A Study Evaluating the Safety and Efficacy of SM04690 for the Treatment of Moderately to Severely Symptomatic Knee Osteoarthritis

• Sponsor: Biosplice Therapeutics, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03122860
• Collaborator: (none)
• Enrollment: 700
• Locations: 74
• Arms: 6
• Actual Duration (Months): 12.2
• Patients Per Site: 9.5
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

This phase 2 study is a placebo-controlled, double-blind, parallel group study of four concentrations of SM04690 (0.03, 0.07, 0.15, and 0.23 mg per 2 mL injection) injected intraarticularly (IA) into the target knee joint of subjects with moderately to severely symptomatic osteoarthritis (OA). Based on previous studies of SM04690, key phenotypes of laterality (unilateral vs bilateral) as well as chronic pain (as measured by the Widespread Pain Index) were identified as confounding variables impacting the overall assessment of both radiologic and clinical efficacy outcomes. The design of SM04690-OA-04 is based upon previous study designs while assessing strategies to combat the confounding impact of laterality and chronic pain. To evaluate the effect of IA vehicle injection on patient-reported outcomes (PRO) such as pain, stiffness, and function in OA, this study also includes one cohort that receives a 2 mL IA injection of vehicle (placebo), and one cohort that receives a sham injection (i.e., a needle stick with 0 mL vehicle injected).

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 700 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, 24-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of SM04690 for the Treatment of Moderately to Severely Symptomatic Knee Osteoarthritis
• Actual Study Start Date: Apr 24, 2017
• Actual Primary Completion Date: Apr 30, 2018
• Actual Study Completion Date: Apr 30, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 0.03 mg SM04690 Single intra-articular injection of 0.03 mg SM04690 in 2 mL vehicle	Drug: SM04690; Healthcare professional-administered intra-articular injection performed once on Day 1 of the study
Experimental: 0.07 mg SM04690 Single intra-articular injection of 0.07 mg SM04690 in 2 mL vehicle	Drug: SM04690; Healthcare professional-administered intra-articular injection performed once on Day 1 of the study
Experimental: 0.15 mg SM04690 Single intra-articular injection of 0.15 mg SM04690 in 2 mL vehicle	Drug: SM04690; Healthcare professional-administered intra-articular injection performed once on Day 1 of the study
Experimental: 0.23 mg SM04690 Single intra-articular injection of 0.23 mg SM04690 in 2 mL vehicle	Drug: SM04690; Healthcare professional-administered intra-articular injection performed once on Day 1 of the study
Placebo Comparator: Placebo Single intra-articular injection of 0 mg SM04690 in 2 mL vehicle	Other: Placebo; Healthcare professional-administered intra-articular injection performed once on Day 1 of the study
Sham Comparator: Sham Single intra-articular injection of 0 mg SM04690 in 0 mL vehicle	Other: Sham; Healthcare professional-administered intra-articular injection performed once on Day 1 of the study

Outcome Measures

Primary Outcome Measures

1. Change From Baseline Osteoarthritis (OA) Pain in the Target Knee as Assessed by the Weekly Average of Daily Pain Numeric Rating Scale (NRS) [Baseline and Week 24]

   Change from baseline OA pain in the target knee as assessed by the weekly average of daily pain NRS at Week 24. The pain NRS is an 11-point scale [0-10] for subject self-reporting of average knee pain in the last 24 hours; 0 indicates no pain, and 10 represents the worst possible pain (pain as bad as one can imagine).

2. Change From Baseline OA Pain in the Target Knee as Assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscore (WOMAC Pain) [Baseline and Week 24]

   Change from baseline OA pain in the target knee as assessed by WOMAC Numeric Rating Scale (NRS 3.1) pain subscore (WOMAC Pain) at Week 24. 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 standardized and reported ranging from 0 to 100 [0 = no pain; 100 = pain as bad as it can be].

3. Change From Baseline OA Function in the Target Knee as Assessed by WOMAC Physical Function Subscore (WOMAC Function) [Baseline and Week 24]

   Change from baseline OA function in the target knee as assessed by WOMAC Numeric Rating Scale (NRS 3.1) physical functioning subscore (WOMAC Function) at Week 24. 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 standardized and reported ranging from 0 to 100 [0 = no functional disability, 100 = unable to function].

4. Change From Baseline in Medial Joint Space Width (mJSW) of the Target Knee [Baseline and Week 24]

   Change from baseline in mJSW as documented by radiograph of the target knee.

Secondary Outcome Measures

1. Change From Baseline OA Disease Activity as Assessed by Patient Global Assessment (PtGA) [Baseline and Week 24]

   Change from baseline OA disease activity as assessed by PtGA at Week 24. The PtGA 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.

Other Outcome Measures

1. Change From Baseline OA Pain in the Target Knee as Assessed by WOMAC Pain Subscore (WOMAC Pain) [Baseline and Week 12]

   Change from baseline OA pain in the target knee as assessed by WOMAC Numeric Rating Scale (NRS 3.1) pain subscore (WOMAC Pain) at Week 12. 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 standardized and reported ranging from 0 to 100 [0 = no pain, 100 = pain as bad as it can be].

2. Change From Baseline OA Function in the Target Knee as Assessed by WOMAC Physical Function Subscore (WOMAC Function) [Baseline and Week 12]

   Change from baseline OA function in the target knee as assessed by WOMAC Numeric Rating Scale (NRS 3.1) physical functioning subscore (WOMAC Function) at Week 12. 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 standardized and reported ranging from 0 to 100 [0 = no functional disability, 100 = unable to function].

3. Change From Baseline OA Pain in the Target Knee as Assesses by the Weekly Average of Daily Pain NRS [Baseline and Week 12]

   Change from baseline OA pain in the target knee as assessed by the weekly average of daily pain NRS at Week 12. The pain NRS is an 11-point scale [0-10] for subject self-reporting of average knee pain in the last 24 hours; 0 indicates no pain, and 10 represents the worst possible pain (pain as bad as one can imagine).

4. Change From Baseline OA Disease Activity as Assessed by Patient Global Assessment (PtGA) [Baseline and Week 12]

   Change from baseline OA disease activity as assessed by PtGA at Week 12. The PtGA 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.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Ambulatory

• Diagnosis of femorotibial OA in the target knee by standard American College of Rheumatology (ACR) criteria at screening (clinical AND radiographic criteria); OA of the knee is not to be secondary to any rheumatologic conditions (e.g., rheumatoid arthritis)

• Pain compatible with OA of the knee(s) for at least 26 weeks prior to screening

• Primary source of pain throughout the body is due to OA in the target knee

• Willingness to use an electronic diary on a daily basis in the evening for the screening period and 24-week study duration

• Negative drug test for opioids and drugs of abuse, except alcohol and marijuana, at screening

• Subjects with depression or anxiety must be clinically stable for 12 weeks prior to screening, and, if on treatment for depression or anxiety, be on 12 weeks of stable therapy

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

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

Exclusion Criteria:

• Women who are pregnant, lactating, or have a positive pregnancy result at screening

• Women of child bearing potential who are sexually active and are not willing to use a highly effective method of birth control during the study period

• Males who are sexually active and have a partner who is capable of becoming pregnant, neither of whom have had surgery to become sterilized or whom are not using a highly effective method of birth control

• Body mass index (BMI) > 35

• Partial or complete joint replacement in either knee

• Currently requires regular use of ambulatory assistive devices (e.g., wheelchair, parallel bars, walker, canes, or crutches) or use of a lower extremity prosthesis, and/or a structural knee brace

• Previous participation in a Samumed clinical trial investigating SM04690

• Any surgery (e.g., arthroscopy) in either knee within 26 weeks prior to screening

• Any planned surgery during the study period

• 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 if completely excised. Subjects with other malignancies are eligible if they have been continuously disease free for at least 5 years prior to any study injection

• Comorbid conditions that could affect study endpoint assessments of the target knee, including, but not limited to, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, gout or pseudogout, and fibromyalgia

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

• Participation in a clinical research trial that included the receipt of an investigational product or any experimental therapeutic procedure, or an observational research trial related to osteoarthritis within 8 weeks prior to any study injection, or planned participation in any such trial

• Treatment of the target knee with intra-articular glucocorticoids (e.g., methylprednisolone) within 12 weeks prior to screening

• Any intra-articular injection into the target knee with a therapeutic aim including, but not limited to, viscosupplementation (e.g., hyaluronic acid), platelet-rich plasma (PRP), and stem cell therapies within 24 weeks prior to screening; treatment of the target knee with intra-articular glucocorticoids greater than 12 weeks prior to screening is allowed

• Treatment with systemic glucocorticoids greater than 10 mg prednisone or the equivalent per day within 4 weeks prior to screening

• Effusion of the target knee clinically requiring aspiration within 12 weeks prior to screening

• Use of electrotherapy, acupuncture, and/or chiropractic treatments for knee OA within 4 weeks prior to screening

• Any known active infections, including urinary tract infection, upper respiratory tract infection, sinusitis, 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) at study start

• Use of centrally acting analgesics (e.g., duloxetine) within 12 weeks prior to screening

• Use of anticonvulsants within 12 weeks prior to screening, unless used for seizure or migraine prophylaxis

• Subjects requiring the usage of opioids >1x per week within 12 weeks prior to screening

• Use of topical local anesthetic agents (gels, creams, or patches such as the Lidoderm patch) for the treatment of knee OA within 7 days of screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Anniston	Alabama	United States	36207
2	Research Site	Birmingham	Alabama	United States	35216
3	Research Site	Mobile	Alabama	United States	36608
4	Research Site	Chandler	Arizona	United States	85224
5	Research Site	Phoenix	Arizona	United States	85018
6	Research Site	Phoenix	Arizona	United States	85053
7	Research Site	Tucson	Arizona	United States	85712
8	Research Site	Anaheim	California	United States	92801
9	Research Site	Canoga Park	California	United States	91303
10	Research Site	Carmichael	California	United States	95608
11	Research Site	Cerritos	California	United States	90703
12	Research Site	El Cajon	California	United States	92020
13	Research Site	Gold River	California	United States	95670
14	Research Site	La Mesa	California	United States	91942
15	Research Site	Los Angeles	California	United States	90036
16	Research Site	Rancho Mirage	California	United States	92270
17	Research Site	Sacramento	California	United States	95817
18	Research Site	San Diego	California	United States	92103
19	Research Site	San Marcos	California	United States	92078
20	Research Site	Spring Valley	California	United States	91978
21	Research Site	Boulder	Colorado	United States	80301
22	Research Site	Stamford	Connecticut	United States	06905
23	Research Site	Trumbull	Connecticut	United States	06606
24	Research Site	Waterbury	Connecticut	United States	06708
25	Research Site	Clearwater	Florida	United States	33761
26	Research Site	Coral Gables	Florida	United States	33134
27	Research Site	DeLand	Florida	United States	32720
28	Research Site	Edgewater	Florida	United States	32132
29	Research Site	Lauderdale Lakes	Florida	United States	33319
30	Research Site	Miami	Florida	United States	33143
31	Research Site	Pinellas Park	Florida	United States	33781
32	Research Site	Marietta	Georgia	United States	30060
33	Research Site	Woodstock	Georgia	United States	30189
34	Research Site	Chicago	Illinois	United States	60607
35	Research Site	Evansville	Indiana	United States	47714
36	Research Site	Newton	Kansas	United States	67114
37	Research Site	Prairie Village	Kansas	United States	66208
38	Research Site	Wichita	Kansas	United States	67205
39	Research Site	Lexington	Kentucky	United States	40504
40	Research Site	Jefferson	Louisiana	United States	70121
41	Research Site	Frederick	Maryland	United States	21702
42	Research Site	Boston	Massachusetts	United States	02111
43	Research Site	Troy	Michigan	United States	48085
44	Research Site	Kansas City	Missouri	United States	64114
45	Research Site	Saint Louis	Missouri	United States	63141
46	Research Site	Saint Peters	Missouri	United States	63303
47	Research Site	Lincoln	Nebraska	United States	68516
48	Research Site	Las Vegas	Nevada	United States	89119
49	Research Site	Albuquerque	New Mexico	United States	87102
50	Research Site	Rochester	New York	United States	14609
51	Research Site	Charlotte	North Carolina	United States	28209
52	Research Site	Charlotte	North Carolina	United States	28210
53	Research Site	High Point	North Carolina	United States	27262
54	Research Site	Salisbury	North Carolina	United States	28144
55	Research Site	Wilmington	North Carolina	United States	28401
56	Research Site	Fargo	North Dakota	United States	58103
57	Research Site	Cincinnati	Ohio	United States	45224
58	Research Site	Cincinnati	Ohio	United States	45246
59	Research Site	Cleveland	Ohio	United States	44122
60	Research Site	Columbus	Ohio	United States	43213
61	Research Site	Duncansville	Pennsylvania	United States	16635
62	Research Site	Philadelphia	Pennsylvania	United States	19152
63	Research Site	State College	Pennsylvania	United States	16801
64	Research Site	Charleston	South Carolina	United States	29406
65	Research Site	Mount Pleasant	South Carolina	United States	29464
66	Research Site	Rapid City	South Dakota	United States	57702
67	Research Site	Austin	Texas	United States	78745
68	Research Site	Bedford	Texas	United States	76021
69	Research Site	Dallas	Texas	United States	75231
70	Research Site	Houston	Texas	United States	77055
71	Research Site	San Angelo	Texas	United States	76904
72	Research Site	Arlington	Virginia	United States	22207
73	Research Site	Charlottesville	Virginia	United States	22911
74	Research Site	Danville	Virginia	United States	24541

Sponsors and Collaborators

• Biosplice Therapeutics, Inc.

Investigators

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

Study Documents (Full-Text)

• Study Protocol - Apr 23, 2018
• Statistical Analysis Plan - Sep 13, 2018

More Information

Publications

None provided.

• Responsible Party: Biosplice Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT03122860
• Other Study ID Numbers: SM04690-OA-04
• First Posted: Apr 21, 2017
• Last Update Posted: Jun 11, 2021
• Last Verified: May 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.: SM04690; Wnt pathway inhibitor; osteoarthritis; Samumed
• Additional relevant MeSH terms: Osteoarthritis; Osteoarthritis, Knee; Lorecivivint

Study Results

Participant Flow

Recruitment Details

The Full Analysis Set (FAS) includes all subjects who were randomized and received a study injection, analyzed as randomized.

Pre-assignment Detail

The Safety Analysis Set (SAS) [see 'Adverse Events' section] includes all subjects who received a study injection, analyzed as treated. Discrepancy in subject counts between FAS and SAS is the result of subjects who received a treatment that is different from the planned treatment group as randomized. Subjects who received a study treatment not as prescribed in the pharmacy manual are summarized in the "Other" treatment group for safety analysis reporting.

Arm/Group Title	0.03 mg SM04690	0.07 mg SM04690	0.15 mg SM04690	0.23 mg SM04690	Placebo	Sham
Arm/Group Description	Single intra-articular injection of 0.03 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.07 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.15 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.23 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0 mg SM04690 in 0 mL vehicle
Period Title: Overall Study
STARTED	117	116	117	116	117	117
Full Analysis Set	116	115	115	116	116	117
COMPLETED	107	111	105	105	102	105
NOT COMPLETED	10	5	12	11	15	12

Baseline Characteristics

Arm/Group Title	0.03 mg SM04690	0.07 mg SM04690	0.15 mg SM04690	0.23 mg SM04690	Placebo	Sham	Total
Arm/Group Description	Single intra-articular injection of 0.03 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.07 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.15 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.23 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0 mg SM04690 in 0 mL vehicle	Total of all reporting groups
Overall Participants	116	115	115	116	116	117	695
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.9 (7.9)	59.9 (8.6)	58.4 (8.3)	58.5 (9.0)	60.1 (9.0)	59.0 (8.0)	59.0 (8.5)
Sex: Female, Male (Count of Participants)
Female	76 65.5%	66 57.4%	69 60%	61 52.6%	64 55.2%	70 59.8%	406 58.4%
Male	40 34.5%	49 42.6%	46 40%	55 47.4%	52 44.8%	47 40.2%	289 41.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	21 18.1%	22 19.1%	22 19.1%	10 8.6%	16 13.8%	24 20.5%	115 16.5%
Not Hispanic or Latino	95 81.9%	93 80.9%	93 80.9%	106 91.4%	100 86.2%	93 79.5%	580 83.5%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.9%	1 0.9%	0 0%	0 0%	2 1.7%	2 1.7%	6 0.9%
Asian	5 4.3%	5 4.3%	6 5.2%	5 4.3%	6 5.2%	3 2.6%	30 4.3%
Native Hawaiian or Other Pacific Islander	0 0%	3 2.6%	0 0%	0 0%	1 0.9%	2 1.7%	6 0.9%
Black or African American	24 20.7%	22 19.1%	25 21.7%	21 18.1%	17 14.7%	24 20.5%	133 19.1%
White	85 73.3%	83 72.2%	84 73%	89 76.7%	90 77.6%	86 73.5%	517 74.4%
More than one race	1 0.9%	1 0.9%	0 0%	1 0.9%	0 0%	0 0%	3 0.4%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Body Mass Index (BMI) (kg/m²) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m²]	29.17 (3.76)	29.14 (3.64)	29.38 (4.10)	28.53 (4.39)	28.62 (4.29)	28.97 (3.84)	28.97 (4.01)
Kellgren-Lawrence Grade (Count of Participants)
Grade 1	0 0%	1 0.9%	0 0%	0 0%	0 0%	0 0%	1 0.1%
Grade 2	53 45.7%	38 33%	47 40.9%	53 45.7%	43 37.1%	57 48.7%	291 41.9%
Grade 3	63 54.3%	74 64.3%	68 59.1%	63 54.3%	72 62.1%	58 49.6%	398 57.3%
Grade 4	0 0%	2 1.7%	0 0%	0 0%	1 0.9%	2 1.7%	5 0.7%
Osteoarthritis Laterality (Count of Participants)
Unilateral	59 50.9%	62 53.9%	63 54.8%	63 54.3%	61 52.6%	62 53%	370 53.2%
Bilateral	57 49.1%	53 46.1%	52 45.2%	53 45.7%	55 47.4%	55 47%	325 46.8%
Widespread Pain (WP) (Count of Participants)
WP-	92 79.3%	93 80.9%	90 78.3%	93 80.2%	93 80.2%	94 80.3%	555 79.9%
WP+	24 20.7%	22 19.1%	25 21.7%	23 19.8%	23 19.8%	23 19.7%	140 20.1%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline Osteoarthritis (OA) Pain in the Target Knee as Assessed by the Weekly Average of Daily Pain Numeric Rating Scale (NRS)
Description	Change from baseline OA pain in the target knee as assessed by the weekly average of daily pain NRS at Week 24. The pain NRS is an 11-point scale [0-10] for subject self-reporting of average knee pain in the last 24 hours; 0 indicates no pain, and 10 represents the worst possible pain (pain as bad as one can imagine).
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

Data is reported as observed with no imputation. Discrepancy between the number of participants analyzed and the number of participants assigned to the arms is the result of missing data and/or subject withdrawal.

Arm/Group Title	0.03 mg SM04690	0.07 mg SM04690	0.15 mg SM04690	0.23 mg SM04690	Placebo	Sham
Arm/Group Description	Single intra-articular injection of 0.03 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.07 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.15 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.23 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0 mg SM04690 in 0 mL vehicle
Measure Participants	98	102	92	90	95	91
Mean (Standard Deviation) [score on a scale]	-2.77 (2.44)	-2.93 (2.21)	-2.43 (2.18)	-3.03 (2.43)	-2.26 (2.44)	-2.21 (2.46)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	0.03 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.179
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.46
	Confidence Interval	(2-Sided) 95%; -1.13 to 0.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	0.07 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.031
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.70
	Confidence Interval	(2-Sided) 95%; -1.34 to -0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	0.15 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.675
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 95%; -0.81 to 0.52
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	0.23 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.022
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.82
	Confidence Interval	(2-Sided) 95%; -1.51 to -0.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sham
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.780
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.79 to 0.59
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Change From Baseline OA Pain in the Target Knee as Assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Subscore (WOMAC Pain)
Description	Change from baseline OA pain in the target knee as assessed by WOMAC Numeric Rating Scale (NRS 3.1) pain subscore (WOMAC Pain) at Week 24. 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 standardized and reported ranging from 0 to 100 [0 = no pain; 100 = pain as bad as it can be].
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

Data is reported as observed with no imputation. Discrepancy between the number of participants analyzed and the number of participants assigned to the arms is the result of missing data and/or subject withdrawal.

Arm/Group Title	0.03 mg SM04690	0.07 mg SM04690	0.15 mg SM04690	0.23 mg SM04690	Placebo	Sham
Arm/Group Description	Single intra-articular injection of 0.03 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.07 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.15 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.23 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0 mg SM04690 in 0 mL vehicle
Measure Participants	94	102	93	93	93	92
Mean (Standard Error) [score on a scale]	-27.6 (22.8)	-30.0 (22.5)	-24.7 (21.6)	-33.3 (22.9)	-25.5 (25.8)	-22.5 (24.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	0.03 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.612
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.70
	Confidence Interval	(2-Sided) 95%; -8.32 to 4.91
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	0.07 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.223
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.01
	Confidence Interval	(2-Sided) 95%; -10.47 to 2.46
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	0.15 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.590
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.84
	Confidence Interval	(2-Sided) 95%; -4.89 to 8.57
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	0.23 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.031
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.36
	Confidence Interval	(2-Sided) 95%; -14.03 to -0.69
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sham
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.403
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.89
	Confidence Interval	(2-Sided) 95%; -9.70 to 3.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Change From Baseline OA Function in the Target Knee as Assessed by WOMAC Physical Function Subscore (WOMAC Function)
Description	Change from baseline OA function in the target knee as assessed by WOMAC Numeric Rating Scale (NRS 3.1) physical functioning subscore (WOMAC Function) at Week 24. 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 standardized and reported ranging from 0 to 100 [0 = no functional disability, 100 = unable to function].
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

Data is reported as observed with no imputation. Discrepancy between the number of participants analyzed and the number of participants assigned to the arms is the result of missing data and/or subject withdrawal.

Arm/Group Title	0.03 mg SM04690	0.07 mg SM04690	0.15 mg SM04690	0.23 mg SM04690	Placebo	Sham
Arm/Group Description	Single intra-articular injection of 0.03 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.07 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.15 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.23 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0 mg SM04690 in 0 mL vehicle
Measure Participants	94	102	93	93	93	92
Mean (Standard Deviation) [score on a scale]	-27.7 (21.1)	-29.3 (23.0)	-23.6 (21.6)	-32.4 (22.1)	-24.9 (23.7)	-23.8 (23.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	0.03 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.432
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.58
	Confidence Interval	(2-Sided) 95%; -9.04 to 3.88
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	0.07 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.180
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.34
	Confidence Interval	(2-Sided) 95%; -10.69 to 2.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	0.15 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.718
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.19
	Confidence Interval	(2-Sided) 95%; -5.33 to 7.72
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	0.23 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.017
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.99
	Confidence Interval	(2-Sided) 95%; -14.54 to -1.45
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sham
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.682
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.39
	Confidence Interval	(2-Sided) 95%; -8.06 to 5.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Change From Baseline in Medial Joint Space Width (mJSW) of the Target Knee
Description	Change from baseline in mJSW as documented by radiograph of the target knee.
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

Data is reported as observed with no imputation. Discrepancy between the number of participants analyzed and the number of participants assigned to the arms is the result of missing data and/or subject withdrawal.

Arm/Group Title	0.03 mg SM04690	0.07 mg SM04690	0.15 mg SM04690	0.23 mg SM04690	Placebo	Sham
Arm/Group Description	Single intra-articular injection of 0.03 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.07 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.15 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.23 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0 mg SM04690 in 0 mL vehicle
Measure Participants	104	109	103	101	96	104
Mean (Standard Deviation) [mm]	0.02 (0.72)	-0.11 (0.53)	-0.11 (0.92)	-0.03 (0.45)	-0.01 (0.60)	-0.08 (0.58)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	0.03 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.822
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.16 to 0.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	0.07 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.162
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.11
	Confidence Interval	(2-Sided) 95%; -0.27 to 0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	0.15 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.267
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.12
	Confidence Interval	(2-Sided) 95%; -0.34 to 0.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	0.23 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.685
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.03
	Confidence Interval	(2-Sided) 95%; -0.18 to 0.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sham
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.342
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 95%; -0.09 to 0.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline OA Disease Activity as Assessed by Patient Global Assessment (PtGA)
Description	Change from baseline OA disease activity as assessed by PtGA at Week 24. The PtGA 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 24

Outcome Measure Data

Analysis Population Description

Data is reported as observed with no imputation. Discrepancy between the number of participants analyzed and the number of participants assigned to the arms is the result of missing data and/or subject withdrawal.

Arm/Group Title	0.03 mg SM04690	0.07 mg SM04690	0.15 mg SM04690	0.23 mg SM04690	Placebo	Sham
Arm/Group Description	Single intra-articular injection of 0.03 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.07 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.15 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.23 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0 mg SM04690 in 0 mL vehicle
Measure Participants	90	99	92	92	90	90
Mean (Standard Deviation) [mm]	-16.0 (23.5)	-19.8 (27.1)	-11.9 (27.5)	-18.3 (24.5)	-13.0 (21.6)	-13.8 (24.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	0.03 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.500
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.13
	Confidence Interval	(2-Sided) 95%; -8.36 to 4.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	0.07 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.082
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.54
	Confidence Interval	(2-Sided) 95%; -11.80 to 0.72
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	0.15 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	-1.94
	Confidence Interval	(2-Sided) 95%; -8.36 to 4.48
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	0.23 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.033
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.86
	Confidence Interval	(2-Sided) 95%; -13.16 to -0.56
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sham
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.887
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.45
	Confidence Interval	(2-Sided) 95%; -5.79 to 6.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Other Pre-specified Outcome

Title	Change From Baseline OA Pain in the Target Knee as Assessed by WOMAC Pain Subscore (WOMAC Pain)
Description	Change from baseline OA pain in the target knee as assessed by WOMAC Numeric Rating Scale (NRS 3.1) pain subscore (WOMAC Pain) at Week 12. 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 standardized and reported ranging from 0 to 100 [0 = no pain, 100 = pain as bad as it can be].
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Data is reported as observed with no imputation. Discrepancy between the number of participants analyzed and the number of participants assigned to the arms is the result of missing data and/or subject withdrawal.

Arm/Group Title	0.03 mg SM04690	0.07 mg SM04690	0.15 mg SM04690	0.23 mg SM04690	Placebo	Sham
Arm/Group Description	Single intra-articular injection of 0.03 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.07 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.15 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.23 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0 mg SM04690 in 0 mL vehicle
Measure Participants	103	98	100	101	101	106
Mean (Standard Deviation) [score on a scale]	-25.8 (20.5)	-29.3 (21.5)	-22.1 (20.2)	-32.1 (21.2)	-23.7 (24.6)	-22.8 (23.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	0.03 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.473
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.14
	Confidence Interval	(2-Sided) 95%; -7.99 to 3.72
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	0.07 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.040
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.31
	Confidence Interval	(2-Sided) 95%; -12.33 to -0.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	0.15 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.577
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.72
	Confidence Interval	(2-Sided) 95%; -4.35 to 7.79
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	0.23 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-8.95
	Confidence Interval	(2-Sided) 95%; -14.90 to -3.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sham
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.947
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.21
	Confidence Interval	(2-Sided) 95%; -6.37 to 5.96
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Other Pre-specified Outcome

Title	Change From Baseline OA Function in the Target Knee as Assessed by WOMAC Physical Function Subscore (WOMAC Function)
Description	Change from baseline OA function in the target knee as assessed by WOMAC Numeric Rating Scale (NRS 3.1) physical functioning subscore (WOMAC Function) at Week 12. 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 standardized and reported ranging from 0 to 100 [0 = no functional disability, 100 = unable to function].
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Data is reported as observed with no imputation. Discrepancy between the number of participants analyzed and the number of participants assigned to the arms is the result of missing data and/or subject withdrawal.

Arm/Group Title	0.03 mg SM04690	0.07 mg SM04690	0.15 mg SM04690	0.23 mg SM04690	Placebo	Sham
Arm/Group Description	Single intra-articular injection of 0.03 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.07 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.15 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.23 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0 mg SM04690 in 0 mL vehicle
Measure Participants	103	98	100	101	101	106
Mean (Standard Deviation) [score on a scale]	-26.0 (19.0)	-29.3 (21.8)	-20.9 (20.2)	-30.4 (21.3)	-22.7 (23.2)	-22.7 (24.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	0.03 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.299
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.05
	Confidence Interval	(2-Sided) 95%; -8.83 to 2.73
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

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	-7.18
	Confidence Interval	(2-Sided) 95%; -13.24 to -1.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	0.15 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.675
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.29
	Confidence Interval	(2-Sided) 95%; -4.75 to 7.33
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	0.23 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-8.63
	Confidence Interval	(2-Sided) 95%; -14.70 to -2.55
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sham
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.925
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.30
	Confidence Interval	(2-Sided) 95%; -5.99 to 6.59
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Other Pre-specified Outcome

Title	Change From Baseline OA Pain in the Target Knee as Assesses by the Weekly Average of Daily Pain NRS
Description	Change from baseline OA pain in the target knee as assessed by the weekly average of daily pain NRS at Week 12. The pain NRS is an 11-point scale [0-10] for subject self-reporting of average knee pain in the last 24 hours; 0 indicates no pain, and 10 represents the worst possible pain (pain as bad as one can imagine).
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Data is reported as observed with no imputation. Discrepancy between the number of participants analyzed and the number of participants assigned to the arms is the result of missing data and/or subject withdrawal.

Arm/Group Title	0.03 mg SM04690	0.07 mg SM04690	0.15 mg SM04690	0.23 mg SM04690	Placebo	Sham
Arm/Group Description	Single intra-articular injection of 0.03 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.07 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.15 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.23 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0 mg SM04690 in 0 mL vehicle
Measure Participants	103	102	101	101	105	105
Mean (Standard Deviation) [score on a scale]	-2.75 (2.22)	-3.02 (2.03)	-2.21 (2.23)	-2.87 (2.10)	-2.15 (2.39)	-2.27 (2.27)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	0.03 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.062
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.58
	Confidence Interval	(2-Sided) 95%; -1.18 to 0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	0.07 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.96
	Confidence Interval	(2-Sided) 95%; -1.54 to -0.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	0.15 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.693
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.12
	Confidence Interval	(2-Sided) 95%; -0.75 to 0.50
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	0.23 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.012
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.78
	Confidence Interval	(2-Sided) 95%; -1.39 to -0.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sham
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.697
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.12
	Confidence Interval	(2-Sided) 95%; -0.49 to 0.74
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Other Pre-specified Outcome

Title	Change From Baseline OA Disease Activity as Assessed by Patient Global Assessment (PtGA)
Description	Change from baseline OA disease activity as assessed by PtGA at Week 12. The PtGA 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 12

Outcome Measure Data

Analysis Population Description

Data is reported as observed with no imputation. Discrepancy between the number of participants analyzed and the number of participants assigned to the arms is the result of missing data and/or subject withdrawal.

Arm/Group Title	0.03 mg SM04690	0.07 mg SM04690	0.15 mg SM04690	0.23 mg SM04690	Placebo	Sham
Arm/Group Description	Single intra-articular injection of 0.03 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.07 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.15 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0.23 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0 mg SM04690 in 2 mL vehicle	Single intra-articular injection of 0 mg SM04690 in 0 mL vehicle
Measure Participants	100	93	94	101	99	104
Mean (Standard Deviation) [score on a scale]	-16.2 (25.0)	-20.0 (28.0)	-10.9 (23.4)	-18.4 (24.9)	-12.7 (21.9)	-12.7 (22.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	0.03 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.254
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.32
	Confidence Interval	(2-Sided) 95%; -9.04 to 2.40
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	0.07 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.031
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.86
	Confidence Interval	(2-Sided) 95%; -13.10 to -0.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	0.15 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.616
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.46
	Confidence Interval	(2-Sided) 95%; -7.20 to 4.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	0.23 mg SM04690, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.010
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.62
	Confidence Interval	(2-Sided) 95%; -13.41 to -1.82
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sham
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.961
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 95%; -5.74 to 5.46
	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 occur during the course of the study that are not present prior to Day 1 study medication injection, or, if present at the time of study medication injection, have worsened in severity during the course of the study. TEAEs were assessed at each study visit from the time of study medication injection on study visit Day 1 through Week 24 (End-of-Study)/Early Termination.
Adverse Event Reporting Description	The Safety Analyses Set [SAS] includes all subjects who received a study injection, analyzed as treated. Discrepancy in subject counts between SAS and Full Analysis Set [FAS] is the result of subjects who received a treatment that is different from the planned treatment group as randomized. Subjects who received a study treatment not as prescribed in the pharmacy manual are summarized in the "Other" treatment group for safety analysis reporting.
Arm/Group Title	0.03 mg SM04690		0.07 mg SM04690		0.15 mg SM04690		0.23 mg SM04690		Placebo		Sham		Other
Arm/Group Description	Single intra-articular injection of 0.03 mg SM04690 in 2 mL vehicle		Single intra-articular injection of 0.07 mg SM04690 in 2 mL vehicle		Single intra-articular injection of 0.15 mg SM04690 in 2 mL vehicle		Single intra-articular injection of 0.23 mg SM04690 in 2 mL vehicle		Single intra-articular injection of 0 mg SM04690 in 2 mL vehicle		Single intra-articular injection of 0 mg SM04690 in 0 mL vehicle		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		0.15 mg SM04690		0.23 mg SM04690		Placebo		Sham		Other
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/106 (0%)		0/104 (0%)		0/106 (0%)		0/106 (0%)		0/114 (0%)		0/120 (0%)		0/39 (0%)
Serious Adverse Events
	0.03 mg SM04690		0.07 mg SM04690		0.15 mg SM04690		0.23 mg SM04690		Placebo		Sham		Other
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/106 (1.9%)		0/104 (0%)		0/106 (0%)		2/106 (1.9%)		1/114 (0.9%)		0/120 (0%)		1/39 (2.6%)
Cardiac disorders
Coronary artery disease	0/106 (0%)	0	0/104 (0%)	0	0/106 (0%)	0	0/106 (0%)	0	1/114 (0.9%)	1	0/120 (0%)	0	0/39 (0%)	0
Supraventricular tachycardia	1/106 (0.9%)	1	0/104 (0%)	0	0/106 (0%)	0	0/106 (0%)	0	0/114 (0%)	0	0/120 (0%)	0	0/39 (0%)	0
Infections and infestations
Appendicitis perforated	0/106 (0%)	0	0/104 (0%)	0	0/106 (0%)	0	0/106 (0%)	0	0/114 (0%)	0	0/120 (0%)	0	1/39 (2.6%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Invasive ductal breast carcinoma	0/106 (0%)	0	0/104 (0%)	0	0/106 (0%)	0	1/106 (0.9%)	1	0/114 (0%)	0	0/120 (0%)	0	0/39 (0%)	0
Renal and urinary disorders
Nephrolithiasis	1/106 (0.9%)	1	0/104 (0%)	0	0/106 (0%)	0	1/106 (0.9%)	1	0/114 (0%)	0	0/120 (0%)	0	0/39 (0%)	0
Other (Not Including Serious) Adverse Events
	0.03 mg SM04690		0.07 mg SM04690		0.15 mg SM04690		0.23 mg SM04690		Placebo		Sham		Other
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/106 (13.2%)		19/104 (18.3%)		14/106 (13.2%)		17/106 (16%)		15/114 (13.2%)		22/120 (18.3%)		9/39 (23.1%)
Gastrointestinal disorders
Abdominal tenderness	0/106 (0%)	0	0/104 (0%)	0	0/106 (0%)	0	1/106 (0.9%)	1	0/114 (0%)	0	0/120 (0%)	0	1/39 (2.6%)	1
Nausea	0/106 (0%)	0	1/104 (1%)	1	0/106 (0%)	0	0/106 (0%)	0	0/114 (0%)	0	0/120 (0%)	0	1/39 (2.6%)	1
Vomiting	0/106 (0%)	0	0/104 (0%)	0	0/106 (0%)	0	0/106 (0%)	0	0/114 (0%)	0	0/120 (0%)	0	1/39 (2.6%)	1
General disorders
Oedema peripheral	0/106 (0%)	0	0/104 (0%)	0	0/106 (0%)	0	0/106 (0%)	0	0/114 (0%)	0	0/120 (0%)	0	1/39 (2.6%)	1
Infections and infestations
Bronchitis	3/106 (2.8%)	3	1/104 (1%)	1	1/106 (0.9%)	1	1/106 (0.9%)	1	0/114 (0%)	0	0/120 (0%)	0	1/39 (2.6%)	1
Gastroenteritis	0/106 (0%)	0	0/104 (0%)	0	0/106 (0%)	0	0/106 (0%)	0	1/114 (0.9%)	1	0/120 (0%)	0	1/39 (2.6%)	1
Sinusitis	1/106 (0.9%)	1	1/104 (1%)	1	1/106 (0.9%)	1	3/106 (2.8%)	3	1/114 (0.9%)	1	4/120 (3.3%)	4	0/39 (0%)	0
Skin infection	0/106 (0%)	0	0/104 (0%)	0	0/106 (0%)	0	0/106 (0%)	0	0/114 (0%)	0	0/120 (0%)	0	1/39 (2.6%)	1
Upper respiratory tract infection	2/106 (1.9%)	2	5/104 (4.8%)	5	0/106 (0%)	0	3/106 (2.8%)	3	4/114 (3.5%)	4	4/120 (3.3%)	5	1/39 (2.6%)	1
Urinary tract infection	1/106 (0.9%)	1	1/104 (1%)	1	1/106 (0.9%)	1	1/106 (0.9%)	1	1/114 (0.9%)	1	4/120 (3.3%)	4	1/39 (2.6%)	1
Viral upper respiratory tract infection	2/106 (1.9%)	2	2/104 (1.9%)	2	0/106 (0%)	0	1/106 (0.9%)	1	3/114 (2.6%)	3	1/120 (0.8%)	1	0/39 (0%)	0
Investigations
Blood lactate dehydrogenase increased	1/106 (0.9%)	1	0/104 (0%)	0	3/106 (2.8%)	3	0/106 (0%)	0	0/114 (0%)	0	0/120 (0%)	0	0/39 (0%)	0
Metabolism and nutrition disorders
Glucose tolerance impaired	0/106 (0%)	0	0/104 (0%)	0	1/106 (0.9%)	1	0/106 (0%)	0	0/114 (0%)	0	0/120 (0%)	0	1/39 (2.6%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	6/106 (5.7%)	6	7/104 (6.7%)	8	2/106 (1.9%)	2	9/106 (8.5%)	12	3/114 (2.6%)	3	7/120 (5.8%)	7	3/39 (7.7%)	4
Back pain	0/106 (0%)	0	1/104 (1%)	1	0/106 (0%)	0	0/106 (0%)	0	0/114 (0%)	0	3/120 (2.5%)	3	0/39 (0%)	0
Joint effusion	0/106 (0%)	0	1/104 (1%)	1	3/106 (2.8%)	3	0/106 (0%)	0	0/114 (0%)	0	0/120 (0%)	0	0/39 (0%)	0
Joint stiffness	0/106 (0%)	0	0/104 (0%)	0	0/106 (0%)	0	1/106 (0.9%)	1	0/114 (0%)	0	0/120 (0%)	0	1/39 (2.6%)	3
Joint swelling	0/106 (0%)	0	1/104 (1%)	1	1/106 (0.9%)	1	0/106 (0%)	0	0/114 (0%)	0	2/120 (1.7%)	2	1/39 (2.6%)	1
Musculoskeletal pain	0/106 (0%)	0	0/104 (0%)	0	0/106 (0%)	0	0/106 (0%)	0	1/114 (0.9%)	1	4/120 (3.3%)	4	0/39 (0%)	0
Pain in extremity	0/106 (0%)	0	0/104 (0%)	0	0/106 (0%)	0	1/106 (0.9%)	1	2/114 (1.8%)	2	1/120 (0.8%)	1	1/39 (2.6%)	1
Nervous system disorders
Dizziness	0/106 (0%)	0	0/104 (0%)	0	0/106 (0%)	0	0/106 (0%)	0	0/114 (0%)	0	0/120 (0%)	0	1/39 (2.6%)	1
Headache	0/106 (0%)	0	1/104 (1%)	1	3/106 (2.8%)	6	0/106 (0%)	0	0/114 (0%)	0	0/120 (0%)	0	0/39 (0%)	0
Renal and urinary disorders
Haematuria	1/106 (0.9%)	1	0/104 (0%)	0	3/106 (2.8%)	3	0/106 (0%)	0	1/114 (0.9%)	1	0/120 (0%)	0	0/39 (0%)	0
Skin and subcutaneous tissue disorders
Skin exfoliation	0/106 (0%)	0	0/104 (0%)	0	0/106 (0%)	0	0/106 (0%)	0	0/114 (0%)	0	0/120 (0%)	0	1/39 (2.6%)	1
Vascular disorders
Flushing	0/106 (0%)	0	0/104 (0%)	0	0/106 (0%)	0	0/106 (0%)	0	0/114 (0%)	0	0/120 (0%)	0	1/39 (2.6%)	1

Limitations/Caveats

[Not Specified]

More Information

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.