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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02068599
Recruitment Status : Completed
First Posted : February 21, 2014
Results First Posted : October 23, 2018
Last Update Posted : November 9, 2021
Sponsor:
Information provided by (Responsible Party):
Teva Branded Pharmaceutical Products R&D, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Osteoarthritis of the Knee
Interventions Drug: TV-45070
Drug: Placebo
Enrollment 389
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 Details 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
Hide 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 [1] 128 [1] 130
Full Analysis Set 129 128 130
Completed 119 119 117
Not Completed 11 10 13
Reason Not Completed
Adverse Event             4             1             1
Withdrawal by Subject             2             7             5
Protocol Violation             4             2             3
Lost to Follow-up             1             0             0
Lack of Efficacy             0             0             3
Noncompliance             0             0             1
[1]
One participant withdrew before taking any study drug.
Arm/Group Title TV-45070 4% TV-45070 8% Placebo Total
Hide 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 Number of Baseline Participants 130 129 130 389
Hide Baseline Analysis Population Description
Randomized participants
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 130 participants 129 participants 130 participants 389 participants
60.2  (9.17) 59.2  (9.52) 59.0  (9.65) 59.5  (9.44)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 130 participants 129 participants 130 participants 389 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)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 130 participants 129 participants 130 participants 389 participants
Hispanic or Latino
20
  15.4%
25
  19.4%
29
  22.3%
74
  19.0%
Not Hispanic or Latino
110
  84.6%
104
  80.6%
101
  77.7%
315
  81.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Race  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 130 participants 129 participants 130 participants 389 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
   7.0%
8
   6.2%
31
   8.0%
American Indian or Alaska Native
1
   0.8%
0
   0.0%
0
   0.0%
1
   0.3%
Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Other
2
   1.5%
4
   3.1%
1
   0.8%
7
   1.8%
R1150W Polymorphism Status   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 130 participants 129 participants 130 participants 389 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
  20.0%
81
  20.8%
Homozygous common allele (negative, GG)
101
  77.7%
98
  76.0%
103
  79.2%
302
  77.6%
[1]
Measure Description: Patients who carry the R1150W polymorphism have a nucleotide containing adenine (A) instead of guanine (G) in the rs6746030 single nucleotide polymorphism in the SCN9A gene. This change causes an arginine to tryptophan amino acid residue change at position 1150 in the alpha subunit of the voltage-gated sodium channel NaV1.7. Those who carry the R1150W polymorphism may be heterozygous (GA) or homozygous (AA) for the minor allele. This R1150W polymorphism in the SCN9A gene may affect pain perception (Reimann et al 2010).
Weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 130 participants 129 participants 130 participants 389 participants
79.83  (14.119) 80.87  (13.010) 80.29  (13.633) 80.33  (13.568)
Height  
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 130 participants 129 participants 130 participants 389 participants
168.41  (10.835) 169.06  (9.927) 167.99  (9.526) 168.48  (10.095)
Body Mass Index  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 130 participants 129 participants 130 participants 389 participants
27.992  (3.0800) 28.190  (3.0207) 28.340  (3.2364) 28.174  (3.1092)
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)
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 121 123 120
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-20.56  (1.937) -23.08  (1.923) -24.82  (1.928)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection TV-45070 4%, Placebo
Comments LSM = least square mean
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1213
Comments 5% level of significance
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LSM difference from placebo
Estimated Value 4.26
Confidence Interval (2-Sided) 95%
-1.13 to 9.66
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection TV-45070 8%, Placebo
Comments LSM = least square mean
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5231
Comments 5% level of significance
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LSM difference from placebo
Estimated Value 1.74
Confidence Interval (2-Sided) 95%
-3.62 to 7.11
Estimation Comments [Not Specified]
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
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 121 123 120
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-99.67  (9.365) -108.52  (9.300) -117.53  (9.329)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection TV-45070 4%, Placebo
Comments LSM = least square mean
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1795
Comments 5% level of significance
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LSM difference from placebo
Estimated Value 17.86
Confidence Interval (2-Sided) 95%
-8.26 to 43.98
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection TV-45070 8%, Placebo
Comments LSM = least square mean
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4956
Comments 5% level of significance
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LSM difference from placebo
Estimated Value 9.00
Confidence Interval (2-Sided) 95%
-16.95 to 34.96
Estimation Comments [Not Specified]
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)
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 121 122 120
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-19.84  (1.968) -21.39  (1.955) -23.45  (1.956)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection TV-45070 4%, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1963
Comments 5% level of significance
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LSM difference from placebo
Estimated Value 3.61
Confidence Interval (2-Sided) 95%
-1.87 to 9.08
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection TV-45070 8%, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4584
Comments 5% level of significance
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LSM difference from placebo
Estimated Value 2.06
Confidence Interval (2-Sided) 95%
-3.39 to 7.50
Estimation Comments [Not Specified]
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
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 120 121 118
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-372.88  (35.169) -446.79  (34.812) -396.39  (35.590)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection TV-45070 4%, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6420
Comments 5% level of significance
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LSM difference from placebo
Estimated Value 23.51
Confidence Interval (2-Sided) 95%
-75.83 to 122.84
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection TV-45070 8%, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3141
Comments 5% level of significance
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LSM difference from placebo
Estimated Value -50.40
Confidence Interval (2-Sided) 95%
-148.72 to 47.92
Estimation Comments [Not Specified]
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
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 120 121 118
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-45.85  (4.414) -52.49  (4.358) -49.01  (4.455)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection TV-45070 4%, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6184
Comments 5% level of significance
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LSM difference from placebo
Estimated Value 3.16
Confidence Interval (2-Sided) 95%
-9.31 to 15.63
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection TV-45070 8%, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5775
Comments 5% level of significance
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LSM difference from placebo
Estimated Value -3.48
Confidence Interval (2-Sided) 95%
-15.78 to 8.81
Estimation Comments [Not Specified]
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
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title TV-45070 4% TV-45070 8% Placebo
Hide 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.
Overall Number of Participants Analyzed 121 123 120
Measure Type: Number
Unit of Measure: percentage of participants
>=50% responder rate 23.3 33.6 31.5
<50% responder rate 70.5 62.5 60.8
>=30% responder rate 45.0 43.8 46.9
<30% responder rate 48.8 52.3 45.4
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection TV-45070 4%, Placebo
Comments >=50% responder rate
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1011
Comments 5% level of significance
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.62
Confidence Interval (2-Sided) 95%
0.345 to 1.099
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection TV-45070 8%, Placebo
Comments >=50% responder rate
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8400
Comments 5% level of significance
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.06
Confidence Interval (2-Sided) 95%
0.615 to 1.819
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection TV-45070 4%, Placebo
Comments >=30% responder rate
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6607
Comments 5% level of significance
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.89
Confidence Interval (2-Sided) 95%
0.531 to 1.494
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection TV-45070 8%, Placebo
Comments >=30% responder rate
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5777
Comments 5% level of significance
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.87
Confidence Interval (2-Sided) 95%
0.520 to 1.441
Estimation Comments [Not Specified]
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
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 120 121 118
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-39.22  (3.489) -40.65  (3.453) -43.16  (3.529)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection TV-45070 4%, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4316
Comments 5% level of significance
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LSM difference from placebo
Estimated Value 3.94
Confidence Interval (2-Sided) 95%
-5.90 to 13.79
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection TV-45070 8%, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6126
Comments 5% level of significance
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LSM difference from placebo
Estimated Value 2.51
Confidence Interval (2-Sided) 95%
-7.24 to 12.26
Estimation Comments [Not Specified]
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)
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set of participants with data at the timepoint.
Arm/Group Title TV-45070 4% TV-45070 8% Placebo
Hide 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.
Overall Number of Participants Analyzed 129 128 130
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
Week 2 Number Analyzed 125 participants 124 participants 120 participants
2.87  (0.086) 2.90  (0.086) 2.86  (0.088)
Week 4 Number Analyzed 120 participants 121 participants 118 participants
2.81  (0.096) 2.66  (0.095) 2.60  (0.097)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection TV-45070 4%, Placebo
Comments Week 2
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9208
Comments 5% level of significance
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LSM difference from placebo
Estimated Value 0.01
Confidence Interval (2-Sided) 95%
-0.232 to 0.257
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection TV-45070 8%, Placebo
Comments Week 2
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7344
Comments 5% level of significance
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LSM difference from placebo
Estimated Value 0.04
Confidence Interval (2-Sided) 95%
-0.200 to 0.284
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection TV-45070 4%, Placebo
Comments Week 4
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1199
Comments 5% level of significance
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LSM difference from placebo
Estimated Value 0.21
Confidence Interval (2-Sided) 95%
-0.056 to 0.486
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection TV-45070 8%, Placebo
Comments Week 4
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6357
Comments 5% level of significance
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LSM difference from placebo
Estimated Value 0.06
Confidence Interval (2-Sided) 95%
-0.204 to 0.334
Estimation Comments [Not Specified]
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)
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set of participants with data at the timepoints.
Arm/Group Title TV-45070 4% TV-45070 8% Placebo
Hide 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.
Overall Number of Participants Analyzed 129 128 130
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
Week 2 Number Analyzed 124 participants 123 participants 119 participants
4.87  (1.819) 3.51  (1.808) 2.10  (1.850)
Week 4 Number Analyzed 120 participants 120 participants 117 participants
5.44  (1.949) 6.35  (1.935) 4.62  (1.973)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection TV-45070 4%, Placebo
Comments Week 2
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2906
Comments 5% level of significance
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LSM difference from placebo
Estimated Value 2.77
Confidence Interval (2-Sided) 95%
-2.377 to 7.916
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection TV-45070 8%, Placebo
Comments Week 2
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5892
Comments 5% level of significance
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LSM difference from placebo
Estimated Value 1.41
Confidence Interval (2-Sided) 95%
-3.707 to 6.518
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection TV-45070 4%, Placebo
Comments Week 4
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7699
Comments 5% level of significance
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LSM difference from placebo
Estimated Value 0.82
Confidence Interval (2-Sided) 95%
-4.678 to 6.315
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection TV-45070 8%, Placebo
Comments Week 4
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5320
Comments 5% level of significance
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LSM difference from placebo
Estimated Value 1.74
Confidence Interval (2-Sided) 95%
-3.721 to 7.193
Estimation Comments [Not Specified]
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
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set
Arm/Group Title TV-45070 4% TV-45070 8% Placebo
Hide 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.
Overall Number of Participants Analyzed 129 128 130
Measure Type: Number
Unit of Measure: percentage of participants
Responder - Yes 47.3 59.4 51.5
Responder - No 46.5 36.7 40.8
Missing 6.2 3.9 7.7
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.5358
Comments 5% level of significance
Method generalized estimating equation (GEE)
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.85
Confidence Interval (2-Sided) 95%
0.501 to 1.433
Estimation Comments [Not Specified]
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.1532
Comments 5% level of significance
Method generalized estimating equation (GEE)
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.45
Confidence Interval (2-Sided) 95%
0.870 to 2.423
Estimation Comments [Not Specified]
11.Secondary Outcome
Title Participants With Treatment-Emergent Adverse Events
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 129 128 130
Measure Type: Count of Participants
Unit of Measure: Participants
Any treatment-emergent adverse event
43
  33.3%
37
  28.9%
47
  36.2%
Treatment-related TEAE
12
   9.3%
10
   7.8%
20
  15.4%
Death
0
   0.0%
0
   0.0%
0
   0.0%
Serious TEAE
1
   0.8%
0
   0.0%
1
   0.8%
Withdrawn from treatment due to TEAE
3
   2.3%
2
   1.6%
2
   1.5%
Time Frame day 1 up to day 57
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title TV-45070 4% TV-45070 8% Placebo
Hide 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 (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/129 (0.00%)      0/128 (0.00%)      0/130 (0.00%)    
Hide 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 (0.78%)      0/128 (0.00%)      1/130 (0.77%)    
Cardiac disorders       
Acute myocardial infarction  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/130 (0.00%)  0
Infections and infestations       
Influenza  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/130 (0.77%)  1
1
Term from vocabulary, MedDRA (16.1)
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
TV-45070 4% TV-45070 8% Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   6/129 (4.65%)      6/128 (4.69%)      9/130 (6.92%)    
General disorders       
Application site exfoliation  1  6/129 (4.65%)  6 6/128 (4.69%)  6 9/130 (6.92%)  9
1
Term from vocabulary, MedDRA (16.1)
Indicates events were collected by systematic assessment
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.
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
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Director, Clinical Research
Organization: Teva Branded Pharmaceutical Products, R&D Inc
Phone: 1-888-483-8279
EMail: USMedInfo@tevapharm.com
Layout table for additonal information
Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
ClinicalTrials.gov Identifier: NCT02068599    
Other Study ID Numbers: TV-45070-CNS-20005
First Submitted: February 19, 2014
First Posted: February 21, 2014
Results First Submitted: September 22, 2018
Results First Posted: October 23, 2018
Last Update Posted: November 9, 2021