk Test During the Double-blind Study [weeks -1 and 26]

   The percent difference in participant pain recorded by the participant during a walk of 50 feet in length between the screening (week -1) and week 26 scores. Scores are measured on a visual analog scale of 100 millimeters; a score of 0 millimeters means there was no pain observed; a score of 100 millimeters means extreme pain was observed.

2. Percent Change From Baseline in Observed Pain Scores on 50-foot Walk Test During the Double-blind Study for a Subpopulation of Participants With More Severe Knee Pain [weeks -1, 0, and 26]

   Percent difference in participant pain during a walk of 50 feet in length between the mean screening (week -1) and baseline(week 0) scores, and week 26 scores. Scores are recorded by participants and measured on a visual analog scale of 100 millimeters, with 0 millimeters meaning there was no pain observed; 100 millimeters meaning extreme pain was observed.

3. Number of Observed Osteoarthritis Research Society International (OARSI30) Responders Using the 50-Foot Walk Test at Week 12 [Week 12]

   Responders are identified based on a calculation of three scales: 50-foot walk test for pain, function and global assessment scales. Each of the individual scales was completed by the participant. A participant was a responder (answer: YES) if there was high 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.

4. Number of Observed Osteoarthritis Research Society International (OARSI30) Responders Using the 50-Foot Walk Test at Week 26 [Week 26]

   Responders are identified based on a calculation of three scales: 50-foot walk test for pain, function and global assessment scales. Each of the individual scales was completed by the participant. A participant was a responder (answer: YES) if there was high 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.

5. Number of Observed Osteoarthritis Research Society International (OARSI30) Responders Using the Western Ontario McMaster University Osteoarthritis Index (WOMAC A) Pain Scale at Week 12 [Week 12]

   Responders are identified based on a calculation of three scales: WOMAC (A) pain, function and global assessment scales. Each of the individual scales was completed by the participant. A participant was a responder (answer: YES) if there was high 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.

6. Number of Observed Osteoarthritis Research Society International (OARSI30) Responders Using the Western Ontario McMaster University Osteoarthritis Index (WOMAC A) Pain Scale at Week 26 [week 26]

   Responders are identified based on a calculation of three scales: WOMAC (A) pain, function and global assessment scales. Each of the individual scales was completed by the participant. A participant was a responder (answer: YES) if there was high 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.

7. Change From Baseline in Patient Global Assessment of Knee Pain at Week 26 [Weeks 0 and 26]

   Participant assessment of knee pain evaluated 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.

8. Change From Baseline in the Number of Tablets of Rescue Medication Used at Week 26. [Weeks 0 and 26]

   The change in the number of tablets of 500 milligram acetaminophen used in a week as rescue medication is compared at weeks 0 and weeks 26.

9. Mean Change From Baseline in Short Form 36 Questionnaire (SF-36) Physical Function (PF) Score at Week 26 [Weeks 0, 26]

   The SF-36 questionnaire yields a score for each domain of health. All domains are scored on a scale from 0 (negative health) to 100 (positive health), with 100 representing the best possible health state. This table summarizes the change from baseline in participants' physical function. The questionnaire is completed by participants.

10. Mean Change From Baseline in Short Form 36 Questionnaire (SF-36) Bodily Pain(BP) Score at Week 26 [weeks 0 and 26]

    The SF-36 questionnaire yields a score for each domain of health. All domains are scored on a scale from 0 (negative health) to 100 (positive health), with 100 representing the best possible health state. This table summarizes the change from baseline in participants' bodily pain scores. The questionnaire is completed by participants.

11. Mean Change From Baseline in Short Form 36 Questionnaire (SF-36) General Health(GH) Score at Week 26 [weeks 0 and 26]

    The SF-36 questionnaire yields a score for each domain of health. All domains are scored on a scale from 0 (negative health) to 100 (positive health), with 100 representing the best possible health state. This table summarizes the change from baseline in participants' general health scores. The questionnaire is completed by participants.

12. Mean Change From Baseline in Short Form 36 Questionnaire (SF-36) Physical Component Summary (PCS) Score at Week 26 [Weeks 0, 26]

    The SF-36 questionnaire yields a score for each domain of health. All domains are scored on a scale from 0 (negative health) to 100 (positive health), with 100 representing the best possible health state. The questionnaire is completed by participants. This table summarizes the change from baseline in participants' physical health.

13. Number of Participants With 20 Millimeter or Greater Improvement in Pain Scores on the 50-foot Walk Test [Weeks 0 and 26]

    Yes represents the number of participants whose pain during a walk of 50 feet in length was improved at week 26 over baseline by at least 20 millimeters. Pain was evaluated on a 100 millimeter visual analog scale by participants. A score of 0 millimeters means there was no pain observed; a score of 100 millimeters means extreme pain was observed.

14. Observed Pain Scores on the 50-foot Walk Test During the Extension Study [Baseline (week 26), week 52]

    Participant pain during a walk of 50 feet in length was evaluated by participants on a 100 millimeter visual analog scale. A score of 0 millimeters means there was no pain observed; a score of 100 millimeters means extreme pain was observed.

15. Mean Change From Baseline in Observed Pain Scores on 50-foot Walk Test During the Extension Study [Extension baseline (week 26), week 52]

    The mean difference in participant pain as measured by participants during a walk of 50 feet in length between the baseline (week 26 pre-dose) and week 52 scores. Scores are measured on a visual analog scale of 100 millimeters, with a score of 0 millimeters meaning there was no pain observed; a score of 100 millimeters meaning extreme pain was observed.

16. Number of Observed Osteoarthritis Research Society International (OARSI30) Responders Using the 50-Foot Walk Test at Week 52 [Week 52 (Extension Study)]

    Responders are identified based on a calculation of three scales: 50-foot walk test for pain, function and global assessment scales. Each of the individual scales was completed by the participant. A participant was a responder (answer:YES) if there was high 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.

17. Change From Baseline (Extension Study Week 26) in Use of Rescue Medication at Week 52. [Extension baseline (week 26 pre-dose), week 52]

    The change in the number of tablets of study-specific acetaminophen taken per week as a rescue medication from knee pain.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Chronic OA of target knee confirmed by ACR Criteria

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

• Moderate to severe pain score of 41 mm to 90 mm recorded on a 100 mm VAS immediately following a 50-foot walk

1. A bilateral standing AP X-ray confirming OA of the target knee-obtained within a 6-month period prior to the Screening Visit-and a grade of 2 or 3 according to the Kellgren and Lawrence Grading Scale

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

• The acetaminophen dose must not exceed 4 grams/day (4000 mg)

• If subject has known chronic liver disease, the maximum dose of acetaminophen must not exceed 2 grams/day (2000 mg)

• The subject must be willing and able to discontinue acetaminophen at least 24 hours prior to all study-specific visits

• The study specific acetaminophen provided will only be used for knee pain.

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

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

3. Signed study-specific Subject Informed Consent Form

Exclusion Criteria:

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

2. Any surgery to the target knee within the 12 months prior to the Screening Visit, or surgery to the contralateral knee or other weight-bearing joint if it will interfere with knee assessments

3. Prior articular procedures, such as transplants or ligament reconstruction to the target knee

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

5. Gout or calcium pyrophosphate (pseudogout) diseases that have flared within the previous 6 months prior to the Screening Visit

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

7. Osteonecrosis of either knee

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

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

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

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

12. Known hypersensitivity to acetaminophen, EUFLEXXA™, or Phosphate buffered saline solution

13. 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

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

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

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

17. Active liver disease based on liver profile of AST, ALT, and conjugated bilirubin >2 times the upper limit of normal

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

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

20. 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

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

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

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

24. Participation in any experimental drug or device study within the 6 months prior to the Screening Visit

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigational site	Los Angeles	California	United States	90025-1670

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: NCT00379236
• Other Study ID Numbers: 2005-01D
• First Posted: Sep 21, 2006
• Last Update Posted: Dec 28, 2011
• Last Verified: Dec 1, 2011

• Keywords provided by Ferring Pharmaceuticals: osteoarthritis; knee
• Additional relevant MeSH terms: Osteoarthritis; Osteoarthritis, Knee

Study Results

Participant Flow

Pre-assignment Detail	A total of 821 patients were screened.

Arm/Group Title	EUFLEXXA™ Double-blind	Placebo Double-blind	EUFLEXXA™ Extension Study
Arm/Group Description	Each subject received 3 single-dose injections of EUFLEXXA™ (20 milligram/2 milliliter 1 percent sodium hyaluronate) into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.	Each subject received 3 single-dose injections of placebo into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.	Each subject received 3 single-dose injections of EUFLEXXA™ (20 milligram/2 milliliter 1 percent sodium hyaluronate) into the target knee; one injection per week at weeks 26, 27 and 28. Patients were followed for 26 additional weeks (to week 52) following the first injection.
Period Title: Double-blind
STARTED	293	295	0
COMPLETED	257	259	0
NOT COMPLETED	36	36	0
Period Title: Double-blind
STARTED	0	0	433
COMPLETED	0	0	378
NOT COMPLETED	0	0	55

Baseline Characteristics

Arm/Group Title	EUFLEXXA™ Double-blind	Placebo Double-blind	Total
Arm/Group Description	Each subject received 3 single-dose injections of EUFLEXXA™ (20 milligram/2 milliliter 1 percent sodium hyaluronate) into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.	Each subject received 3 single-dose injections of placebo into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.	Total of all reporting groups
Overall Participants	293	295	588
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.5 (10.62)	60.8 (10.31)	61.6 (10.50)
Sex: Female, Male (Count of Participants)
Female	185 63.1%	186 63.1%	371 63.1%
Male	108 36.9%	109 36.9%	217 36.9%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	231 78.8%	228 77.3%	459 78.1%
African American	26 8.9%	33 11.2%	59 10%
Asian	5 1.7%	5 1.7%	10 1.7%
Hispanic	29 9.9%	25 8.5%	54 9.2%
Unknown or Not Reported	2 0.7%	4 1.4%	6 1%
Region of Enrollment (participants) [Number]
United States	293 100%	295 100%	588 100%
Body Mass Index (BMI) (kilograms/meters square) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms/meters square]	32.36 (7.446)	33.03 (7.444)	32.70 (7.446)
Weight (kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms]	91.0 (21.95)	92.8 (21.68)	91.9 (21.81)

Outcome Measures

1. Primary Outcome

Title	Observed Pain Scores on 50-foot Walk Test During the Double-blind Study
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 evaluated on a 100 millimeter visual analog scale. A score of 0 millimeters means there was no pain observed; a score of 100 millimeters means extreme pain was observed.
Time Frame	Weeks 0, 26

Outcome Measure Data

Analysis Population Description

Intent to treat (ITT) population.

Arm/Group Title	EUFLEXXA™ Double-blind	Placebo Double-blind
Arm/Group Description	Each subject received 3 single-dose injections of EUFLEXXA™ (20 milligram/2 milliliter 1 percent sodium hyaluronate) into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.	Each subject received 3 single-dose injections of placebo into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.
Measure Participants	291	295
Baseline (Week 0) (n=291,295)	55.6 (22.06)	54.7 (21.81)
Week 26 (n=251,259)	30.0 (26.06)	36.1 (28.55)

2. Secondary Outcome

Title	Percent Change From Screening in Observed Pain Scores on 50-foot Walk Test During the Double-blind Study
Description	The percent difference in participant pain recorded by the participant during a walk of 50 feet in length between the screening (week -1) and week 26 scores. Scores are measured on a visual analog scale of 100 millimeters; a score of 0 millimeters means there was no pain observed; a score of 100 millimeters means extreme pain was observed.
Time Frame	weeks -1 and 26

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	EUFLEXXA™ Double-Blind	Placebo Double-Blind
Arm/Group Description	Each subject received 3 single-dose injections of EUFLEXXA™ (20 milligram/2 milliliter 1 percent sodium hyaluronate) into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.	Each subject received 3 single-dose injections of placebo into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.
Measure Participants	249	259
Mean (Standard Deviation) [percent change from screening value]	-29.3 (277.14)	-38.4 (55.25)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	EUFLEXXA™ Double-blind, Placebo Double-blind
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments
	Method	ANCOVA
	Comments	Screening pain score was the covariate; study center was modeled as a random effect while all other variables were modeled as fixed effects.

3. Secondary Outcome

Title	Percent Change From Baseline in Observed Pain Scores on 50-foot Walk Test During the Double-blind Study for a Subpopulation of Participants With More Severe Knee Pain
Description	Percent difference in participant pain during a walk of 50 feet in length between the mean screening (week -1) and baseline(week 0) scores, and week 26 scores. Scores are recorded by participants and measured on a visual analog scale of 100 millimeters, with 0 millimeters meaning there was no pain observed; 100 millimeters meaning extreme pain was observed.
Time Frame	weeks -1, 0, and 26

Outcome Measure Data

Analysis Population Description

Intent to treat population. A subpopulation of patients with more severe knee pain, as measured by having a greater than or equal to 41 millimeter screening score on the 50-foot walk test.

Arm/Group Title	EUFLEXXA™ Double-Blind	Placebo Double-Blind
Arm/Group Description	Each subject received 3 single-dose injections of EUFLEXXA™ (20 milligram/2 milliliter 1 percent sodium hyaluronate) into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.	Each subject received 3 single-dose injections of placebo into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.
Measure Participants	239	254
Mean (Standard Deviation) [percentage change from baseline score]	-50.5 (42.26)	-36.8 (53.71)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	EUFLEXXA™ Double-blind, Placebo Double-blind
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	P-value is purely nominal
	Method	ANCOVA
	Comments

4. Secondary Outcome

Title	Number of Observed Osteoarthritis Research Society International (OARSI30) Responders Using the 50-Foot Walk Test at Week 12
Description	Responders are identified based on a calculation of three scales: 50-foot walk test for pain, function and global assessment scales. Each of the individual scales was completed by the participant. A participant was a responder (answer: YES) if there was high 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.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	EUFLEXXA™ Double-blind	Placebo Double-blind
Arm/Group Description	Each subject received 3 single-dose injections of EUFLEXXA™ (20 milligram/2 milliliter 1 percent sodium hyaluronate) into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.	Each subject received 3 single-dose injections of placebo into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.
Measure Participants	263	274
Yes	173 59%	167 56.6%
No	90 30.7%	107 36.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	EUFLEXXA™ Double-blind, Placebo Double-blind
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.202
	Comments
	Method	Chi-squared
	Comments

5. Secondary Outcome

Title	Number of Observed Osteoarthritis Research Society International (OARSI30) Responders Using the 50-Foot Walk Test at Week 26
Description	Responders are identified based on a calculation of three scales: 50-foot walk test for pain, function and global assessment scales. Each of the individual scales was completed by the participant. A participant was a responder (answer: YES) if there was high 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.
Time Frame	Week 26

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	EUFLEXXA™ Double-blind	Placebo Double-blind
Arm/Group Description	Each subject received 3 single-dose injections of EUFLEXXA™ (20 milligram/2 milliliter 1 percent sodium hyaluronate) into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.	Each subject received 3 single-dose injections of placebo into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.
Measure Participants	254	264
Yes	169 57.7%	155 52.5%
No	85 29%	109 36.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	EUFLEXXA™ Double-blind, Placebo Double-blind
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.047
	Comments
	Method	Chi-squared
	Comments

6. Secondary Outcome

Title	Number of Observed Osteoarthritis Research Society International (OARSI30) Responders Using the Western Ontario McMaster University Osteoarthritis Index (WOMAC A) Pain Scale at Week 12
Description	Responders are identified based on a calculation of three scales: WOMAC (A) pain, function and global assessment scales. Each of the individual scales was completed by the participant. A participant was a responder (answer: YES) if there was high 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.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	EUFLEXXA™ Double-blind	Placebo Double-blind
Arm/Group Description	Each subject received 3 single-dose injections of EUFLEXXA™ (20 milligram/2 milliliter 1 percent sodium hyaluronate) into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.	Each subject received 3 single-dose injections of placebo into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.
Measure Participants	262	273
Yes	153 52.2%	155 52.5%
No	109 37.2%	118 40%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	EUFLEXXA™ Double-blind, Placebo Double-blind
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.618
	Comments
	Method	Chi-squared
	Comments

7. Secondary Outcome

Title	Number of Observed Osteoarthritis Research Society International (OARSI30) Responders Using the Western Ontario McMaster University Osteoarthritis Index (WOMAC A) Pain Scale at Week 26
Description	Responders are identified based on a calculation of three scales: WOMAC (A) pain, function and global assessment scales. Each of the individual scales was completed by the participant. A participant was a responder (answer: YES) if there was high 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.
Time Frame	week 26

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	EUFLEXXA™ Double-blind	Placebo Double-blind
Arm/Group Description	Each subject received 3 single-dose injections of EUFLEXXA™ (20 milligram/2 milliliter 1 percent sodium hyaluronate) into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.	Each subject received 3 single-dose injections of EUFLEXXA™ into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.
Measure Participants	253	264
Yes	155 52.9%	137 46.4%
No	98 33.4%	127 43.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	EUFLEXXA™ Double-blind, Placebo Double-blind
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.028
	Comments
	Method	Chi-squared
	Comments

8. Primary Outcome

Title	Percent Change From Baseline in Observed Pain Scores on 50-foot Walk Test During the Double-blind Study
Description	The percent difference in participant pain recorded by the participant during a walk of 50 feet in length between the baseline (week 0) and week 26 scores. Scores are measured on a visual analog scale of 100 millimeters; a score of 0 millimeters meaning no pain was observed; a score of 100 millimeters meaning extreme pain was observed.
Time Frame	Weeks 0 and 26

Outcome Measure Data

Analysis Population Description

Intent to treat population.

Arm/Group Title	EUFLEXXA™ Double-blind	Placebo Double-blind
Arm/Group Description	Each subject received 3 single-dose injections of EUFLEXXA™ (20 milligram/2 milliliter 1 percent sodium hyaluronate) into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.	Each subject received 3 single-dose injections of placebo into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.
Measure Participants	251	259
Mean (Standard Deviation) [percent change from baseline value]	-30.9 (117.20)	-14.9 (114.87)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	EUFLEXXA™ Double-blind, Placebo Double-blind
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	ANCOVA
	Comments	Baseline pain score was the covariate; study center was modeled as a random effect while all other variables were modeled as fixed effects.

9. Primary Outcome

Title	Shifts From Extension Study Baseline (Week 26) in Range of Motion Findings at Week 52
Description	Number of participants in various categories of target knee joint examination findings from baseline (week 26 pre-injection) to week 52. Range of motion indicates the flexibility of the knee, and is measured by the number of degrees between when the knee is hyper-extended and when the knee is flexed.
Time Frame	weeks 26 and 52

Outcome Measure Data

Analysis Population Description

Safety population which includes all participants who received at least one injection during the extension phase of the study.

Arm/Group Title	EUFLEXXA™ Extension Study
Arm/Group Description	Each subject received 3 single-dose injections of EUFLEXXA™ (20 milligram/2 milliliter 1 percent sodium hyaluronate) into the target knee; one injection per week at weeks 26, 27 and 28. Patients were followed for 26 additional weeks (to week 52) following the first injection.
Measure Participants	375
>135 degrees week 26 / >135 degrees week 52	76 25.9%
90-135 degrees week 26 / >135 degrees week 52	33 11.3%
45-89 degrees week 26 / >135 degrees week 52	6 2%
<45 degrees week 26 / >135 degrees week 52	0 0%
>135 degrees week 26 / 90-135 degrees week 52	42 14.3%
90-135 degrees week 26/ 90-135 degrees week 52	171 58.4%
45-89 degrees week 26/ 90-135 degrees week 52	15 5.1%
<45 degrees week 26/ 90-135 degrees week 52	2 0.7%
>135 degrees week 26 / 45-89 degrees week 52	1 0.3%
90-135 degrees week 26 / 45-89 degrees week 52	12 4.1%
45-89 degrees week 26 / 45-89 degrees week 52	17 5.8%
<45 degrees week 26 / 45-89 degrees week 52	0 0%
>135 degrees week 26 / <45 degrees week 52	0 0%
90-135 degrees week 26 / <45 degrees week 52	0 0%
45-89 degrees week 26 / <45 degrees week 52	0 0%
<45 degrees week 26 / <45 degrees week 52	0 0%

10. Primary Outcome

Title	Shifts From Extension Study Baseline (Week 26) in Ratings of Knee Tenderness at Week 52
Description	Number of participants in various categories of target knee joint examination findings from baseline (week 26 pre-injection) to week 52. Tenderness of the knee was subjectively rated by participants as none, mild, moderate or severe.
Time Frame	weeks 26 and 52

Outcome Measure Data

Analysis Population Description

Safety population which includes all participants who received at least one injection during the extension phase of the study.

Arm/Group Title	EUFLEXXA™ Extension Study
Arm/Group Description	Each subject received 3 single-dose injections of EUFLEXXA™ (20 milligram/2 milliliter 1 percent sodium hyaluronate) into the target knee; one injection per week at weeks 26, 27 and 28. Patients were followed for 26 additional weeks (to week 52) following the first injection.
Measure Participants	377
None week 26 / none week 52	129 44%
Mild week 26 / none week 52	44 15%
Moderate week 26 / none week 52	5 1.7%
Severe week 26 / none week 52	0 0%
None week 26 / mild week 52	61 20.8%
Mild week 26 / mild week 52	75 25.6%
Moderate week 26 / mild week 52	17 5.8%
Severe week 26 / mild week 52	0 0%
None week 26 / moderate week 52	18 6.1%
Mild week 26 / moderate week 52	15 5.1%
Moderate week 26 / moderate week 52	9 3.1%
Severe week 26 / moderate week 52	1 0.3%
None week 26 / severe week 52	1 0.3%
Mild week 26 / severe week 52	1 0.3%
Moderate week 26 / severe week 52	1 0.3%
Severe week 26 / severe week 52	0 0%

11. Primary Outcome

Title	Shifts From Extension Study Baseline (Week 26) in Ratings of Knee Local Warmth at Week 52
Description	Number of participants in various categories of target knee joint examination findings from baseline (week 26 pre-injection) to week 52. Local warmth of the target knee was recorded as Yes (warmth present) or No (knee was not warmer than expected).
Time Frame	weeks 26 and 52

Outcome Measure Data

Analysis Population Description

Safety population which includes all participants who received at least one injection during the extension phase of the study.

Arm/Group Title	EUFLEXXA™ Extension Study
Arm/Group Description	Each subject received 3 single-dose injections of EUFLEXXA™ (20 milligram/2 milliliter 1 percent sodium hyaluronate) into the target knee; one injection per week at weeks 26, 27 and 28. Patients were followed for 26 additional weeks (to week 52) following the first injection.
Measure Participants	377
Yes week 26 / yes week 52	2 0.7%
No week 26 / yes week 52	11 3.8%
Yes week 26 / no week 52	11 3.8%
No week 26 / no week 52	353 120.5%

12. Primary Outcome

Title	Shifts From Extension Study Baseline (Week 26) in Ratings of Knee Redness at Week 52
Description	Number of participants in various categories of target knee joint examination findings from baseline (week 26 pre-injection) to week 52. Redness of the knee was subjectively rated as Yes (knee was red) and No (knee was not red).
Time Frame	weeks 26 and 52

Outcome Measure Data

Analysis Population Description

Safety population which includes all participants who received at least one injection during the extension phase of the study.

Arm/Group Title	EUFLEXXA™ Extension Study
Arm/Group Description	Each subject received 3 single-dose injections of EUFLEXXA™ (20 milligram/2 milliliter 1 percent sodium hyaluronate) into the target knee; one injection per week at weeks 26, 27 and 28. Patients were followed for 26 additional weeks (to week 52) following the first injection.
Measure Participants	377
Yes week 26 / yes week 52	0 0%
No week 26 / yes week 52	0 0%
Yes week 26 / no week 52	4 1.4%
No week 26 / no week 52	373 127.3%

13. Secondary Outcome

Title	Change From Baseline in Patient Global Assessment of Knee Pain at Week 26
Description	Participant assessment of knee pain evaluated 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.
Time Frame	Weeks 0 and 26

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	EUFLEXXA™ Double-Blind	Placebo Double-Blind
Arm/Group Description	Each subject received 3 single-dose injections of EUFLEXXA™ (20 milligram/2 milliliter 1 percent sodium hyaluronate) into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.	Each subject received 3 single-dose injections of placebo into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.
Measure Participants	253	263
Mean (Standard Deviation) [units on a scale]	-22.0 (30.38)	-17.8 (28.82)

14. Secondary Outcome

Title	Change From Baseline in the Number of Tablets of Rescue Medication Used at Week 26.
Description	The change in the number of tablets of 500 milligram acetaminophen used in a week as rescue medication is compared at weeks 0 and weeks 26.
Time Frame	Weeks 0 and 26

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	EUFLEXXA™ Double-blind	Placebo Double-blind
Arm/Group Description	Each subject received 3 single-dose injections of EUFLEXXA™ (20 milligram/2 milliliter 1 percent sodium hyaluronate) into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.	Each subject received 3 single-dose injections of placebo into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.
Measure Participants	232	240
Mean (Standard Deviation) [tablets per week]	12.7 (14.56)	12.9 (15.23)

15. Secondary Outcome

Title	Mean Change From Baseline in Short Form 36 Questionnaire (SF-36) Physical Function (PF) Score at Week 26
Description	The SF-36 questionnaire yields a score for each domain of health. All domains are scored on a scale from 0 (negative health) to 100 (positive health), with 100 representing the best possible health state. This table summarizes the change from baseline in participants' physical function. The questionnaire is completed by participants.
Time Frame	Weeks 0, 26

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	EUFLEXXA™ Double Blind	Placebo Double-Blind
Arm/Group Description	Each subject received 3 single-dose injections of EUFLEXXA™ (20 milligram/2 milliliter 1 percent sodium hyaluronate) into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.	Each subject received 3 single-dose injections of placebo into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.
Measure Participants	253	264
Mean (Standard Deviation) [units on a scale]	4.77 (9.65)	3.18 (9.05)

16. Secondary Outcome

Title	Mean Change From Baseline in Short Form 36 Questionnaire (SF-36) Bodily Pain(BP) Score at Week 26
Description	The SF-36 questionnaire yields a score for each domain of health. All domains are scored on a scale from 0 (negative health) to 100 (positive health), with 100 representing the best possible health state. This table summarizes the change from baseline in participants' bodily pain scores. The questionnaire is completed by participants.
Time Frame	weeks 0 and 26

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	EUFLEXXA™ Double-blind	Placebo Double-blind
Arm/Group Description	Each subject received 3 single-dose injections of EUFLEXXA™ (20 milligram/2 milliliter 1 percent sodium hyaluronate) into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.	Each subject received 3 single-dose injections of placebo into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.
Measure Participants	254	265
Mean (Standard Deviation) [units on a scale]	3.85 (9.93)	2.94 (9.56)

17. Secondary Outcome

Title	Mean Change From Baseline in Short Form 36 Questionnaire (SF-36) General Health(GH) Score at Week 26
Description	The SF-36 questionnaire yields a score for each domain of health. All domains are scored on a scale from 0 (negative health) to 100 (positive health), with 100 representing the best possible health state. This table summarizes the change from baseline in participants' general health scores. The questionnaire is completed by participants.
Time Frame	weeks 0 and 26

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	EUFLEXXA™ Double-Blind	Placebo Double-Blind
Arm/Group Description	Each subject received 3 single-dose injections of EUFLEXXA™ (20 milligram/2 milliliter 1 percent sodium hyaluronate) into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.	Each subject received 3 single-dose injections of placebo into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.
Measure Participants	253	265
Mean (Standard Deviation) [units on a scale]	1.38 (6.22)	0.19 (6.75)

18. Secondary Outcome

Title	Mean Change From Baseline in Short Form 36 Questionnaire (SF-36) Physical Component Summary (PCS) Score at Week 26
Description	The SF-36 questionnaire yields a score for each domain of health. All domains are scored on a scale from 0 (negative health) to 100 (positive health), with 100 representing the best possible health state. The questionnaire is completed by participants. This table summarizes the change from baseline in participants' physical health.
Time Frame	Weeks 0, 26

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	EUFLEXXA™ Double-Blind	Placebo Double-Blind
Arm/Group Description	Each subject received 3 single-dose injections of EUFLEXXA™ (20 milligram/2 milliliter 1 percent sodium hyaluronate) into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.	Each subject received 3 single-dose injections of placebo into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.
Measure Participants	251	263
Mean (Standard Deviation) [units on a scale]	4.55 (8.50)	2.71 (8.58)

19. Secondary Outcome

Title	Number of Participants With 20 Millimeter or Greater Improvement in Pain Scores on the 50-foot Walk Test
Description	Yes represents the number of participants whose pain during a walk of 50 feet in length was improved at week 26 over baseline by at least 20 millimeters. Pain was evaluated on a 100 millimeter visual analog scale by participants. A score of 0 millimeters means there was no pain observed; a score of 100 millimeters means extreme pain was observed.
Time Frame	Weeks 0 and 26

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	EUFLEXXA™ Double-blind	Placebo Double-blind
Arm/Group Description	Each subject received 3 single-dose injections of EUFLEXXA™ (20 milligram/2 milliliter 1 percent sodium hyaluronate) into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.	Each subject received 3 single-dose injections of placebo into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.
Measure Participants	251	259
Yes	145 49.5%	120 40.7%
No	106 36.2%	139 47.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	EUFLEXXA™ Double-blind, Placebo Double-blind
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments
	Method	Chi-squared
	Comments

20. Secondary Outcome

Title	Observed Pain Scores on the 50-foot Walk Test During the Extension Study
Description	Participant pain during a walk of 50 feet in length was evaluated by participants on a 100 millimeter visual analog scale. A score of 0 millimeters means there was no pain observed; a score of 100 millimeters means extreme pain was observed.
Time Frame	Baseline (week 26), week 52

Outcome Measure Data

Analysis Population Description

Intent to treat population. No imputation for missing values.

Arm/Group Title	EUFLEXXA™ Extension Study
Arm/Group Description	Each subject received 3 single-dose injections of EUFLEXXA™ (20 milligram/2 milliliter 1 percent sodium hyaluronate) into the target knee; one injection per week at weeks 26, 27 and 28. Patients were followed for 26 additional weeks (to week 52) following the first injection.
Measure Participants	425
Extension baseline (week 26) (n=418)	33.1 (27.26)
Week 52 (n=372)	24.7 (24.88)

21. Secondary Outcome

Title	Mean Change From Baseline in Observed Pain Scores on 50-foot Walk Test During the Extension Study
Description	The mean difference in participant pain as measured by participants during a walk of 50 feet in length between the baseline (week 26 pre-dose) and week 52 scores. Scores are measured on a visual analog scale of 100 millimeters, with a score of 0 millimeters meaning there was no pain observed; a score of 100 millimeters meaning extreme pain was observed.
Time Frame	Extension baseline (week 26), week 52

Outcome Measure Data

Analysis Population Description

Intent to treat population. No imputation for missing values.

Arm/Group Title	EUFLEXXA™ Extension Study
Arm/Group Description	Each subject received 3 single-dose injections of EUFLEXXA™ (20 milligram/2 milliliter 1 percent sodium hyaluronate) into the target knee; one injection per week at weeks 26, 27 and 28. Patients were followed for 26 additional weeks (to week 52) following the first injection.
Measure Participants	367
Mean (Standard Deviation) [units on a scale]	-7.8 (23.59)

22. Secondary Outcome

Title	Number of Observed Osteoarthritis Research Society International (OARSI30) Responders Using the 50-Foot Walk Test at Week 52
Description	Responders are identified based on a calculation of three scales: 50-foot walk test for pain, function and global assessment scales. Each of the individual scales was completed by the participant. A participant was a responder (answer:YES) if there was high 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.
Time Frame	Week 52 (Extension Study)

Outcome Measure Data

Analysis Population Description

Intent to treat population.

Arm/Group Title	EUFLEXXA™ Extension Study
Arm/Group Description	Each subject received 3 single-dose injections of EUFLEXXA™ (20 milligram/2 milliliter 1 percent sodium hyaluronate) into the target knee; one injection per week at weeks 26, 27 and 28. Patients were followed for 26 additional weeks (to week 52) following the first injection.
Measure Participants	374
Yes	144 49.1%
No	230 78.5%

23. Secondary Outcome

Title	Change From Baseline (Extension Study Week 26) in Use of Rescue Medication at Week 52.
Description	The change in the number of tablets of study-specific acetaminophen taken per week as a rescue medication from knee pain.
Time Frame	Extension baseline (week 26 pre-dose), week 52

Outcome Measure Data

Analysis Population Description

Intent to treat population

Arm/Group Title	EUFLEXXA™ Extension Study
Arm/Group Description	Each subject received 3 single-dose injections of EUFLEXXA™ (20 milligram/2 milliliter 1 percent sodium hyaluronate) into the target knee; one injection per week at weeks 26, 27 and 28. Patients were followed for 26 additional weeks (to week 52) following the first injection.
Measure Participants	311
Mean (Standard Deviation) [tablets per week]	9.5 (11.90)

Adverse Events

Arm/Group Title	EUFLEXXA™ Double-blind		Placebo Double-blind		EUFLEXXA™ Extension Study
Arm/Group Description	Each subject received 3 single-dose injections of EUFLEXXA™ (20 milligram/2 milliliter 1 percent sodium hyaluronate) into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.		Each subject received 3 single-dose injections of placebo into the target knee; one injection per week at weeks 0, 1 and 2. Patients were followed for 26 weeks following the first injection.		Each subject received 3 single-dose injections of EUFLEXXA™ (20 milligram/2 milliliter 1 percent sodium hyaluronate) into the target knee; one injection per week at weeks 26, 27 and 28. Patients were followed for 26 additional weeks (to week 52) following the first injection.
All Cause Mortality
	EUFLEXXA™ Double-blind		Placebo Double-blind		EUFLEXXA™ Extension Study
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	EUFLEXXA™ Double-blind		Placebo Double-blind		EUFLEXXA™ Extension Study
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/293 (3.4%)		9/295 (3.1%)		12/433 (2.8%)
Blood and lymphatic system disorders
Coagulopathy	0/293 (0%)	0	0/295 (0%)	0	1/433 (0.2%)	1
Cardiac disorders
acute myocardial infarction	1/293 (0.3%)	1	0/295 (0%)	0	0/433 (0%)	0
angina unstable	0/293 (0%)	0	1/295 (0.3%)	1	0/433 (0%)	0
arrhythmia	1/293 (0.3%)	1	0/295 (0%)	0	0/433 (0%)	0
atrial fibrillation	0/293 (0%)	0	0/295 (0%)	0	1/433 (0.2%)	1
mitral valve incompetence	0/293 (0%)	0	0/295 (0%)	0	1/433 (0.2%)	1
myocardial infarction	0/293 (0%)	0	0/295 (0%)	0	1/433 (0.2%)	1
Ear and labyrinth disorders
vertigo	0/293 (0%)	0	0/295 (0%)	0	1/433 (0.2%)	1
Gastrointestinal disorders
abdominal pain	0/293 (0%)	0	1/295 (0.3%)	1	0/433 (0%)	0
salivary gland mass	1/293 (0.3%)	1	0/295 (0%)	0	0/433 (0%)	0
umbilical hernia	0/293 (0%)	0	1/295 (0.3%)	1	0/433 (0%)	0
Hepatobiliary disorders
cholelithiasis	0/293 (0%)	0	0/295 (0%)	0	1/433 (0.2%)	1
Infections and infestations
pneumonia	2/293 (0.7%)	2	0/295 (0%)	0	1/433 (0.2%)	1
appendicitis	0/293 (0%)	0	1/295 (0.3%)	1	0/433 (0%)	0
gastroenteritis salmonella	0/293 (0%)	0	1/295 (0.3%)	1	0/433 (0%)	0
bacterial bronchitis	0/293 (0%)	0	0/295 (0%)	0	1/433 (0.2%)	1
Injury, poisoning and procedural complications
ankle fracture	1/293 (0.3%)	1	0/295 (0%)	0	0/433 (0%)	0
injury	0/293 (0%)	0	1/295 (0.3%)	1	1/433 (0.2%)	1
lower limb fracture	1/293 (0.3%)	1	0/295 (0%)	0	0/433 (0%)	0
spinal compression fracture	1/293 (0.3%)	1	0/295 (0%)	0	0/433 (0%)	0
Metabolism and nutrition disorders
hyponatraemia	0/293 (0%)	0	1/295 (0.3%)	1	0/433 (0%)	0
Musculoskeletal and connective tissue disorders
arthralgia	0/293 (0%)	0	1/295 (0.3%)	1	1/433 (0.2%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
pancreatic carcinoma	0/293 (0%)	0	1/295 (0.3%)	1	0/433 (0%)	0
Nervous system disorders
transient ischaemic attack	1/293 (0.3%)	1	1/295 (0.3%)	1	0/433 (0%)	0
cerebrovascular accident	0/293 (0%)	0	0/295 (0%)	0	1/433 (0.2%)	1
Psychiatric disorders
depression	0/293 (0%)	0	0/295 (0%)	0	1/433 (0.2%)	1
Respiratory, thoracic and mediastinal disorders
asthma	0/293 (0%)	0	0/295 (0%)	0	1/433 (0.2%)	1
pneumothorax	0/293 (0%)	0	0/295 (0%)	0	1/433 (0.2%)	1
Skin and subcutaneous tissue disorders
erythema	1/293 (0.3%)	1	0/295 (0%)	0	0/433 (0%)	0
Surgical and medical procedures
hysterectomy	1/293 (0.3%)	1	0/295 (0%)	0	0/433 (0%)	0
oophorectomy bilateral	1/293 (0.3%)	1	0/295 (0%)	0	0/433 (0%)	0
cholecystectomy	0/293 (0%)	0	0/295 (0%)	0	1/433 (0.2%)	1
intervertebral disc operation	0/293 (0%)	0	0/295 (0%)	0	1/433 (0.2%)	1
spinal fusion surgery	0/293 (0%)	0	0/295 (0%)	0	1/433 (0.2%)	1
Vascular disorders
deep vein thrombosis	0/293 (0%)	0	1/295 (0.3%)	1	0/433 (0%)	0
hypertension	0/293 (0%)	0	0/295 (0%)	0	1/433 (0.2%)	1
Other (Not Including Serious) Adverse Events
	EUFLEXXA™ Double-blind		Placebo Double-blind		EUFLEXXA™ Extension Study
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/293 (9.2%)		35/295 (11.9%)		43/433 (9.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	27/293 (9.2%)	27	35/295 (11.9%)	35	43/433 (9.9%)	43

Limitations/Caveats

[Not Specified]

More Information

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.