A Study to Evaluate the Safety and Efficacy of Topically Applied TV-45070 (Ointment) in Participants With Primary Osteoarthritis (OA) Affecting a Single Knee

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02068599
• Collaborator: (none)
• Enrollment: 389
• Locations: 42
• Arms: 3
• Actual Duration (Months): 12.6
• Patients Per Site: 9.3
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

The primary purpose of the study is to evaluate the change from baseline after 4 weeks of topical administration of TV-45070 (4% and 8% ointment) compared with placebo for the relief of symptoms of primary OA affecting a single knee

Condition or Disease	Intervention/Treatment	Phase
Osteoarthritis of the Knee	Drug: TV-45070; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 389 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Topically Applied TV-45070 (4% and 8% w/w Ointment) in Patients With Primary Osteoarthritis Affecting a Single Knee
• Actual Study Start Date: Apr 14, 2014
• Actual Primary Completion Date: Apr 6, 2015
• Actual Study Completion Date: May 4, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TV-45070 4% TV-45070 ointment in a 4% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	Drug: TV-45070; TV-45070 ointment administered twice a day (morning and evening) to target knee. Participants were provided with a laminated instruction sheet including pictures that both described and illustrated how the ointment was to be spread over the entire knee anteriorly, medially, and laterally in a thin layer that fully covered the area. The ointment was gently massaged into the skin.; Other Names: funapide XEN402
Experimental: TV-45070 8% TV-45070 ointment in a 8% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	Drug: TV-45070; TV-45070 ointment administered twice a day (morning and evening) to target knee. Participants were provided with a laminated instruction sheet including pictures that both described and illustrated how the ointment was to be spread over the entire knee anteriorly, medially, and laterally in a thin layer that fully covered the area. The ointment was gently massaged into the skin.; Other Names: funapide XEN402
Placebo Comparator: Placebo Placebo ointment applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	Drug: Placebo; Placebo ointment matching active intervention administered twice a day (morning and evening) to target knee. Participants were provided with a laminated instruction sheet including pictures that both described and illustrated how the ointment was to be spread over the entire knee anteriorly, medially, and laterally in a thin layer that fully covered the area. The ointment was gently massaged into the skin.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Last 5 Days of Treatment in the Average Evening Pain Intensity In the Target Knee When Walking on a Flat Surface Using a Mixed Model for Repeated Measures (MMRM) [Baseline (day -5 to day -1), Last 5 days of treatment (day 24 to day 28)]

   The Western Ontario and McMasters Universities Arthritis Index [WOMAC] is a widely used, validated, patient-reported questionnaire used to assess pain, stiffness, and physical function in patients with OA of the knee. It consists of 24 items separated into 3 domains (pain [5 items], stiffness [2 items], and physical function [17 items]). WOMAC Question 1 is the first question in the pain domain and asks patients to rate their pain in the target knee while walking on a flat surface. The possible score for each item ranges from 0 (no pain) to 100 mm (worst pain). Participants record their response to WOMAC Question 1 in the study diary based on average pain upon walking since the last assessment or over the past 12 hours. Negative change from baseline scores indicate improvement in pain. MMRM includes week, treatment, study center, and treatment by week interaction as fixed factors; baseline average evening WOMAC Question 1 score as a covariate; and patient as a random factor.

Secondary Outcome Measures

1. Change From Baseline to Last 5 Days of Treatment in the Average Daily WOMAC Pain Subscale Score In the Target Knee Using a Mixed Model for Repeated Measures [Baseline (day -5 to day -1), Last 5 days of treatment (day 24 to day 28)]

   The five items in the WOMAC Pain Subscale cover pain during walking, using stairs, in bed, sitting or lying, and standing. Daily WOMAC pain subscale score is calculated as the sum of the 5-item pain subscale scores (WOMAC) recorded at evening for a total range of 0 (no pain) to 500 (worst pain on all 5 items). Negative change from baseline scores indicate improvement in pain. MMRM includes week, treatment, study center, and treatment by week interaction as fixed factors; baseline average evening WOMAC scores for the 5-item pain subscale as a covariate; and patient as a random factor.

2. Change From Baseline to Last 5 Days of Treatment in the Average Morning Pain Intensity In the Target Knee When Walking on a Flat Surface Using a Mixed Model for Repeated Measures (MMRM) [Baseline (day -5 to day -1), Last 5 days of treatment (day 24 to day 28)]

   The Western Ontario and McMasters Universities Arthritis Index [WOMAC] is a widely used, validated, patient-reported questionnaire used to assess pain, stiffness, and physical function in patients with OA of the knee. It consists of 24 items separated into 3 domains (pain [5 items], stiffness [2 items], and physical function [17 items]). The possible score for each item ranges from 0 (no pain) to 100 mm (worst pain). WOMAC Question 1 is the first question in the pain domain and asks patients to rate their pain in the target knee while walking on a flat surface. Participants record their response to WOMAC Question 1 in the study diary based on average pain upon walking since the last assessment or over the past 12 hours. Negative change from baseline scores indicate improvement in pain. MMRM includes week, treatment, study center, and treatment by week interaction as fixed factors; baseline average morning WOMAC Question 1 score as a covariate; and patient as a random factor.

3. Change From Baseline (Randomization Visit) to the Week 4 Visit in the WOMAC Physical Function Subscale Score for the Target Knee Using a Mixed Model for Repeated Measures [Baseline (day 1, predose), Treatment: Week 4 (day 29)]

   The seventeen items in the WOMAC physical function subscale cover stair use, rising from sitting, standing, bending, walking, getting in / out of a car, shopping, putting on / taking off socks, rising from bed, lying in bed, getting in / out of bath, sitting, getting on / off toilet, heavy household duties, light household duties. WOMAC physical function subscale score is calculated as the sum of the 17-item physical function subscale scores (WOMAC) for a total range of 0 (no pain) to 1700 (worst pain on all 17 items). Negative change from baseline scores indicate improvement in pain. MMRM includes week, treatment, study center, and treatment by week interaction as fixed factors; baseline physical function WOMAC scores for the 17-item subscale as a covariate; and patient as a random factor.

4. Change From Baseline (Randomization Visit) to the Week 4 Visit in the WOMAC Stiffness Subscale Score for the Target Knee Using a Mixed Model for Repeated Measures [Baseline (day 1, predose), Treatment: Week 4 (day 29)]

   The two items in the WOMAC stiffness subscale cover stiffness after first waking and later in the day. WOMAC stiffness subscale score is calculated as the sum of the 2-item stiffness subscale scores (WOMAC) for a total range of 0 (no stiffness) to 200 (worst stiffness on both items). Negative change from baseline scores indicate improvement in stiffness. MMRM includes week, treatment, study center, and treatment by week interaction as fixed factors; baseline stiffness WOMAC scores for the 2-item subscale as a covariate; and patient as a random factor.

5. Percentage of Participants With a >=30% and a >=50% Response in Average Evening Pain Intensity of WOMAC Question 1 in the Target Knee During the Last 5 Days of Treatment Compared With Baseline [Baseline (day -5 to day -1), Last 5 days of treatment (day 24 to day 28)]

   WOMAC Question 1 is the first question in the pain domain and asks patients to rate their pain in the target knee while walking on a flat surface. The possible score for each item ranges from 0 (no pain) to 100 mm (worst pain). Average pain is calculated using a MMRM which includes week, treatment, study center, and treatment by week interaction as fixed factors; baseline average evening WOMAC Question 1 score as a covariate; and patient as a random factor. Responder rate was calculated as 100 * the value of (average WOMAC pain subscale during the last 5 days of treatment [Days 24 to 28]) - average WOMAC pain subscale at baseline [the 5 days prior to randomization])/average WOMAC pain subscale at baseline (the 5 days prior to randomization). Participants with missing responder rates were treated as nonresponders.

6. Change From Baseline (Randomization Visit) to the Week 4 Visit in the Pain Quality Assessment Scale - Revised (PQAS-R) for the Target Knee Using a Mixed Model for Repeated Measures [Baseline (day 1, predose), Treatment: Week 4 (day 29)]

   PQAS-R is a standardized self-report tool that measures various aspects of a participant's pain. There are 19 questions (question 19 has 2 parts) that ask the participant to rate the various aspects (intensity, sharpness, heat, cold, etc.) of his/her pain over the past week on average on a scale of 0 to 10 (0 = not [aspect] and 10 = the most or worst imaginable [aspect]). PQAS-R score at each visit is the sum of responses for the 19 questions for a total range of 0=no pain to 200=worst imaginable pain in all aspects. Negative change from baseline scores indicate improvement in stiffness. MMRM includes week, treatment, study center, and treatment by week interaction as fixed factors; baseline PQAS-R score for the 19 questions (20 parts) as a covariate; and patient as a random factor.

7. Participants' Global Assess of Treatment as Measured by the Patient Global Impression of Change (PGIC) at Weeks 2 and 4 Using a Mixed Model for Repeated Measures (MMRM) [Weeks 2 (day 15), 4 (day 29)]

   PGIC is a standardized self-report tool that measures the change in a participants overall status rating since the start of treatment on 7-point scale. The 7-point scale is defined as: 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very much worse. The MMRM model includes week, treatment, study center, and treatment by week interaction as the fixed factors and unconstructed variance-covariance structure.

8. Change From Baseline in the Patient Global Assessment (PGA) Scores at Weeks 2 and 4 Using a Mixed Model for Repeated Measures (MMRM) [Baseline (day 1, predose), Week 2 (day 15) and Week 4 (day 29)]

   PGA is a simple self-report tool for measuring the overall way arthritis is affecting the patient at a particular point in time. There is 1 question and the response is provided on a visual analog scale (VAS) from 0 (very poor) to 100 (very good). The question is: Considering all the ways your arthritis affect you, how are you feeling today? Positive change from baseline scores indicate improvement. The MMRM model includes week, treatment, study center, and treatment by week interaction as the fixed factors; baseline PGA score as a covariate and unconstructed variance-covariance structure.

9. Percentage of Participants Who Are Responders Per Outcome Measures in Rheumatoid Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) Criteria at Week 4 [Week 4 (day 29)]

   Participants are classified as 'Yes' if the following criteria are met: - >=50% improvement from baseline and an absolute change >=20 on a scale of 1-100 in either the pain or physical function subscale (WOMAC). or 2 of the 3 criteria as below met: - 1) >=20% improvement from baseline and an absolute change >=10 on a scale of 1-100 in the pain subscale (WOMAC); - 2) >=20% improvement from baseline and an absolute change >=10 on a scale of 1-100 in the physical function subscale (WOMAC); - 3) at least a 20% improvement from baseline and an absolute change >=10 on a scale of 1-100 in PGA. Otherwise, 'No' The responder rate per OMERACT-OARSI criteria was analyzed using a generalized estimating equation (GEE) method, where binary variable responder rate (Yes/No) was modeled through logit link function, with treatment, center, week, and treatment*week as explanatory factors. The unstructured working correlation structure was applied.

10. Participants With Treatment-Emergent Adverse Events [day 1 up to day 57]

    An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patient is between 40 and 85 years of age, Patient has primary OA in a single knee (target knee) confirmed by American College of Rheumatology criteria.

• For patients taking non-steroidal anti-inflammatory drugs (NSAIDs) or other analgesics at the time of the screening visit,

• Patient has visual analog scale (VAS) pain scores with acceptable ranges as determined by the investigator during screening

• Except for OA, patient is judged by the investigator to be medically healthy and able to participate in the study.

• Other criteria apply, please contact the investigator for additional information

Exclusion Criteria:

• Patient has secondary or inflammatory arthritis of the knee such as psoriasis, rheumatoid arthritis (RA), gout, other primary bone disease, or acute trauma.

• Patient has symptomatic chondrocalcinosis

• Patient has a history of fibromyalgia.

• Patient has any painful or disabling conditions that in the opinion of the investigator may confound assessment of pain scoring.

• Patient has uncontrolled cardiac, renal, hepatic or other systemic disorders that in the opinion of the investigator may jeopardize the patient.

• Patient has significant edema or skin disorder (including sores, rashes, or ulcers) at the target knee and surrounding area.

• Patient has a history of total or partial knee replacement in either leg.

• Patient had a major reconstructive knee surgery or arthroscopy of the target knee within 6 months before the screening visit.

• Patient is unable or unwilling to discontinue opioid and/or other prescription analgesics for control of OA pain.

• Patient is intolerant to study drug, its excipients, and/or acetaminophen.

• Patient uses any over the counter oral medications such as glucosamine or chondroitin sulfate products, unless the patient has been receiving the medication for ≥3 months at the time of the screening visit and maintains the medication as stable therapy for the duration of the study.

• Other criteria apply, please contact the investigator for additional information

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Teva Investigational Site 12217	Anaheim	California	United States
2	Teva Investigational Site 12244	Anaheim	California	United States
3	Teva Investigational Site 12252	Cerritos	California	United States
4	Teva Investigational Site 13009	Cerritos	California	United States
5	Teva Investigational Site 12233	El Cajon	California	United States
6	Teva Investigational Site 12240	Lomita	California	United States
7	Teva Investigational Site 12251	Sacramento	California	United States
8	Teva Investigational Site 12234	Spring Valley	California	United States
9	Teva Investigational Site 12256	Clearwater	Florida	United States
10	Teva Investigational Site 12241	DeLand	Florida	United States
11	Teva Investigational Site 12246	Eustis	Florida	United States
12	Teva Investigational Site 12231	Fort Myers	Florida	United States
13	Teva Investigational Site 12216	Hialeah	Florida	United States
14	Teva Investigational Site 12230	Jacksonville	Florida	United States
15	Teva Investigational Site 12220	Miami	Florida	United States
16	Teva Investigational Site 12221	Oldsmar	Florida	United States
17	Teva Investigational Site 12226	Orlando	Florida	United States
18	Teva Investigational Site 12237	Orlando	Florida	United States
19	Teva Investigational Site 12255	Ormond Beach	Florida	United States
20	Teva Investigational Site 12225	Plantation	Florida	United States
21	Teva Investigational Site 12229	Sanford	Florida	United States
22	Teva Investigational Site 12235	Tampa	Florida	United States
23	Teva Investigational Site 12253	Atlanta	Georgia	United States
24	Teva Investigational Site 12250	Marietta	Georgia	United States
25	Teva Investigational Site 12243	Evansville	Indiana	United States
26	Teva Investigational Site 12238	Overland Park	Kansas	United States
27	Teva Investigational Site 12218	New Orleans	Louisiana	United States
28	Teva Investigational Site 12245	Watertown	Massachusetts	United States
29	Teva Investigational Site 12228	Bingham Farms	Michigan	United States
30	Teva Investigational Site 12242	Hazelwood	Missouri	United States
31	Teva Investigational Site 12249	Saint Louis	Missouri	United States
32	Teva Investigational Site 12223	Omaha	Nebraska	United States
33	Teva Investigational Site 12219	New York	New York	United States
34	Teva Investigational Site 12239	Charlotte	North Carolina	United States
35	Teva Investigational Site 12248	Raleigh	North Carolina	United States
36	Teva Investigational Site 12247	Winston-Salem	North Carolina	United States
37	Teva Investigational Site 12254	Winston-Salem	North Carolina	United States
38	Teva Investigational Site 12224	Cincinnati	Ohio	United States
39	Teva Investigational Site 12236	Memphis	Tennessee	United States
40	Teva Investigational Site 12232	Dallas	Texas	United States
41	Teva Investigational Site 12227	Plano	Texas	United States
42	Teva Investigational Site 12222	Charlottesville	Virginia	United States

Sponsors and Collaborators

• Teva Branded Pharmaceutical Products R&D, Inc.

Investigators

• Study Director: Sr. Director, GCO, Theraputic Area Head, Teva Branded Pharmaceutical Products R&D, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• ClinicalTrials.gov Identifier: NCT02068599
• Other Study ID Numbers: TV-45070-CNS-20005
• First Posted: Feb 21, 2014
• Last Update Posted: Nov 9, 2021
• Last Verified: Nov 1, 2021

• Keywords provided by Teva Branded Pharmaceutical Products R&D, Inc.: Osteoarthritis; OA; Arthritis pain
• Additional relevant MeSH terms: Osteoarthritis; Osteoarthritis, Knee

Study Results

Participant Flow

Recruitment Details	978 patients with primary OA of the knee were screened for enrollment into this study. 389 patients at 41 centers in the US met entry criteria. Of the 589 patients not enrolled, 551 were excluded on the basis of inclusion/exclusion criteria, 25 patients withdrew consent, and 8 patients were lost to follow-up before the baseline visit.
Pre-assignment Detail	After stratification by R1150W polymorphism status: - homozygous minor allele (positive, AA), - heterozygous (positive, AG), and - homozygous common allele (negative, GG), participants were randomly assigned by interactive response technology (IRT) to receive treatment in 1 of 3 treatment groups in a 1:1:1 ratio.

Arm/Group Title	TV-45070 4%	TV-45070 8%	Placebo
Arm/Group Description	TV-45070 ointment in a 4% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	TV-45070 ointment in a 8% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	Placebo ointment applied topically twice daily to the target knee during the treatment period from day 1 through day 28.
Period Title: Overall Study
STARTED	130	129	130
Safety Analysis Set	129	128	130
Full Analysis Set	129	128	130
COMPLETED	119	119	117
NOT COMPLETED	11	10	13

Baseline Characteristics

Arm/Group Title	TV-45070 4%	TV-45070 8%	Placebo	Total
Arm/Group Description	TV-45070 ointment in a 4% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	TV-45070 ointment in a 8% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	Placebo ointment applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	Total of all reporting groups
Overall Participants	130	129	130	389
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.2 (9.17)	59.2 (9.52)	59.0 (9.65)	59.5 (9.44)
Sex: Female, Male (Count of Participants)
Female	71 54.6%	75 58.1%	82 63.1%	228 58.6%
Male	59 45.4%	54 41.9%	48 36.9%	161 41.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	20 15.4%	25 19.4%	29 22.3%	74 19%
Not Hispanic or Latino	110 84.6%	104 80.6%	101 77.7%	315 81%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (Count of Participants)
White	88 67.7%	83 64.3%	88 67.7%	259 66.6%
Black	25 19.2%	33 25.6%	33 25.4%	91 23.4%
Asian	14 10.8%	9 7%	8 6.2%	31 8%
American Indian or Alaska Native	1 0.8%	0 0%	0 0%	1 0.3%
Pacific Islander	0 0%	0 0%	0 0%	0 0%
Other	2 1.5%	4 3.1%	1 0.8%	7 1.8%
R1150W Polymorphism Status (Count of Participants)
Homozygous minor allele (positive, AA)	2 1.5%	3 2.3%	1 0.8%	6 1.5%
Heterozygous (positive, AG)	27 20.8%	28 21.7%	26 20%	81 20.8%
Homozygous common allele (negative, GG)	101 77.7%	98 76%	103 79.2%	302 77.6%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	79.83 (14.119)	80.87 (13.010)	80.29 (13.633)	80.33 (13.568)
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	168.41 (10.835)	169.06 (9.927)	167.99 (9.526)	168.48 (10.095)
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	27.992 (3.0800)	28.190 (3.0207)	28.340 (3.2364)	28.174 (3.1092)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Last 5 Days of Treatment in the Average Evening Pain Intensity In the Target Knee When Walking on a Flat Surface Using a Mixed Model for Repeated Measures (MMRM)
Description	The Western Ontario and McMasters Universities Arthritis Index [WOMAC] is a widely used, validated, patient-reported questionnaire used to assess pain, stiffness, and physical function in patients with OA of the knee. It consists of 24 items separated into 3 domains (pain [5 items], stiffness [2 items], and physical function [17 items]). WOMAC Question 1 is the first question in the pain domain and asks patients to rate their pain in the target knee while walking on a flat surface. The possible score for each item ranges from 0 (no pain) to 100 mm (worst pain). Participants record their response to WOMAC Question 1 in the study diary based on average pain upon walking since the last assessment or over the past 12 hours. Negative change from baseline scores indicate improvement in pain. MMRM includes week, treatment, study center, and treatment by week interaction as fixed factors; baseline average evening WOMAC Question 1 score as a covariate; and patient as a random factor.
Time Frame	Baseline (day -5 to day -1), Last 5 days of treatment (day 24 to day 28)

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS) include all patients in the intent to treat (ITT) population who receive at least 1 dose of study drug and have at least 1 post baseline efficacy assessment. Both baseline and treatment values must be available for a participant to be included.

Arm/Group Title	TV-45070 4%	TV-45070 8%	Placebo
Arm/Group Description	TV-45070 ointment in a 4% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	TV-45070 ointment in a 8% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	Placebo ointment applied topically twice daily to the target knee during the treatment period from day 1 through day 28.
Measure Participants	121	123	120
Least Squares Mean (Standard Error) [units on a scale]	-20.56 (1.937)	-23.08 (1.923)	-24.82 (1.928)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TV-45070 4%, Placebo
	Comments	LSM = least square mean
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1213
	Comments	5% level of significance
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference from placebo
	Estimated Value	4.26
	Confidence Interval	(2-Sided) 95%; -1.13 to 9.66
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	TV-45070 8%, Placebo
	Comments	LSM = least square mean
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5231
	Comments	5% level of significance
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference from placebo
	Estimated Value	1.74
	Confidence Interval	(2-Sided) 95%; -3.62 to 7.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline to Last 5 Days of Treatment in the Average Daily WOMAC Pain Subscale Score In the Target Knee Using a Mixed Model for Repeated Measures
Description	The five items in the WOMAC Pain Subscale cover pain during walking, using stairs, in bed, sitting or lying, and standing. Daily WOMAC pain subscale score is calculated as the sum of the 5-item pain subscale scores (WOMAC) recorded at evening for a total range of 0 (no pain) to 500 (worst pain on all 5 items). Negative change from baseline scores indicate improvement in pain. MMRM includes week, treatment, study center, and treatment by week interaction as fixed factors; baseline average evening WOMAC scores for the 5-item pain subscale as a covariate; and patient as a random factor.
Time Frame	Baseline (day -5 to day -1), Last 5 days of treatment (day 24 to day 28)

Outcome Measure Data

Analysis Population Description

Full analysis set. Both baseline and treatment values must be available for a participant to be included. For pain subscale, if more than 1 item is missing, the subscale total will not be calculated; otherwise the missing value will be replaced by average of the non-missing values in the subscale.

Arm/Group Title	TV-45070 4%	TV-45070 8%	Placebo
Arm/Group Description	TV-45070 ointment in a 4% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	TV-45070 ointment in a 8% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	Placebo ointment applied topically twice daily to the target knee during the treatment period from day 1 through day 28.
Measure Participants	121	123	120
Least Squares Mean (Standard Error) [units on a scale]	-99.67 (9.365)	-108.52 (9.300)	-117.53 (9.329)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TV-45070 4%, Placebo
	Comments	LSM = least square mean
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1795
	Comments	5% level of significance
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference from placebo
	Estimated Value	17.86
	Confidence Interval	(2-Sided) 95%; -8.26 to 43.98
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	TV-45070 8%, Placebo
	Comments	LSM = least square mean
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4956
	Comments	5% level of significance
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference from placebo
	Estimated Value	9.00
	Confidence Interval	(2-Sided) 95%; -16.95 to 34.96
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline to Last 5 Days of Treatment in the Average Morning Pain Intensity In the Target Knee When Walking on a Flat Surface Using a Mixed Model for Repeated Measures (MMRM)
Description	The Western Ontario and McMasters Universities Arthritis Index [WOMAC] is a widely used, validated, patient-reported questionnaire used to assess pain, stiffness, and physical function in patients with OA of the knee. It consists of 24 items separated into 3 domains (pain [5 items], stiffness [2 items], and physical function [17 items]). The possible score for each item ranges from 0 (no pain) to 100 mm (worst pain). WOMAC Question 1 is the first question in the pain domain and asks patients to rate their pain in the target knee while walking on a flat surface. Participants record their response to WOMAC Question 1 in the study diary based on average pain upon walking since the last assessment or over the past 12 hours. Negative change from baseline scores indicate improvement in pain. MMRM includes week, treatment, study center, and treatment by week interaction as fixed factors; baseline average morning WOMAC Question 1 score as a covariate; and patient as a random factor.
Time Frame	Baseline (day -5 to day -1), Last 5 days of treatment (day 24 to day 28)

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS) include all patients in the intent to treat (ITT) population who receive at least 1 dose of study drug and have at least 1 post baseline efficacy assessment. Both baseline and treatment values must be available for a participant to be included.

Arm/Group Title	TV-45070 4%	TV-45070 8%	Placebo
Arm/Group Description	TV-45070 ointment in a 4% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	TV-45070 ointment in a 8% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	Placebo ointment applied topically twice daily to the target knee during the treatment period from day 1 through day 28.
Measure Participants	121	122	120
Least Squares Mean (Standard Error) [units on a scale]	-19.84 (1.968)	-21.39 (1.955)	-23.45 (1.956)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TV-45070 4%, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1963
	Comments	5% level of significance
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference from placebo
	Estimated Value	3.61
	Confidence Interval	(2-Sided) 95%; -1.87 to 9.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	TV-45070 8%, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4584
	Comments	5% level of significance
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference from placebo
	Estimated Value	2.06
	Confidence Interval	(2-Sided) 95%; -3.39 to 7.50
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline (Randomization Visit) to the Week 4 Visit in the WOMAC Physical Function Subscale Score for the Target Knee Using a Mixed Model for Repeated Measures
Description	The seventeen items in the WOMAC physical function subscale cover stair use, rising from sitting, standing, bending, walking, getting in / out of a car, shopping, putting on / taking off socks, rising from bed, lying in bed, getting in / out of bath, sitting, getting on / off toilet, heavy household duties, light household duties. WOMAC physical function subscale score is calculated as the sum of the 17-item physical function subscale scores (WOMAC) for a total range of 0 (no pain) to 1700 (worst pain on all 17 items). Negative change from baseline scores indicate improvement in pain. MMRM includes week, treatment, study center, and treatment by week interaction as fixed factors; baseline physical function WOMAC scores for the 17-item subscale as a covariate; and patient as a random factor.
Time Frame	Baseline (day 1, predose), Treatment: Week 4 (day 29)

Outcome Measure Data

Analysis Population Description

Full analysis set. Both baseline and treatment values must be available for a participant to be included. For physical function subscale, if more than 3 items are missing the subscale total will not be calculated; otherwise the missing value will be replaced by the average of the non-missing values in the subscale.

Arm/Group Title	TV-45070 4%	TV-45070 8%	Placebo
Arm/Group Description	TV-45070 ointment in a 4% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	TV-45070 ointment in a 8% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	Placebo ointment applied topically twice daily to the target knee during the treatment period from day 1 through day 28.
Measure Participants	120	121	118
Least Squares Mean (Standard Error) [units on a scale]	-372.88 (35.169)	-446.79 (34.812)	-396.39 (35.590)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TV-45070 4%, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6420
	Comments	5% level of significance
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference from placebo
	Estimated Value	23.51
	Confidence Interval	(2-Sided) 95%; -75.83 to 122.84
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	TV-45070 8%, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3141
	Comments	5% level of significance
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference from placebo
	Estimated Value	-50.40
	Confidence Interval	(2-Sided) 95%; -148.72 to 47.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline (Randomization Visit) to the Week 4 Visit in the WOMAC Stiffness Subscale Score for the Target Knee Using a Mixed Model for Repeated Measures
Description	The two items in the WOMAC stiffness subscale cover stiffness after first waking and later in the day. WOMAC stiffness subscale score is calculated as the sum of the 2-item stiffness subscale scores (WOMAC) for a total range of 0 (no stiffness) to 200 (worst stiffness on both items). Negative change from baseline scores indicate improvement in stiffness. MMRM includes week, treatment, study center, and treatment by week interaction as fixed factors; baseline stiffness WOMAC scores for the 2-item subscale as a covariate; and patient as a random factor.
Time Frame	Baseline (day 1, predose), Treatment: Week 4 (day 29)

Outcome Measure Data

Analysis Population Description

Full analysis set. Both baseline and treatment values must be available for a participant to be included. For stiffness subscale, if both items are missing, the subscale total will not be calculated; otherwise the missing value will be replaced with the non-missing one in the subscale.

Arm/Group Title	TV-45070 4%	TV-45070 8%	Placebo
Arm/Group Description	TV-45070 ointment in a 4% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	TV-45070 ointment in a 8% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	Placebo ointment applied topically twice daily to the target knee during the treatment period from day 1 through day 28.
Measure Participants	120	121	118
Least Squares Mean (Standard Error) [units on a scale]	-45.85 (4.414)	-52.49 (4.358)	-49.01 (4.455)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TV-45070 4%, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6184
	Comments	5% level of significance
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference from placebo
	Estimated Value	3.16
	Confidence Interval	(2-Sided) 95%; -9.31 to 15.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	TV-45070 8%, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5775
	Comments	5% level of significance
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference from placebo
	Estimated Value	-3.48
	Confidence Interval	(2-Sided) 95%; -15.78 to 8.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Percentage of Participants With a >=30% and a >=50% Response in Average Evening Pain Intensity of WOMAC Question 1 in the Target Knee During the Last 5 Days of Treatment Compared With Baseline
Description	WOMAC Question 1 is the first question in the pain domain and asks patients to rate their pain in the target knee while walking on a flat surface. The possible score for each item ranges from 0 (no pain) to 100 mm (worst pain). Average pain is calculated using a MMRM which includes week, treatment, study center, and treatment by week interaction as fixed factors; baseline average evening WOMAC Question 1 score as a covariate; and patient as a random factor. Responder rate was calculated as 100 * the value of (average WOMAC pain subscale during the last 5 days of treatment [Days 24 to 28]) - average WOMAC pain subscale at baseline [the 5 days prior to randomization])/average WOMAC pain subscale at baseline (the 5 days prior to randomization). Participants with missing responder rates were treated as nonresponders.
Time Frame	Baseline (day -5 to day -1), Last 5 days of treatment (day 24 to day 28)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	TV-45070 4%	TV-45070 8%	Placebo
Arm/Group Description	TV-45070 ointment in a 4% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	TV-45070 ointment in a 8% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	Placebo ointment applied topically twice daily to the target knee during the treatment period from day 1 through day 28.
Measure Participants	121	123	120
>=50% responder rate	23.3 17.9%	33.6 26%	31.5 24.2%
<50% responder rate	70.5 54.2%	62.5 48.4%	60.8 46.8%
>=30% responder rate	45.0 34.6%	43.8 34%	46.9 36.1%
<30% responder rate	48.8 37.5%	52.3 40.5%	45.4 34.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TV-45070 4%, Placebo
	Comments	>=50% responder rate
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1011
	Comments	5% level of significance
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.62
	Confidence Interval	(2-Sided) 95%; 0.345 to 1.099
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	TV-45070 8%, Placebo
	Comments	>=50% responder rate
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8400
	Comments	5% level of significance
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95%; 0.615 to 1.819
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	TV-45070 4%, Placebo
	Comments	>=30% responder rate
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6607
	Comments	5% level of significance
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95%; 0.531 to 1.494
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	TV-45070 8%, Placebo
	Comments	>=30% responder rate
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5777
	Comments	5% level of significance
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; 0.520 to 1.441
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline (Randomization Visit) to the Week 4 Visit in the Pain Quality Assessment Scale - Revised (PQAS-R) for the Target Knee Using a Mixed Model for Repeated Measures
Description	PQAS-R is a standardized self-report tool that measures various aspects of a participant's pain. There are 19 questions (question 19 has 2 parts) that ask the participant to rate the various aspects (intensity, sharpness, heat, cold, etc.) of his/her pain over the past week on average on a scale of 0 to 10 (0 = not [aspect] and 10 = the most or worst imaginable [aspect]). PQAS-R score at each visit is the sum of responses for the 19 questions for a total range of 0=no pain to 200=worst imaginable pain in all aspects. Negative change from baseline scores indicate improvement in stiffness. MMRM includes week, treatment, study center, and treatment by week interaction as fixed factors; baseline PQAS-R score for the 19 questions (20 parts) as a covariate; and patient as a random factor.
Time Frame	Baseline (day 1, predose), Treatment: Week 4 (day 29)

Outcome Measure Data

Analysis Population Description

Full analysis set. If any of the 19 questions is missing, the PQAS-R total score will not be calculated for a given visit. If the entire questionnaire is not done at a scheduled time point, it will be considered missing and will not be imputed.

Arm/Group Title	TV-45070 4%	TV-45070 8%	Placebo
Arm/Group Description	TV-45070 ointment in a 4% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	TV-45070 ointment in a 8% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	Placebo ointment applied topically twice daily to the target knee during the treatment period from day 1 through day 28.
Measure Participants	120	121	118
Least Squares Mean (Standard Error) [units on a scale]	-39.22 (3.489)	-40.65 (3.453)	-43.16 (3.529)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TV-45070 4%, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4316
	Comments	5% level of significance
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference from placebo
	Estimated Value	3.94
	Confidence Interval	(2-Sided) 95%; -5.90 to 13.79
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	TV-45070 8%, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6126
	Comments	5% level of significance
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference from placebo
	Estimated Value	2.51
	Confidence Interval	(2-Sided) 95%; -7.24 to 12.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Participants' Global Assess of Treatment as Measured by the Patient Global Impression of Change (PGIC) at Weeks 2 and 4 Using a Mixed Model for Repeated Measures (MMRM)
Description	PGIC is a standardized self-report tool that measures the change in a participants overall status rating since the start of treatment on 7-point scale. The 7-point scale is defined as: 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very much worse. The MMRM model includes week, treatment, study center, and treatment by week interaction as the fixed factors and unconstructed variance-covariance structure.
Time Frame	Weeks 2 (day 15), 4 (day 29)

Outcome Measure Data

Analysis Population Description

Full analysis set of participants with data at the timepoint.

Arm/Group Title	TV-45070 4%	TV-45070 8%	Placebo
Arm/Group Description	TV-45070 ointment in a 4% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	TV-45070 ointment in a 8% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	Placebo ointment applied topically twice daily to the target knee during the treatment period from day 1 through day 28.
Measure Participants	129	128	130
Week 2	2.87 (0.086)	2.90 (0.086)	2.86 (0.088)
Week 4	2.81 (0.096)	2.66 (0.095)	2.60 (0.097)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TV-45070 4%, Placebo
	Comments	Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9208
	Comments	5% level of significance
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference from placebo
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -0.232 to 0.257
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	TV-45070 8%, Placebo
	Comments	Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7344
	Comments	5% level of significance
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference from placebo
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; -0.200 to 0.284
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	TV-45070 4%, Placebo
	Comments	Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1199
	Comments	5% level of significance
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference from placebo
	Estimated Value	0.21
	Confidence Interval	(2-Sided) 95%; -0.056 to 0.486
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	TV-45070 8%, Placebo
	Comments	Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6357
	Comments	5% level of significance
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference from placebo
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 95%; -0.204 to 0.334
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Change From Baseline in the Patient Global Assessment (PGA) Scores at Weeks 2 and 4 Using a Mixed Model for Repeated Measures (MMRM)
Description	PGA is a simple self-report tool for measuring the overall way arthritis is affecting the patient at a particular point in time. There is 1 question and the response is provided on a visual analog scale (VAS) from 0 (very poor) to 100 (very good). The question is: Considering all the ways your arthritis affect you, how are you feeling today? Positive change from baseline scores indicate improvement. The MMRM model includes week, treatment, study center, and treatment by week interaction as the fixed factors; baseline PGA score as a covariate and unconstructed variance-covariance structure.
Time Frame	Baseline (day 1, predose), Week 2 (day 15) and Week 4 (day 29)

Outcome Measure Data

Analysis Population Description

Full analysis set of participants with data at the timepoints.

Arm/Group Title	TV-45070 4%	TV-45070 8%	Placebo
Arm/Group Description	TV-45070 ointment in a 4% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	TV-45070 ointment in a 8% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	Placebo ointment applied topically twice daily to the target knee during the treatment period from day 1 through day 28.
Measure Participants	129	128	130
Week 2	4.87 (1.819)	3.51 (1.808)	2.10 (1.850)
Week 4	5.44 (1.949)	6.35 (1.935)	4.62 (1.973)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TV-45070 4%, Placebo
	Comments	Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2906
	Comments	5% level of significance
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference from placebo
	Estimated Value	2.77
	Confidence Interval	(2-Sided) 95%; -2.377 to 7.916
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	TV-45070 8%, Placebo
	Comments	Week 2
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5892
	Comments	5% level of significance
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference from placebo
	Estimated Value	1.41
	Confidence Interval	(2-Sided) 95%; -3.707 to 6.518
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	TV-45070 4%, Placebo
	Comments	Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7699
	Comments	5% level of significance
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference from placebo
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; -4.678 to 6.315
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	TV-45070 8%, Placebo
	Comments	Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5320
	Comments	5% level of significance
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference from placebo
	Estimated Value	1.74
	Confidence Interval	(2-Sided) 95%; -3.721 to 7.193
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Percentage of Participants Who Are Responders Per Outcome Measures in Rheumatoid Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) Criteria at Week 4
Description	Participants are classified as 'Yes' if the following criteria are met: - >=50% improvement from baseline and an absolute change >=20 on a scale of 1-100 in either the pain or physical function subscale (WOMAC). or 2 of the 3 criteria as below met: - 1) >=20% improvement from baseline and an absolute change >=10 on a scale of 1-100 in the pain subscale (WOMAC); - 2) >=20% improvement from baseline and an absolute change >=10 on a scale of 1-100 in the physical function subscale (WOMAC); - 3) at least a 20% improvement from baseline and an absolute change >=10 on a scale of 1-100 in PGA. Otherwise, 'No' The responder rate per OMERACT-OARSI criteria was analyzed using a generalized estimating equation (GEE) method, where binary variable responder rate (Yes/No) was modeled through logit link function, with treatment, center, week, and treatment*week as explanatory factors. The unstructured working correlation structure was applied.
Time Frame	Week 4 (day 29)

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	TV-45070 4%	TV-45070 8%	Placebo
Arm/Group Description	TV-45070 ointment in a 4% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	TV-45070 ointment in a 8% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	Placebo ointment applied topically twice daily to the target knee during the treatment period from day 1 through day 28.
Measure Participants	129	128	130
Responder - Yes	47.3 36.4%	59.4 46%	51.5 39.6%
Responder - No	46.5 35.8%	36.7 28.4%	40.8 31.4%
Missing	6.2 4.8%	3.9 3%	7.7 5.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TV-45070 4%, Placebo
	Comments	For the responder analyses, participants with missing values were deemed non-responders. Analysis performed using a generalized estimating equation (GEE) method where binary variable responder rate (Yes/No) was modeled through logit link function, with treatment, center, week, and treatment*week as explanatory factors. The unstructured working correlation structure was applied.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5358
	Comments	5% level of significance
	Method	generalized estimating equation (GEE)
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95%; 0.501 to 1.433
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	TV-45070 8%, Placebo
	Comments	For the responder analyses, participants with missing values were deemed non-responders. Analysis performed using a generalized estimating equation (GEE) method where binary variable responder rate (Yes/No) was modeled through logit link function, with treatment, center, week, and treatment*week as explanatory factors. The unstructured working correlation structure was applied.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1532
	Comments	5% level of significance
	Method	generalized estimating equation (GEE)
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.45
	Confidence Interval	(2-Sided) 95%; 0.870 to 2.423
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Participants With Treatment-Emergent Adverse Events
Description	An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.
Time Frame	day 1 up to day 57

Outcome Measure Data

Analysis Population Description

Safety analysis population. The safety population includes all randomized participants who receive at least one dose of study medication. In this population, treatment was assigned based upon the treatment participants actually receive regardless of the treatment to which they were randomized.

Arm/Group Title	TV-45070 4%	TV-45070 8%	Placebo
Arm/Group Description	TV-45070 ointment in a 4% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	TV-45070 ointment in a 8% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.	Placebo ointment applied topically twice daily to the target knee during the treatment period from day 1 through day 28.
Measure Participants	129	128	130
Any treatment-emergent adverse event	43 33.1%	37 28.7%	47 36.2%
Treatment-related TEAE	12 9.2%	10 7.8%	20 15.4%
Death	0 0%	0 0%	0 0%
Serious TEAE	1 0.8%	0 0%	1 0.8%
Withdrawn from treatment due to TEAE	3 2.3%	2 1.6%	2 1.5%

Adverse Events

Time Frame	day 1 up to day 57
Arm/Group Title	TV-45070 4%		TV-45070 8%		Placebo
Arm/Group Description	TV-45070 ointment in a 4% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.		TV-45070 ointment in a 8% strength applied topically twice daily to the target knee during the treatment period from day 1 through day 28.		Placebo ointment applied topically twice daily to the target knee during the treatment period from day 1 through day 28.
All Cause Mortality
	TV-45070 4%		TV-45070 8%		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/129 (0%)		0/128 (0%)		0/130 (0%)
Serious Adverse Events
	TV-45070 4%		TV-45070 8%		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/129 (0.8%)		0/128 (0%)		1/130 (0.8%)
Cardiac disorders
Acute myocardial infarction	1/129 (0.8%)	1	0/128 (0%)	0	0/130 (0%)	0
Infections and infestations
Influenza	0/129 (0%)	0	0/128 (0%)	0	1/130 (0.8%)	1
Other (Not Including Serious) Adverse Events
	TV-45070 4%		TV-45070 8%		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/129 (4.7%)		6/128 (4.7%)		9/130 (6.9%)
General disorders
Application site exfoliation	6/129 (4.7%)	6	6/128 (4.7%)	6	9/130 (6.9%)	9

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Sponsor has the right 60 days before submission for publication to review/provide comments. If the Sponsor's review shows that potentially patentable subject matter would be disclosed, publication or public disclosure shall be delayed for up to 90 additional days in order for the Sponsor, or Sponsor's designees, to file the necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data