A Study Evaluating the Safety, Tolerability, and Efficacy of SM04690 Injected in the Target Knee Joint of Moderately to Severely Symptomatic Osteoarthritis Subjects

• Sponsor: Biosplice Therapeutics, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02536833
• Collaborator: (none)
• Enrollment: 455
• Locations: 36
• Arms: 4
• Actual Duration (Months): 19.4
• Patients Per Site: 12.6
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the efficacy, safety, and tolerability of three different strengths of SM04690 injected in the target knee joint of moderately to severely symptomatic osteoarthritis (OA) subjects.

Condition or Disease	Intervention/Treatment	Phase
Osteoarthritis	Drug: SM04690; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 455 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety, Tolerability, and Efficacy of SM04690 Injected in the Target Knee Joint of Moderately to Severely Symptomatic Osteoarthritis Subjects
• Actual Study Start Date: Sep 9, 2015
• Actual Primary Completion Date: Apr 20, 2017
• Actual Study Completion Date: Apr 20, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 0.03 mg SM04690 Single intra-articular injection of SM04690 0.03 mg in 2 mL injectable suspension	Drug: SM04690
Experimental: 0.07 mg SM04690 Single intra-articular injection of SM04690 0.07 mg in 2 mL injectable suspension	Drug: SM04690
Experimental: 0.23 mg SM04690 Single intra-articular injection of SM04690 0.23 mg in 2 mL injectable suspension	Drug: SM04690
Placebo Comparator: Placebo Single intra-articular injection of SM04690 0 mg in 2 mL phosphate buffered saline	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Change From Baseline Osteoarthritis (OA) Pain in the Target Knee [Baseline and Week 13]

   Change from baseline OA pain in the target knee as assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Numeric Rating Scale (NRS 3.1) pain subscore (WOMAC Pain) at Week 13. The WOMAC is a widely-used, proprietary outcome measurement tool used by health professionals to evaluate the condition of subjects with OA of the knee and hip, including pain (5 questions), stiffness (2 questions), and physical functioning (17 questions) of the joints. Each question is measured on a scale from 0 (lowest pain/lowest stiffness/highest function) to 10 (highest pain/highest stiffness/lowest function). The WOMAC Pain subscore is reported ranging from 0 to 100.

Secondary Outcome Measures

1. Change From Baseline OA Pain in the Target Knee [Baseline and Week 26]

   Change from baseline OA pain in the target knee as assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Numeric Rating Scale (NRS 3.1) pain subscore (WOMAC Pain) at Week 26. The WOMAC is a widely-used, proprietary outcome measurement tool used by health professionals to evaluate the condition of subjects with OA of the knee and hip, including pain (5 questions), stiffness (2 questions), and physical functioning (17 questions) of the joints. Each question is measured on a scale from 0 (lowest pain/lowest stiffness/highest function) to 10 (highest pain/highest stiffness/lowest function). The WOMAC Pain subscore is reported ranging from 0 to 100.

2. Change From Baseline OA Function in the Target Knee [Baseline and Week 13]

   Change from baseline OA function in the target knee as assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Numeric Rating Scale (NRS 3.1) physical functioning subscore (WOMAC Function) at Week 13. The WOMAC is a widely-used, proprietary outcome measurement tool used by health professionals to evaluate the condition of subjects with OA of the knee and hip, including pain (5 questions), stiffness (2 questions), and physical functioning (17 questions) of the joints. Each question is measured on a scale from 0 (lowest pain/lowest stiffness/highest function) to 10 (highest pain/highest stiffness/lowest function). The WOMAC Function subscore is reported ranging from 0 to 100.

3. Change From Baseline OA Function in the Target Knee [Baseline and Week 26]

   Change from baseline OA function in the target knee as assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Numeric Rating Scale (NRS 3.1) physical functioning subscore (WOMAC Function) at Week 26. The WOMAC is a widely-used, proprietary outcome measurement tool used by health professionals to evaluate the condition of subjects with OA of the knee and hip, including pain (5 questions), stiffness (2 questions), and physical functioning (17 questions) of the joints. Each question is measured on a scale from 0 (lowest pain/lowest stiffness/highest function) to 10 (highest pain/highest stiffness/lowest function). The WOMAC Function subscore is reported ranging from 0 to 100.

4. Change From Baseline OA Disease Activity as Assessed by the Patient [Baseline and Week 13]

   Change from baseline OA disease activity as assessed by the Patient Global Assessment at Week 13. The Patient Global Assessment was completed using a 100 mm visual analog scale (VAS) adapted from the Patient Assessment Form © 1999, American College of Rheumatology. The subject rated how well he/she was doing, considering all the ways in which illness and health conditions may affected him/her. The VAS scale was anchored by "Very Well" on the left (scored as 0) and "Very Poorly" on the right (scored as 100). Higher scores indicated poorer disease assessment by the subject.

5. Change From Baseline OA Disease Activity as Assessed by the Patient [Baseline and Week 26]

   Change from baseline OA disease activity as assessed by the Patient Global Assessment at Week 26. The Patient Global Assessment was completed using a 100 mm visual analog scale (VAS) adapted from the Patient Assessment Form © 1999, American College of Rheumatology. The subject rated how well he/she was doing, considering all the ways in which illness and health conditions may affected him/her. The VAS scale was anchored by "Very Well" on the left (scored as 0) and "Very Poorly" on the right (scored as 100). Higher scores indicated poorer disease assessment by the subject.

6. Change From Baseline in Medial Joint Space Width of Target Knee [Baseline and Week 26]

   Change from baseline in medial joint space width as documented by X-ray of the target knee at Week 26.

Other Outcome Measures

1. Change From Baseline OA Pain in the Target Knee [Baseline and Week 52]

   Change from baseline OA pain in the target knee as assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Numeric Rating Scale (NRS 3.1) pain subscore (WOMAC Pain) at Week 52. The WOMAC is a widely-used, proprietary outcome measurement tool used by health professionals to evaluate the condition of subjects with OA of the knee and hip, including pain (5 questions), stiffness (2 questions), and physical functioning (17 questions) of the joints. Each question is measured on a scale from 0 (lowest pain/lowest stiffness/highest function) to 10 (highest pain/highest stiffness/lowest function). The WOMAC Pain subscore is reported ranging from 0 to 100.

2. Change From Baseline OA Function in the Target Knee [Baseline and Week 52]

   Change from baseline OA function in the target knee as assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Numeric Rating Scale (NRS 3.1) physical functioning subscore (WOMAC Function) at Week 52. The WOMAC is a widely-used, proprietary outcome measurement tool used by health professionals to evaluate the condition of subjects with OA of the knee and hip, including pain (5 questions), stiffness (2 questions), and physical functioning (17 questions) of the joints. Each question is measured on a scale from 0 (lowest pain/lowest stiffness/highest function) to 10 (highest pain/highest stiffness/lowest function). The WOMAC Function subscore is reported ranging from 0 to 100.

3. Change From Baseline in Medial Joint Space Width of Target Knee [Baseline and Week 52]

   Change from baseline in medial joint space width as documented by X-ray of the target knee at Week 52.

4. Change From Baseline OA Pain in the Target Knee [Unilateral Symptomatic OA] [Baseline and Week 52]

   Change from baseline OA pain in the target knee as assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Numeric Rating Scale (NRS 3.1) pain subscore (WOMAC Pain) at Week 52. The WOMAC is a widely-used, proprietary outcome measurement tool used by health professionals to evaluate the condition of subjects with OA of the knee and hip, including pain (5 questions), stiffness (2 questions), and physical functioning (17 questions) of the joints. Each question is measured on a scale from 0 (lowest pain/lowest stiffness/highest function) to 10 (highest pain/highest stiffness/lowest function). The WOMAC Pain subscore is reported ranging from 0 to 100.

5. Change From Baseline OA Function in the Target Knee [Unilateral Symptomatic OA] [Baseline and Week 52]

   Change from baseline OA function in the target knee as assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Numeric Rating Scale (NRS 3.1) physical functioning subscore (WOMAC Function) at Week 52. The WOMAC is a widely-used, proprietary outcome measurement tool used by health professionals to evaluate the condition of subjects with OA of the knee and hip, including pain (5 questions), stiffness (2 questions), and physical functioning (17 questions) of the joints. Each question is measured on a scale from 0 (lowest pain/lowest stiffness/highest function) to 10 (highest pain/highest stiffness/lowest function). The WOMAC Function subscore is reported ranging from 0 to 100.

6. Change From Baseline in Medial Joint Space Width of Target Knee [Unilateral Symptomatic OA] [Baseline and Week 52]

   Change from baseline in medial joint space width as documented by X-ray of the target knee at Week 52.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Males and females between 40 and 80 years of age, inclusive, in general good health

2. Ambulatory (single assistive devices such as canes allowed if needed less than 50% of the time, subjects requiring a walker are excluded)

3. Established diagnosis of primary femorotibial OA in the target knee by standard American College of Rheumatology (ACR) criteria for at least 6 months (clinical AND radiographic criteria); if bilateral knee OA is present, the target knee is defined as the knee with greater pain at screening based on the subject's evaluation and the Investigator's clinical judgment

4. Radiographic disease Stage 2 or 3 in the target knee according to the Kellgren-Lawrence grading of knee OA as assessed by independent central readers

5. Screening pain visual analog scale (VAS) score of 30-80 mm (on a scale of 0-100 mm) for the target knee while on symptomatic oral treatment at screening (if the subject requires oral treatment)

6. Total WOMAC score of 72-192 (out of 240) for the target knee while on symptomatic oral treatment at screening (if the subject requires oral treatment)

7. Willingness to omit the following for 24 hours prior to all Study Visits, excluding the Screening Visit:

8. Pain medications

9. Medications or supplements for the treatment of OA

10. Participation in a formalized in-office and/or supervised OA disease program (e.g., a prescribed patient education program, physiotherapy, etc.)

11. Full understanding of the requirements of the study and willingness to comply with all study visits and assessments

12. Subjects must have read and understood the informed consent form, and must have signed it prior to any study-related procedure being performed

13. Subject's Day 1 visit must occur while enrollment into the study is open

Exclusion Criteria:

1. Women who are pregnant or lactating

2. Women of childbearing potential (i.e., who are not surgically sterile or postmenopausal as defined by no menstrual periods for 12 consecutive months and no other biological or physiological cause for amenorrhea can be identified); males who are sexually active and have a partner who is capable of becoming pregnant, neither of which have had surgery to become sterilized, who are not using an effective method of birth control (e.g., surgically-implanted hormonal therapy, intrauterine devices or oral birth control with barrier method)

3. Body mass index (BMI) >40

4. Partial or complete joint replacement in the target knee

5. Previous exposure to SM04690

6. Major surgery (e.g., interventional arthroscopy) in the target knee within 52 weeks prior to any study injection

7. Any planned or elective surgery during the study period

8. Significant and clinically evident misalignment of the target knee that would impact subject function, as determined by the Investigator

9. History of malignancy within the last 5 years; however, subjects with prior history of in situ cancer or basal or squamous cell skin cancer are eligible. Subjects with other malignancies are eligible if they have been continuously disease free for at least 5 years prior to any study injection

10. Clinically significant abnormal Screening Visit hematology values, blood chemistry values, HbA1c, or urinalysis values as determined by the investigator

11. Any condition, including laboratory findings (not included in the Screening Visit laboratory tests) and findings in the medical history or in the pre-study assessments, that, in the opinion of the Investigator, constitutes a risk or contraindication for participation in the study or that could interfere with the study objectives, conduct, or evaluation

12. Comorbid conditions that could affect pain assessment of the target knee, including, but not limited to, inflammatory rheumatic conditions such as rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, diabetic neuropathy, pseudogout, gout, and fibromyalgia

13. Other conditions that, in the opinion of the Investigator, could affect pain assessment of the target knee, including, but not limited to, symptomatic hip osteoarthritis and symptomatic degenerative disc disease

14. Any diagnosed psychiatric condition that includes, but is not limited to, a history of mania, bipolar disorder, psychotic disorder, schizophrenia, major depressive disorder, or generalized anxiety disorder

15. Participation in a clinical research trial that included the receipt of an investigational product or any experimental therapeutic procedure within 12 weeks prior to any study injection; the last date of participation in the trial, not the last date of receipt of investigational product, must be at least 12 weeks prior to Study Visit Day 1

16. Treatment of the target knee with systemic or intra-articular corticosteroids (e.g., methylprednisolone) within 8 weeks prior to Study Visit Day 1

17. Viscosupplementation (e.g., hyaluronic acid) in the target knee within 24 weeks prior to Study Visit Day 1

18. Effusion of the target knee clinically requiring aspiration within 12 weeks prior to Study Visit Day 1

19. Use of electrotherapy, acupuncture, and/or chiropractic treatments for knee OA within 4 weeks prior to Study Visit Day 1

20. Any known active infections, including suspicion of intra-articular infection, hepatitis B or hepatitis C infection, and/or infections that may compromise the immune system such as human immunodeficiency virus (HIV)

21. Subjects taking prescription medications for OA who have not maintained a stable therapeutic regimen for a minimum of 12 weeks prior to Study Visit Day 1

22. Subjects requiring the chronic use (i.e., regular and consistent use for ≥ 12 weeks) of the medications listed below within 12 weeks prior to Study Visit Day 1:

23. Opioids, both oral (e.g., tramadol) or transdermal (e.g., fentanyl patches) formulations

24. Centrally acting analgesics (e.g., duloxetine)

25. Glucocorticoids (e.g., methylprednisolone) administered by any route, with exception of inhaled, intranasal, and ophthalmic solutions

26. Any chronic condition that has not been well controlled or subjects with a chronic condition who have not maintained a stable therapeutic regimen of a prescription therapy for a minimum of 12 weeks prior to Study Visit Day 1. In addition, the following subjects will be excluded:

27. Subjects with a baseline HbA1c >9

28. Subjects with uncontrolled hypertension in the opinion of the investigator

29. Subjects with symptomatic coronary artery disease in the opinion of the investigator

30. Subjects who have a current or pending disability claim, workers' compensation, or litigation(s) that may compromise response to treatment

31. Subjects who are immediate family members (spouse, parent, child, or sibling; biological or legally adopted) of personnel directly affiliated with the study at the investigative site, or are directly affiliated with the study at the investigative site

32. Subjects employed by Samumed, LLC, or any of its affiliates or development partners (that is, an employee, temporary contract worker, or designee) responsible for the conduct of the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Mobile	Alabama	United States	36608
2	Research Site	Phoenix	Arizona	United States	85029
3	Research Site	Tucson	Arizona	United States	85712
4	Research Site	El Cajon	California	United States	92020
5	Research Site	Rancho Mirage	California	United States	92270
6	Research Site	Spring Valley	California	United States	91978
7	Research Site	Denver	Colorado	United States	80230
8	Research Site	Clearwater	Florida	United States	33761
9	Research Site	Coral Gables	Florida	United States	33134
10	Research Site	Jacksonville	Florida	United States	32216
11	Research Site	Miami	Florida	United States	33173
12	Research Site	West Palm Beach	Florida	United States	33409
13	Research Site	Woodstock	Georgia	United States	30189
14	Research Site	Newton	Kansas	United States	67114
15	Research Site	Wichita	Kansas	United States	67205
16	Research Site	Lexington	Kentucky	United States	40504
17	Research Site	Frederick	Maryland	United States	21702
18	Research Site	Boston	Massachusetts	United States	02111
19	Research Site	Worcester	Massachusetts	United States	01605
20	Research Site 1	Saint Louis	Missouri	United States	63141
21	Research Site 2	Saint Louis	Missouri	United States	63141
22	Research Site	Orchard Park	New York	United States	14127
23	Research Site	Rochester	New York	United States	14609
24	Research Site	Raleigh	North Carolina	United States	27612
25	Research Site	Salisbury	North Carolina	United States	28144
26	Research Site	Cincinnati	Ohio	United States	45246
27	Research Site	Duncansville	Pennsylvania	United States	16635
28	Research Site	Mount Pleasant	South Carolina	United States	29464
29	Research Site	Rapid City	South Dakota	United States	57702
30	Research Site	Knoxville	Tennessee	United States	37912
31	Research Site	Austin	Texas	United States	78745
32	Research Site	Houston	Texas	United States	77074
33	Research Site	West Layton	Utah	United States	84041
34	Research Site	Charlottesville	Virginia	United States	22911
35	Research Site	Richmond	Virginia	United States	23225
36	Research Site	Franklin	Wisconsin	United States	53132

Sponsors and Collaborators

• Biosplice Therapeutics, Inc.

Investigators

• Study Director: Yusuf Yazici, M.D., Biosplice Therapeutics, Inc.

Study Documents (Full-Text)

• Study Protocol - Oct 13, 2016
• Statistical Analysis Plan - Oct 14, 2016

More Information

Publications

None provided.

• Responsible Party: Biosplice Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT02536833
• Other Study ID Numbers: SM04690-OA-02
• First Posted: Sep 1, 2015
• Last Update Posted: Mar 17, 2021
• Last Verified: Mar 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Biosplice Therapeutics, Inc.: Osteoarthritis; Samumed; SM04690
• Additional relevant MeSH terms: Osteoarthritis; Lorecivivint

Study Results

Participant Flow

Arm/Group Title	0.03 mg SM04690	0.07 mg SM04690	0.23 mg SM04690	Placebo
Arm/Group Description	Single intra-articular injection of SM04690 0.03 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.07 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.23 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0 mg in 2 mL phosphate buffered saline
Period Title: Overall Study
STARTED	112	117	110	116
COMPLETED	103	107	95	97
NOT COMPLETED	9	10	15	19

Baseline Characteristics

Arm/Group Title	0.03 mg SM04690	0.07 mg SM04690	0.23 mg SM04690	Placebo	Total
Arm/Group Description	Single intra-articular injection of SM04690 0.03 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.07 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.23 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0 mg in 2 mL phosphate buffered saline	Total of all reporting groups
Overall Participants	112	117	110	116	455
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59 (9)	60 (8.2)	61.3 (8.7)	60.7 (8.9)	60.3 (8.7)
Sex: Female, Male (Count of Participants)
Female	68 60.7%	60 51.3%	68 61.8%	72 62.1%	268 58.9%
Male	44 39.3%	57 48.7%	42 38.2%	44 37.9%	187 41.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	20 17.9%	23 19.7%	17 15.5%	21 18.1%	81 17.8%
Not Hispanic or Latino	92 82.1%	94 80.3%	93 84.5%	95 81.9%	374 82.2%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 0.9%	0 0%	2 1.7%	3 0.7%
Asian	1 0.9%	0 0%	2 1.8%	0 0%	3 0.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	1 0.9%	1 0.2%
Black or African American	18 16.1%	14 12%	12 10.9%	10 8.6%	54 11.9%
White	92 82.1%	102 87.2%	96 87.3%	102 87.9%	392 86.2%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	1 0.9%	0 0%	0 0%	1 0.9%	2 0.4%
Kellgren-Lawrence Grade (Count of Participants)
Grade 2	38 33.9%	43 36.8%	39 35.5%	41 35.3%	161 35.4%
Grade 3	74 66.1%	74 63.2%	70 63.6%	74 63.8%	292 64.2%
Grade 4	0 0%	0 0%	1 0.9%	1 0.9%	2 0.4%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline Osteoarthritis (OA) Pain in the Target Knee
Description	Change from baseline OA pain in the target knee as assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Numeric Rating Scale (NRS 3.1) pain subscore (WOMAC Pain) at Week 13. The WOMAC is a widely-used, proprietary outcome measurement tool used by health professionals to evaluate the condition of subjects with OA of the knee and hip, including pain (5 questions), stiffness (2 questions), and physical functioning (17 questions) of the joints. Each question is measured on a scale from 0 (lowest pain/lowest stiffness/highest function) to 10 (highest pain/highest stiffness/lowest function). The WOMAC Pain subscore is reported ranging from 0 to 100.
Time Frame	Baseline and Week 13

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	0.03 mg SM04690	0.07 mg SM04690	0.23 mg SM04690	Placebo
Arm/Group Description	Single intra-articular injection of SM04690 0.03 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.07 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.23 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0 mg in 2 mL phosphate buffered saline
Measure Participants	112	117	110	116
Least Squares Mean (Standard Error) [score on a scale]	-23.3 (2.2)	-23.5 (2.1)	-21.3 (2.2)	-22.1 (2.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	0.07 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.575
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.46
	Confidence Interval	(2-Sided) 95%; -6.57 to 3.65
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	0.03 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.643
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.27
	Confidence Interval	(2-Sided) 95%; -6.63 to 4.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	0.23 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.901
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.34
	Confidence Interval	(2-Sided) 95%; -5.07 to 5.75
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline OA Pain in the Target Knee
Description	Change from baseline OA pain in the target knee as assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Numeric Rating Scale (NRS 3.1) pain subscore (WOMAC Pain) at Week 26. The WOMAC is a widely-used, proprietary outcome measurement tool used by health professionals to evaluate the condition of subjects with OA of the knee and hip, including pain (5 questions), stiffness (2 questions), and physical functioning (17 questions) of the joints. Each question is measured on a scale from 0 (lowest pain/lowest stiffness/highest function) to 10 (highest pain/highest stiffness/lowest function). The WOMAC Pain subscore is reported ranging from 0 to 100.
Time Frame	Baseline and Week 26

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	0.03 mg SM04690	0.07 mg SM04690	0.23 mg SM04690	Placebo
Arm/Group Description	Single intra-articular injection of SM04690 0.03 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.07 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.23 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0 mg in 2 mL phosphate buffered saline
Measure Participants	112	117	110	116
Least Squares Mean (Standard Error) [score on a scale]	-24.7 (2.3)	-27.3 (2.0)	-23.3 (2.1)	-24.4 (2.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	0.07 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.271
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.99
	Confidence Interval	(2-Sided) 95%; -8.31 to 2.33
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	0.03 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.898
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.37
	Confidence Interval	(2-Sided) 95%; -6.06 to 5.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	0.23 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.795
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 95%; -4.74 to 6.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline OA Function in the Target Knee
Description	Change from baseline OA function in the target knee as assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Numeric Rating Scale (NRS 3.1) physical functioning subscore (WOMAC Function) at Week 13. The WOMAC is a widely-used, proprietary outcome measurement tool used by health professionals to evaluate the condition of subjects with OA of the knee and hip, including pain (5 questions), stiffness (2 questions), and physical functioning (17 questions) of the joints. Each question is measured on a scale from 0 (lowest pain/lowest stiffness/highest function) to 10 (highest pain/highest stiffness/lowest function). The WOMAC Function subscore is reported ranging from 0 to 100.
Time Frame	Baseline and Week 13

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	0.03 mg SM04690	0.07 mg SM04690	0.23 mg SM04690	Placebo
Arm/Group Description	Single intra-articular injection of SM04690 0.03 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.07 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.23 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0 mg in 2 mL phosphate buffered saline
Measure Participants	112	117	110	116
Least Squares Mean (Standard Error) [score on a scale]	-24.5 (2.1)	-26.3 (2.0)	-22.6 (2.1)	-22.8 (2.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	0.07 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.283
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.74
	Confidence Interval	(2-Sided) 95%; -7.74 to 2.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	0.03 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.588
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.48
	Confidence Interval	(2-Sided) 95%; -6.82 to 3.86
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	0.23 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.853
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.50
	Confidence Interval	(2-Sided) 95%; -5.76 to 4.76
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline OA Function in the Target Knee
Description	Change from baseline OA function in the target knee as assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Numeric Rating Scale (NRS 3.1) physical functioning subscore (WOMAC Function) at Week 26. The WOMAC is a widely-used, proprietary outcome measurement tool used by health professionals to evaluate the condition of subjects with OA of the knee and hip, including pain (5 questions), stiffness (2 questions), and physical functioning (17 questions) of the joints. Each question is measured on a scale from 0 (lowest pain/lowest stiffness/highest function) to 10 (highest pain/highest stiffness/lowest function). The WOMAC Function subscore is reported ranging from 0 to 100.
Time Frame	Baseline and Week 26

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	0.03 mg SM04690	0.07 mg SM04690	0.23 mg SM04690	Placebo
Arm/Group Description	Single intra-articular injection of SM04690 0.03 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.07 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.23 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0 mg in 2 mL phosphate buffered saline
Measure Participants	112	117	110	116
Least Squares Mean (Standard Error) [score on a scale]	-25.1 (2.2)	-28.6 (2.0)	-24.1 (2.0)	-25.1 (2.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	0.07 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.292
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.89
	Confidence Interval	(2-Sided) 95%; -8.26 to 2.49
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	0.03 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.931
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.25
	Confidence Interval	(2-Sided) 95%; -5.34 to 5.83
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	0.23 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.878
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.42
	Confidence Interval	(2-Sided) 95%; -4.92 to 5.76
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline OA Disease Activity as Assessed by the Patient
Description	Change from baseline OA disease activity as assessed by the Patient Global Assessment at Week 13. The Patient Global Assessment was completed using a 100 mm visual analog scale (VAS) adapted from the Patient Assessment Form © 1999, American College of Rheumatology. The subject rated how well he/she was doing, considering all the ways in which illness and health conditions may affected him/her. The VAS scale was anchored by "Very Well" on the left (scored as 0) and "Very Poorly" on the right (scored as 100). Higher scores indicated poorer disease assessment by the subject.
Time Frame	Baseline and Week 13

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	0.03 mg SM04690	0.07 mg SM04690	0.23 mg SM04690	Placebo
Arm/Group Description	Single intra-articular injection of SM04690 0.03 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.07 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.23 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0 mg in 2 mL phosphate buffered saline
Measure Participants	112	117	110	116
Least Squares Mean (Standard Error) [mm]	-18.1 (2.3)	-13.7 (2.3)	-14.6 (2.6)	-14.0 (2.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	0.07 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.648
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.16
	Confidence Interval	(2-Sided) 95%; -3.83 to 6.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	0.03 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.209
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.14
	Confidence Interval	(2-Sided) 95%; -8.02 to 1.75
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	0.23 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.915
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.28
	Confidence Interval	(2-Sided) 95%; -4.78 to 5.33
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline OA Disease Activity as Assessed by the Patient
Description	Change from baseline OA disease activity as assessed by the Patient Global Assessment at Week 26. The Patient Global Assessment was completed using a 100 mm visual analog scale (VAS) adapted from the Patient Assessment Form © 1999, American College of Rheumatology. The subject rated how well he/she was doing, considering all the ways in which illness and health conditions may affected him/her. The VAS scale was anchored by "Very Well" on the left (scored as 0) and "Very Poorly" on the right (scored as 100). Higher scores indicated poorer disease assessment by the subject.
Time Frame	Baseline and Week 26

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	0.03 mg SM04690	0.07 mg SM04690	0.23 mg SM04690	Placebo
Arm/Group Description	Single intra-articular injection of SM04690 0.03 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.07 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.23 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0 mg in 2 mL phosphate buffered saline
Measure Participants	112	117	110	116
Least Squares Mean (Standard Error) [score on a scale]	-21.3 (2.4)	-17.5 (2.3)	-17.2 (2.6)	-16.6 (2.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	0.07 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.969
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.10
	Confidence Interval	(2-Sided) 95%; -5.16 to 5.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	0.03 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.174
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.64
	Confidence Interval	(2-Sided) 95%; -8.89 to 1.61
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	0.23 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.908
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.31
	Confidence Interval	(2-Sided) 95%; -4.97 to 5.59
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in Medial Joint Space Width of Target Knee
Description	Change from baseline in medial joint space width as documented by X-ray of the target knee at Week 26.
Time Frame	Baseline and Week 26

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	0.03 mg SM04690	0.07 mg SM04690	0.23 mg SM04690	Placebo
Arm/Group Description	Single intra-articular injection of SM04690 0.03 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.07 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.23 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0 mg in 2 mL phosphate buffered saline
Measure Participants	112	117	110	116
Least Squares Mean (Standard Error) [mm]	-0.07 (0.06)	-0.11 (0.08)	-0.02 (0.06)	-0.20 (0.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	0.07 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.334
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.10
	Confidence Interval	(2-Sided) 95%; -0.10 to 0.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	0.03 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.124
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.13
	Confidence Interval	(2-Sided) 95%; -0.04 to 0.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	0.23 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.032
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.19
	Confidence Interval	(2-Sided) 95%; 0.02 to 0.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Other Pre-specified Outcome

Title	Change From Baseline OA Pain in the Target Knee
Description	Change from baseline OA pain in the target knee as assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Numeric Rating Scale (NRS 3.1) pain subscore (WOMAC Pain) at Week 52. The WOMAC is a widely-used, proprietary outcome measurement tool used by health professionals to evaluate the condition of subjects with OA of the knee and hip, including pain (5 questions), stiffness (2 questions), and physical functioning (17 questions) of the joints. Each question is measured on a scale from 0 (lowest pain/lowest stiffness/highest function) to 10 (highest pain/highest stiffness/lowest function). The WOMAC Pain subscore is reported ranging from 0 to 100.
Time Frame	Baseline and Week 52

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	0.03 mg SM04690	0.07 mg SM04690	0.23 mg SM04690	Placebo
Arm/Group Description	Single intra-articular injection of SM04690 0.03 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.07 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.23 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0 mg in 2 mL phosphate buffered saline
Measure Participants	112	117	110	116
Least Squares Mean (Standard Error) [score on a scale]	-24.7 (2.5)	-29.0 (2.1)	-25.5 (2.1)	-26.7 (2.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	0.07 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.405
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.38
	Confidence Interval	(2-Sided) 95%; -8.00 to 3.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	0.03 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.552
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.89
	Confidence Interval	(2-Sided) 95%; -4.37 to 8.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	0.23 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.763
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95%; -4.91 to 6.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Other Pre-specified Outcome

Title	Change From Baseline OA Function in the Target Knee
Description	Change from baseline OA function in the target knee as assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Numeric Rating Scale (NRS 3.1) physical functioning subscore (WOMAC Function) at Week 52. The WOMAC is a widely-used, proprietary outcome measurement tool used by health professionals to evaluate the condition of subjects with OA of the knee and hip, including pain (5 questions), stiffness (2 questions), and physical functioning (17 questions) of the joints. Each question is measured on a scale from 0 (lowest pain/lowest stiffness/highest function) to 10 (highest pain/highest stiffness/lowest function). The WOMAC Function subscore is reported ranging from 0 to 100.
Time Frame	Baseline and Week 52

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	0.03 mg SM04690	0.07 mg SM04690	0.23 mg SM04690	Placebo
Arm/Group Description	Single intra-articular injection of SM04690 0.03 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.07 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.23 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0 mg in 2 mL phosphate buffered saline
Measure Participants	112	117	110	116
Least Squares Mean (Standard Error) [score on a scale]	-24.1 (2.5)	-29.6 (2.0)	-24.9 (2.1)	-25.1 (2.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	0.07 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.173
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.90
	Confidence Interval	(2-Sided) 95%; -9.50 to 1.71
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	0.03 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.724
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.12
	Confidence Interval	(2-Sided) 95%; -5.12 to 7.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	0.23 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.914
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.32
	Confidence Interval	(2-Sided) 95%; -6.17 to 5.53
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Other Pre-specified Outcome

Title	Change From Baseline in Medial Joint Space Width of Target Knee
Description	Change from baseline in medial joint space width as documented by X-ray of the target knee at Week 52.
Time Frame	Baseline and Week 52

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	0.03 mg SM04690	0.07 mg SM04690	0.23 mg SM04690	Placebo
Arm/Group Description	Single intra-articular injection of SM04690 0.03 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.07 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.23 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0 mg in 2 mL phosphate buffered saline
Measure Participants	112	117	110	116
Least Squares Mean (Standard Error) [mm]	-0.04 (0.06)	-0.09 (0.06)	-0.16 (0.07)	-0.14 (0.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	0.07 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.529
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 95%; -0.12 to 0.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	0.03 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.259
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.10
	Confidence Interval	(2-Sided) 95%; -0.08 to 0.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	0.23 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.807
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 95%; -0.21 to 0.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Other Pre-specified Outcome

Title	Change From Baseline OA Pain in the Target Knee [Unilateral Symptomatic OA]
Description	Change from baseline OA pain in the target knee as assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Numeric Rating Scale (NRS 3.1) pain subscore (WOMAC Pain) at Week 52. The WOMAC is a widely-used, proprietary outcome measurement tool used by health professionals to evaluate the condition of subjects with OA of the knee and hip, including pain (5 questions), stiffness (2 questions), and physical functioning (17 questions) of the joints. Each question is measured on a scale from 0 (lowest pain/lowest stiffness/highest function) to 10 (highest pain/highest stiffness/lowest function). The WOMAC Pain subscore is reported ranging from 0 to 100.
Time Frame	Baseline and Week 52

Outcome Measure Data

Analysis Population Description

Subjects with unilateral symptomatic OA in the ITT Analysis Set.

Arm/Group Title	0.03 mg SM04690	0.07 mg SM04690	0.23 mg SM04690	Placebo
Arm/Group Description	Single intra-articular injection of SM04690 0.03 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.07 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.23 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0 mg in 2 mL phosphate buffered saline
Measure Participants	45	35	45	39
Least Squares Mean (Standard Error) [score on a scale]	-28.6 (3.5)	-30.1 (3.2)	-26.6 (3.1)	-23.8 (3.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	0.07 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.049
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-8.73
	Confidence Interval	(2-Sided) 95%; -17.44 to -0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	0.03 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.211
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.03
	Confidence Interval	(2-Sided) 95%; -15.49 to 3.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	0.23 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.254
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.23
	Confidence Interval	(2-Sided) 95%; -14.24 to 3.78
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Other Pre-specified Outcome

Title	Change From Baseline OA Function in the Target Knee [Unilateral Symptomatic OA]
Description	Change from baseline OA function in the target knee as assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Numeric Rating Scale (NRS 3.1) physical functioning subscore (WOMAC Function) at Week 52. The WOMAC is a widely-used, proprietary outcome measurement tool used by health professionals to evaluate the condition of subjects with OA of the knee and hip, including pain (5 questions), stiffness (2 questions), and physical functioning (17 questions) of the joints. Each question is measured on a scale from 0 (lowest pain/lowest stiffness/highest function) to 10 (highest pain/highest stiffness/lowest function). The WOMAC Function subscore is reported ranging from 0 to 100.
Time Frame	Baseline and Week 52

Outcome Measure Data

Analysis Population Description

Subjects with unilateral symptomatic OA in the ITT Analysis Set.

Arm/Group Title	0.03 mg SM04690	0.07 mg SM04690	0.23 mg SM04690	Placebo
Arm/Group Description	Single intra-articular injection of SM04690 0.03 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.07 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.23 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0 mg in 2 mL phosphate buffered saline
Measure Participants	45	35	45	39
Least Squares Mean (Standard Error) [score on a scale]	-29.0 (3.9)	-29.9 (3.4)	-25.6 (3.1)	-21.5 (3.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	0.07 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.036
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-10.26
	Confidence Interval	(2-Sided) 95%; -19.82 to -0.69
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	0.03 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.170
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.07
	Confidence Interval	(2-Sided) 95%; -17.18 to 3.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	0.23 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.171
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.29
	Confidence Interval	(2-Sided) 95%; -15.33 to 2.74
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Other Pre-specified Outcome

Title	Change From Baseline in Medial Joint Space Width of Target Knee [Unilateral Symptomatic OA]
Description	Change from baseline in medial joint space width as documented by X-ray of the target knee at Week 52.
Time Frame	Baseline and Week 52

Outcome Measure Data

Analysis Population Description

Subjects with unilateral symptomatic OA in the ITT Analysis Set.

Arm/Group Title	0.03 mg SM04690	0.07 mg SM04690	0.23 mg SM04690	Placebo
Arm/Group Description	Single intra-articular injection of SM04690 0.03 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.07 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0.23 mg in 2 mL injectable suspension	Single intra-articular injection of SM04690 0 mg in 2 mL phosphate buffered saline
Measure Participants	45	35	45	39
Least Squares Mean (Standard Error) [mm]	0.03 (0.10)	0.19 (0.12)	-0.22 (0.11)	-0.21 (0.12)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	0.07 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.021
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.39
	Confidence Interval	(2-Sided) 95%; 0.06 to 0.72
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	0.03 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.131
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.24
	Confidence Interval	(2-Sided) 95%; -0.07 to 0.55
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	0.23 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.789
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 95%; -0.35 to 0.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Data regarding treatment-emergent adverse events (TEAEs) was collected in this study. TEAEs are events that were not present prior to study medication injection or, if present prior to study medication injection, had worsened in severity. The reporting period for TEAEs started after the injection of study medication on Study Visit Day 1 through Week 52 (End of Study)/Early Termination.
Adverse Event Reporting Description	Safety Analyses Set: All participants who were exposed to SM04690 or placebo. Safety was assessed using the actual treatment.
Arm/Group Title	0.03 mg SM04690		0.07 mg SM04690		0.23 mg SM04690		Placebo		Other
Arm/Group Description	Single intra-articular injection of SM04690 0.03 mg in 2 mL injectable suspension		Single intra-articular injection of SM04690 0.07 mg in 2 mL injectable suspension		Single intra-articular injection of SM04690 0.23 mg in 2 mL injectable suspension		Single intra-articular injection of SM04690 0 mg in 2 mL phosphate buffered saline		Single intra-articular injection of an unidentified dose of SM04690 or Placebo due to incorrectly performed dilution or documentation by a pharmacist.
All Cause Mortality
	0.03 mg SM04690		0.07 mg SM04690		0.23 mg SM04690		Placebo		Other
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/111 (0%)		0/114 (0%)		0/104 (0%)		0/108 (0%)		0/15 (0%)
Serious Adverse Events
	0.03 mg SM04690		0.07 mg SM04690		0.23 mg SM04690		Placebo		Other
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/111 (4.5%)		4/114 (3.5%)		4/104 (3.8%)		3/108 (2.8%)		1/15 (6.7%)
Cardiac disorders
Acute myocardial infarction	1/111 (0.9%)	1	1/114 (0.9%)	1	0/104 (0%)	0	0/108 (0%)	0	0/15 (0%)	0
Aortic valve incompetence	0/111 (0%)	0	1/114 (0.9%)	1	0/104 (0%)	0	0/108 (0%)	0	0/15 (0%)	0
Atrial fibrillation	0/111 (0%)	0	1/114 (0.9%)	1	0/104 (0%)	0	0/108 (0%)	0	0/15 (0%)	0
Congenital, familial and genetic disorders
Atrial septal defect	0/111 (0%)	0	1/114 (0.9%)	1	0/104 (0%)	0	0/108 (0%)	0	0/15 (0%)	0
Gastrointestinal disorders
Gastroesophageal reflux disease	1/111 (0.9%)	1	0/114 (0%)	0	0/104 (0%)	0	0/108 (0%)	0	0/15 (0%)	0
General disorders
Non-cardiac chest pain	0/111 (0%)	0	0/114 (0%)	0	1/104 (1%)	1	0/108 (0%)	0	1/15 (6.7%)	1
Hepatobiliary disorders
Cholecystitis acute	0/111 (0%)	0	1/114 (0.9%)	1	0/104 (0%)	0	0/108 (0%)	0	0/15 (0%)	0
Infections and infestations
Cellulitis	1/111 (0.9%)	1	0/114 (0%)	0	0/104 (0%)	0	0/108 (0%)	0	0/15 (0%)	0
Diverticulitis	1/111 (0.9%)	1	1/114 (0.9%)	1	1/104 (1%)	1	0/108 (0%)	0	0/15 (0%)	0
Influenza	1/111 (0.9%)	1	0/114 (0%)	0	0/104 (0%)	0	0/108 (0%)	0	0/15 (0%)	0
Pyelonephritis	0/111 (0%)	0	1/114 (0.9%)	1	0/104 (0%)	0	0/108 (0%)	0	0/15 (0%)	0
Injury, poisoning and procedural complications
Patella fracture	0/111 (0%)	0	0/114 (0%)	0	1/104 (1%)	2	1/108 (0.9%)	1	0/15 (0%)	0
Musculoskeletal and connective tissue disorders
Osteoarthritis	0/111 (0%)	0	0/114 (0%)	0	0/104 (0%)	0	1/108 (0.9%)	1	0/15 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	0/111 (0%)	0	0/114 (0%)	0	0/104 (0%)	0	0/108 (0%)	0	1/15 (6.7%)	1
Gallbladder adenocarcinoma	0/111 (0%)	0	1/114 (0.9%)	1	0/104 (0%)	0	0/108 (0%)	0	0/15 (0%)	0
Nervous system disorders
Myelitis transverse	1/111 (0.9%)	1	0/114 (0%)	0	0/104 (0%)	0	0/108 (0%)	0	0/15 (0%)	0
Renal and urinary disorders
Nephrolithiasis	0/111 (0%)	0	1/114 (0.9%)	1	0/104 (0%)	0	0/108 (0%)	0	0/15 (0%)	0
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/111 (0%)	0	1/114 (0.9%)	1	0/104 (0%)	0	0/108 (0%)	0	0/15 (0%)	0
Uterine prolapse	0/111 (0%)	0	0/114 (0%)	0	1/104 (1%)	1	0/108 (0%)	0	0/15 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/111 (0%)	0	0/114 (0%)	0	0/104 (0%)	0	1/108 (0.9%)	1	0/15 (0%)	0
Vascular disorders
Aortic aneurysm	0/111 (0%)	0	1/114 (0.9%)	1	0/104 (0%)	0	0/108 (0%)	0	0/15 (0%)	0
Arteriosclerosis	0/111 (0%)	0	1/114 (0.9%)	1	0/104 (0%)	0	0/108 (0%)	0	0/15 (0%)	0
Hypertensive crisis	1/111 (0.9%)	1	0/114 (0%)	0	0/104 (0%)	0	0/108 (0%)	0	0/15 (0%)	0
Other (Not Including Serious) Adverse Events
	0.03 mg SM04690		0.07 mg SM04690		0.23 mg SM04690		Placebo		Other
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/111 (22.5%)		23/114 (20.2%)		19/104 (18.3%)		18/108 (16.7%)		11/15 (73.3%)
Blood and lymphatic system disorders
Anaemia	0/111 (0%)	0	1/114 (0.9%)	1	1/104 (1%)	1	0/108 (0%)	0	1/15 (6.7%)	1
Ear and labyrinth disorders
Vertigo	0/111 (0%)	0	0/114 (0%)	0	0/104 (0%)	0	0/108 (0%)	0	1/15 (6.7%)	1
Eye disorders
Visual acuity reduced	0/111 (0%)	0	0/114 (0%)	0	0/104 (0%)	0	0/108 (0%)	0	1/15 (6.7%)	1
Gastrointestinal disorders
Hiatus hernia	0/111 (0%)	0	0/114 (0%)	0	0/104 (0%)	0	0/108 (0%)	0	1/15 (6.7%)	1
Large intestine polyp	0/111 (0%)	0	0/114 (0%)	0	0/104 (0%)	0	0/108 (0%)	0	1/15 (6.7%)	1
Oesophageal motility disorder	0/111 (0%)	0	0/114 (0%)	0	0/104 (0%)	0	0/108 (0%)	0	1/15 (6.7%)	1
Oesophagitis	0/111 (0%)	0	0/114 (0%)	0	0/104 (0%)	0	0/108 (0%)	0	1/15 (6.7%)	1
General disorders
Oedema	0/111 (0%)	0	0/114 (0%)	0	0/104 (0%)	0	0/108 (0%)	0	1/15 (6.7%)	1
Infections and infestations
Nasopharyngitis	4/111 (3.6%)	4	3/114 (2.6%)	3	3/104 (2.9%)	3	0/108 (0%)	0	1/15 (6.7%)	1
Tooth abscess	0/111 (0%)	0	0/114 (0%)	0	0/104 (0%)	0	0/108 (0%)	0	1/15 (6.7%)	1
Upper respiratory tract infection	5/111 (4.5%)	5	2/114 (1.8%)	2	1/104 (1%)	1	3/108 (2.8%)	3	1/15 (6.7%)	1
Injury, poisoning and procedural complications
Joint injury	2/111 (1.8%)	2	0/114 (0%)	0	1/104 (1%)	1	1/108 (0.9%)	1	2/15 (13.3%)	2
Meniscus injury	2/111 (1.8%)	2	2/114 (1.8%)	2	0/104 (0%)	0	0/108 (0%)	0	1/15 (6.7%)	1
Metabolism and nutrition disorders
Diabetes mellitus	0/111 (0%)	0	0/114 (0%)	0	0/104 (0%)	0	0/108 (0%)	0	1/15 (6.7%)	1
Hypercholesterolaemia	1/111 (0.9%)	1	0/114 (0%)	0	1/104 (1%)	1	1/108 (0.9%)	1	1/15 (6.7%)	1
Hyperlipidaemia	0/111 (0%)	0	1/114 (0.9%)	1	0/104 (0%)	0	1/108 (0.9%)	1	1/15 (6.7%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	13/111 (11.7%)	16	13/114 (11.4%)	14	9/104 (8.7%)	13	10/108 (9.3%)	12	4/15 (26.7%)	6
Joint crepitation	0/111 (0%)	0	0/114 (0%)	0	0/104 (0%)	0	0/108 (0%)	0	1/15 (6.7%)	1
Muscle spasms	1/111 (0.9%)	1	0/114 (0%)	0	0/104 (0%)	0	0/108 (0%)	0	1/15 (6.7%)	1
Musculoskeletal stiffness	0/111 (0%)	0	0/114 (0%)	0	0/104 (0%)	0	0/108 (0%)	0	1/15 (6.7%)	2
Patellofemoral pain syndrome	0/111 (0%)	0	0/114 (0%)	0	1/104 (1%)	1	0/108 (0%)	0	1/15 (6.7%)	1
Nervous system disorders
Decreased vibratory sense	0/111 (0%)	0	0/114 (0%)	0	0/104 (0%)	0	0/108 (0%)	0	1/15 (6.7%)	1
Headache	0/111 (0%)	0	3/114 (2.6%)	6	2/104 (1.9%)	2	4/108 (3.7%)	4	1/15 (6.7%)	1
Respiratory, thoracic and mediastinal disorders
Asthma	0/111 (0%)	0	0/114 (0%)	0	0/104 (0%)	0	0/108 (0%)	0	1/15 (6.7%)	1
Vascular disorders
Varicose vein	0/111 (0%)	0	0/114 (0%)	0	0/104 (0%)	0	0/108 (0%)	0	1/15 (6.7%)	1

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.