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Clinical Trial Results:
A Phase 2a, Randomized, Double-blind, Placebo- and Naproxen-controlled, Parallel-group Study to Assess the Analgesic Efficacy of ASP7962 in Patients With Pain Due to Osteoarthritis of the Knee

Summary
EudraCT number	2014-004996-22
Trial protocol	BE HU GB CZ ES
Global end of trial date	29 Sep 2017

Results information
Results version number	v2(current)
This version publication date	29 Jul 2018
First version publication date	20 Jun 2018
Other versions	v1
Version creation reason	New data added to full data set Results updated for consistency

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

7962-CL-0022

ISRCTN number

US NCT number

NCT02611466

WHO universal trial number (UTN)

Sponsor organisation name

Astellas Pharma Europe B.V.

Sponsor organisation address

Sylviusweg 62, Leiden, Netherlands, 2333 BE

Public contact

Clinical Trial Disclosure, Astellas Pharma Europe B.V., Astellas.resultsdisclosure@astellas.com

Scientific contact

Clinical Trial Disclosure, Astellas Pharma Europe B.V., Astellas.resultsdisclosure@astellas.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

29 Sep 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

29 Sep 2017

Was the trial ended prematurely?

Main objective of the trial

The primary objective of the study, conducted in participants with pain due to osteoarthritis (OA) of the knee, was to evaluate the analgesic efficacy of ASP7962 relative to placebo. The study consisted of a screening period (up to 3 weeks), a 1-week baseline period, a 4-week double-blind treatment period and a 4-week follow-up period.

Protection of trial subjects

This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.

Background therapy

Evidence for comparator

Actual start date of recruitment

16 Feb 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 6

Country: Number of subjects enrolled

Czech Republic: 20

Country: Number of subjects enrolled

Germany: 64

Country: Number of subjects enrolled

Hungary: 67

Country: Number of subjects enrolled

Spain: 50

Country: Number of subjects enrolled

United Kingdom: 8

Worldwide total number of subjects

215

EEA total number of subjects

215

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

108

From 65 to 84 years

107

85 years and over

Subject disposition

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Recruitment details

Participants with pain due to OA of the knee were enrolled in sites in Western and Eastern Europe.

Screening details

Participants who met the screening criteria entered a washout of all pain medication for at least 7 days and recorded daily average pain ratings for at least 5 days in an e-diary. After entry criteria were reassessed, eligible participants were randomized to receive ASP7962, placebo or naproxen treatment in a ratio of 2:2:1.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Monitor, Subject, Data analyst

Are arms mutually exclusive

Yes

Placebo

Arm description

Participants received placebo orally twice daily for a period of 4 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received matching placebo orally twice daily, in the morning and evening with or without food (approximately 12 hours).

ASP7962

Arm description

Participants received 100 mg of ASP7962 orally twice daily for 4 weeks.

Arm type

Experimental

Investigational medicinal product name

ASP7962

Investigational medicinal product code

ASP7962

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received ASP7962 100 mg orally twice daily, in the morning and evening with or without food (approximately 12 hours).

Naproxen

Arm description

Participants received 500 mg of Naproxen orally twice daily for 4 weeks.

Arm type

Active comparator

Investigational medicinal product name

Naproxen

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received naproxen 500 mg orally twice daily, in the morning and evening with or without food (approximately 12 hours).

Number of subjects in period 1	Placebo	ASP7962	Naproxen
Started	87	85	43
Completed	77	79	40
Not completed	10	6	3
Did Not Receive Study Drug	2	-	1
Adverse Event	3	3	2
Protocol Deviation	2	2	-
Miscellaneous	-	1	-
Withdrawal by Subject	3	-	-

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Participants received placebo orally twice daily for a period of 4 weeks.

Reporting group title

ASP7962

Reporting group description

Participants received 100 mg of ASP7962 orally twice daily for 4 weeks.

Reporting group title

Naproxen

Reporting group description

Participants received 500 mg of Naproxen orally twice daily for 4 weeks.

Reporting group values	Placebo	ASP7962	Naproxen	Total
Number of subjects	87	85	43
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	64.0 ( 8.4 )	63.6 ( 8.4 )	65.7 ( 7.5 )	-
Gender categorical
Units:
Male	29	26	17	72
Female	58	59	26	143
Race
Units: Subjects
White	86	82	43	211
Black or African American	1	1	0	2
Asian	0	1	0	1
Other	0	1	0	1
Index Knee Location
Units: Subjects
Right	46	39	22	107
Left	41	46	21	108
Western Ontario and McMaster Universities Arthritis Index (WOMAC) Pain Subscale Score
WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The pain subscale contains five questions that ask about pain during the last 48 hours caused by arthritis in the index knee.
Units: units on a scale
arithmetic mean (standard deviation)	5.63 ( 1.33 )	6.08 ( 1.37 )	5.83 ( 1.04 )	-
WOMAC Stiffness Subscale Score
WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The stiffness subscale contains two questions that ask about stiffness during the last 48 hours caused by the arthritis.
Units: units on a scale
arithmetic mean (standard deviation)	5.78 ( 1.71 )	6.20 ( 1.72 )	5.88 ( 1.76 )	-
WOMAC Physical Function Subscale Score
WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The physical function subscale contains 17 questions that ask about the difficulty following daily physical activities.
Units: units on a scale
arithmetic mean (standard deviation)	5.82 ( 1.37 )	6.27 ( 1.40 )	5.99 ( 0.99 )	-
WOMAC Walking Pain Score
WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The walking pain score is based on question 1 of the questionnaire on pain when walking on a flat surface.
Units: units on a scale
arithmetic mean (standard deviation)	5.54 ( 1.50 )	6.12 ( 1.61 )	6.02 ( 1.41 )	-
WOMAC Total Score
WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The total score is the sum of scores from pain, physical function and stiffness subscales. Total score ranges from 0 to 30.
Units: units on a scale
arithmetic mean (standard deviation)	17.22 ( 4.07 )	18.54 ( 4.05 )	17.71 ( 3.36 )	-
Mean Daily Average Numerical Rating Scale (NRS) Pain Score: Index Knee
The NRS is an 11-point scale used to capture the participant’s average pain in the last 24 hours on a daily basis. This scale is composed of a single question and the score ranges from 0 to 10, where 0 anchors “no pain” and 10 anchors “pain as bad as you can imagine." The mean daily average NRS pain score was derived from the daily index knee pain ratings recorded by participants in an electronic diary (e-diary) on the last 4 days prior to randomization. Data only available for 214 participants [86, 85 43].
Units: units on a scale
arithmetic mean (standard deviation)	6.15 ( 1.39 )	6.26 ( 1.57 )	6.40 ( 1.29 )	-
Patient Global Assessment Score
The PGA is an 11-point NRS scale used to capture the participant’s overall impression at the time of the assessment in the index knee. This is a single question and the score ranges from 0 to 10, where 0 anchors “very good” and 10 anchors “very poor.” Data only available for 211 participants [84, 84 43].
Units: units on a scale
arithmetic mean (standard deviation)	5.98 ( 1.69 )	6.36 ( 1.71 )	6.23 ( 1.57 )	-

End points

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Reporting group title

Placebo

Reporting group description

Participants received placebo orally twice daily for a period of 4 weeks.

Reporting group title

ASP7962

Reporting group description

Participants received 100 mg of ASP7962 orally twice daily for 4 weeks.

Reporting group title

Naproxen

Reporting group description

Participants received 500 mg of Naproxen orally twice daily for 4 weeks.

Primary: Change from Baseline to Week 4 in Western Ontario and McMaster Universities Arthritis Index (WOMAC) Pain Subscale Score

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End point title

Change from Baseline to Week 4 in Western Ontario and McMaster Universities Arthritis Index (WOMAC) Pain Subscale Score

End point description

WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The pain subscale contains five questions that ask about pain during the last 48 hours caused by arthritis in the index knee. A negative change indicated a reduction/improvement from baseline. The analysis population was the full analysis set (FAS), which included all randomized participants who took at least 1 dose of study drug and who had a baseline and at least 1 double-blind treatment value for the WOMAC pain subscale score. Only participants with data available at baseline and at each timepoint were included.

End point type

Primary

End point timeframe

Baseline and week 4

End point values	Placebo	ASP7962	Naproxen
Number of subjects analysed	75	77	39
Units: units on a scale
least squares mean (standard error)	-1.73 ( 0.21 )	-1.87 ( 0.20 )	-2.40 ( 0.28 )

Difference: ASP7962 vs. Placebo

Statistical analysis description

MMRM analysis was performed using change from baseline (week 1, 2 and 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline and week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group.

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.316 ^[1]

Method

Mixed-effect model, Repeated measures

Parameter type

Least Squares Mean (LSM) Difference

Point estimate

-0.14

Confidence interval

level

90%

sides

2-sided

lower limit

-0.62

upper limit

0.34

Variability estimate

Standard error of the mean

Dispersion value

0.29

Notes
[1] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

114

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.027 ^[2]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.67

Confidence interval

level

80%

sides

2-sided

lower limit

-1.12

upper limit

-0.23

Variability estimate

Standard error of the mean

Dispersion value

0.35

Notes
[2] - One-sided P-value for pairwise treatment comparison with placebo.

Secondary: Change from Baseline to End of Treatment (EOT) in WOMAC Pain Subscale Score

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End point title

Change from Baseline to End of Treatment (EOT) in WOMAC Pain Subscale Score

End point description

WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The pain subscale contains five questions that ask about pain during the last 48 hours caused by arthritis in the index knee. A negative change indicated a reduction/improvement from baseline. The analysis population was the FAS. The EOT value was defined as the last available postbaseline measurement within the treatment period.

End point type

Secondary

End point timeframe

Baseline and EOT (up to 4 weeks)

End point values	Placebo	ASP7962	Naproxen
Number of subjects analysed	79	81	42
Units: units on a scale
least squares mean (standard error)	-1.74 ( 0.20 )	-1.91 ( 0.20 )	-2.41 ( 0.27 )

Difference: ASP7962 vs. Placebo

Statistical analysis description

Analysis of covariance (ANCOVA) model was performed with change from baseline at the EOT timepoint as response and terms for baseline, treatment and study site. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group.

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.276 ^[3]

Method

ANCOVA

Parameter type

LSM Difference

Point estimate

-0.17

Confidence interval

level

90%

sides

2-sided

lower limit

-0.63

upper limit

0.3

Variability estimate

Standard error of the mean

Dispersion value

0.28

Notes
[3] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo

Statistical analysis description

ANCOVA model was performed with change from baseline at the EOT timepoint as response and terms for baseline, treatment and study site. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group.

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.025 ^[4]

Method

ANCOVA

Parameter type

LSM Difference

Point estimate

-0.66

Confidence interval

level

80%

sides

2-sided

lower limit

-1.1

upper limit

-0.23

Variability estimate

Standard error of the mean

Dispersion value

0.34

Notes
[4] - One-sided P-value for pairwise treatment comparison with placebo.

Secondary: Change from Baseline to EOT in WOMAC Physical Function Subscale Score

Top of page

End point title

Change from Baseline to EOT in WOMAC Physical Function Subscale Score

End point description

WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The physical function subscale contains 17 questions that ask about the difficulty following daily physical activities. A negative change indicated a reduction/improvement from baseline. The analysis population was the FAS. The EOT value was defined as the last available postbaseline measurement within the treatment period.

End point type

Secondary

End point timeframe

Baseline and EOT (up to 4 weeks)

End point values	Placebo	ASP7962	Naproxen
Number of subjects analysed	79	81	42
Units: units on a scale
least squares mean (standard error)	-1.67 ( 0.19 )	-1.81 ( 0.19 )	-2.51 ( 0.26 )

Difference: ASP7962 vs. Placebo

Statistical analysis description

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.306 ^[5]

Method

ANCOVA

Parameter type

LSM Difference

Point estimate

-0.14

Confidence interval

level

90%

sides

2-sided

lower limit

-0.59

upper limit

0.31

Variability estimate

Standard error of the mean

Dispersion value

0.27

Notes
[5] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.005 ^[6]

Method

ANCOVA

Parameter type

LSM Difference

Point estimate

-0.84

Confidence interval

level

80%

sides

2-sided

lower limit

-1.26

upper limit

-0.42

Variability estimate

Standard error of the mean

Dispersion value

0.33

Notes
[6] - One-sided P-value for pairwise treatment comparison with placebo.

Secondary: Change from Baseline to EOT in WOMAC Stiffness Subscale Score

Top of page

End point title

Change from Baseline to EOT in WOMAC Stiffness Subscale Score

End point description

WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The stiffness subscale contains two questions that ask about stiffness during the last 48 hours caused by the arthritis. A negative change indicated a reduction/improvement from baseline. The analysis population was the FAS. The EOT value was defined as the last available postbaseline measurement within the treatment period.

End point type

Secondary

End point timeframe

Baseline and EOT (up to 4 weeks)

End point values	Placebo	ASP7962	Naproxen
Number of subjects analysed	79	81	42
Units: units on a scale
least squares mean (standard error)	-1.68 ( 0.20 )	-1.89 ( 0.20 )	-2.82 ( 0.28 )

Difference ASP7962 vs. Placebo

Statistical analysis description

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.232 ^[7]

Method

ANCOVA

Parameter type

LSM Difference

Point estimate

-0.21

Confidence interval

level

90%

sides

2-sided

lower limit

-0.68

upper limit

0.26

Variability estimate

Standard error of the mean

Dispersion value

0.28

Notes
[7] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001 ^[8]

Method

ANCOVA

Parameter type

LSM Difference

Point estimate

-1.14

Confidence interval

level

80%

sides

2-sided

lower limit

-1.58

upper limit

-0.7

Variability estimate

Standard error of the mean

Dispersion value

0.34

Notes
[8] - One-sided P-value for pairwise treatment comparison with placebo.

Secondary: Change from Baseline to EOT in WOMAC Total Score

Top of page

End point title

Change from Baseline to EOT in WOMAC Total Score

End point description

WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The total score is the sum of scores from pain, physical function and stiffness subscales. Total score ranges from 0 to 30. A negative change indicated a reduction/improvement from baseline. The analysis population was the FAS. The EOT value was defined as the last available postbaseline measurement within the treatment period.

End point type

Secondary

End point timeframe

Baseline and EOT (up to 4 weeks)

End point values	Placebo	ASP7962	Naproxen
Number of subjects analysed	79	81	42
Units: units on a scale
least squares mean (standard error)	-5.07 ( 0.56 )	-5.65 ( 0.56 )	-7.71 ( 0.77 )

Difference: ASP7962 vs. Placebo

Statistical analysis description

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.232 ^[9]

Method

ANCOVA

Parameter type

LSM Difference

Point estimate

-0.59

Confidence interval

level

90%

sides

2-sided

lower limit

-1.91

upper limit

0.74

Variability estimate

Standard error of the mean

Dispersion value

0.8

Notes
[9] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003 ^[10]

Method

ANCOVA

Parameter type

LSM Difference

Point estimate

-2.64

Confidence interval

level

80%

sides

2-sided

lower limit

-3.87

upper limit

-1.41

Variability estimate

Standard error of the mean

Dispersion value

0.95

Notes
[10] - One-sided P-value for pairwise treatment comparison with placebo.

Secondary: Change from Baseline to EOT in WOMAC Walking Pain Score

Top of page

End point title

Change from Baseline to EOT in WOMAC Walking Pain Score

End point description

WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The walking pain score is based on question 1 of the questionnaire on pain when walking on a flat surface. A negative change indicated a reduction/improvement from baseline. The analysis population was the FAS. The EOT value was defined as the last available postbaseline measurement within the treatment period.

End point type

Secondary

End point timeframe

Baseline and EOT (up to 4 weeks)

End point values	Placebo	ASP7962	Naproxen
Number of subjects analysed	79	81	42
Units: units on a scale
least squares mean (standard error)	-1.56 ( 0.22 )	-1.82 ( 0.21 )	-2.53 ( 0.29 )

Difference: ASP7962 vs. Placebo

Statistical analysis description

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.197 ^[11]

Method

ANCOVA

Parameter type

LSM Difference

Point estimate

-0.26

Confidence interval

level

90%

sides

2-sided

lower limit

-0.77

upper limit

0.24

Variability estimate

Standard error of the mean

Dispersion value

0.31

Notes
[11] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.005 ^[12]

Method

ANCOVA

Parameter type

LSM Difference

Point estimate

-0.96

Confidence interval

level

80%

sides

2-sided

lower limit

-1.44

upper limit

-0.49

Variability estimate

Standard error of the mean

Dispersion value

0.37

Notes
[12] - One-sided P-value for pairwise treatment comparison with placebo.

Secondary: Change from Baseline to Weeks 1 and 2 in WOMAC Pain Subscale Score

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End point title

Change from Baseline to Weeks 1 and 2 in WOMAC Pain Subscale Score

End point description

WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The pain subscale contains five questions that ask about pain during the last 48 hours caused by arthritis in the index knee. A negative change indicated a reduction/improvement from baseline. The analysis population was the FAS. N is the number of participants with data available at baseline and at each time point that were included in the analysis.

End point type

Secondary

End point timeframe

Baseline and Weeks 1 and 2

End point values	Placebo	ASP7962	Naproxen
Number of subjects analysed	79	81	42
Units: units on a scale
least squares mean (standard error)
Week 1 [N=76, 79, 42]	-1.13 ( 0.17 )	-1.12 ( 0.17 )	-1.90 ( 0.23 )
Week 2 [N=75, 80, 41]	-1.19 ( 0.19 )	-1.49 ( 0.18 )	-1.83 ( 0.25 )

Difference: ASP7962 vs. Placebo (Week 1)

Statistical analysis description

MMRM analysis was performed using change from baseline (week 1, 2 & 4) as response and treatment group, study site, week, week x treatment group interaction as fixed effects, baseline & week x baseline interaction as covariates. Unstructured covariance structure was used among the within-participant results. Differences of the adjusted means were calculated by subtracting the adjusted mean of placebo from the adjusted mean of treatment group. The subject number is incorrect due to system limit.

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.516 ^[13]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

0.01

Confidence interval

level

90%

sides

2-sided

lower limit

-0.38

upper limit

0.4

Variability estimate

Standard error of the mean

Dispersion value

0.24

Notes
[13] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo (Week 1)

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003 ^[14]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.77

Confidence interval

level

80%

sides

2-sided

lower limit

-1.13

upper limit

-0.41

Variability estimate

Standard error of the mean

Dispersion value

0.28

Notes
[14] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: ASP7962 vs. Placebo (Week 2)

Statistical analysis description

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.122 ^[15]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.31

Confidence interval

level

90%

sides

2-sided

lower limit

-0.74

upper limit

0.13

Variability estimate

Standard error of the mean

Dispersion value

0.26

Notes
[15] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo (Week 2)

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.02 ^[16]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.64

Confidence interval

level

80%

sides

2-sided

lower limit

-1.05

upper limit

-0.24

Variability estimate

Standard error of the mean

Dispersion value

0.31

Notes
[16] - One-sided P-value for pairwise treatment comparison with placebo.

Secondary: Change from Baseline to Weeks 1, 2 and 4 in WOMAC Physical Function Subscale Score

Top of page

End point title

Change from Baseline to Weeks 1, 2 and 4 in WOMAC Physical Function Subscale Score

End point description

WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The physical function subscale contains 17 questions that ask about the difficulty following daily physical activities. A negative change indicated a reduction/improvement from baseline. The analysis population was the FAS. N is the number of participants with data available at baseline and at each time point that were included in the analysis.

End point type

Secondary

End point timeframe

Baseline and Weeks 1, 2, and 4

End point values	Placebo	ASP7962	Naproxen
Number of subjects analysed	79	81	42
Units: units on a scale
least squares mean (standard error)
Week 1 [N=76, 79, 42]	-1.00 ( 0.16 )	-1.07 ( 0.16 )	-1.87 ( 0.21 )
Week 2 [N=75, 80, 41]	-1.14 ( 0.18 )	-1.42 ( 0.18 )	-1.92 ( 0.24 )
Week 4 [N=75, 77, 39]	-1.65 ( 0.20 )	-1.77 ( 0.20 )	-2.48 ( 0.27 )

Difference: ASP7962 vs. Placebo (Week 1)

Statistical analysis description

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.375 ^[17]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.07

Confidence interval

level

90%

sides

2-sided

lower limit

-0.44

upper limit

0.3

Variability estimate

Standard error of the mean

Dispersion value

0.22

Notes
[17] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo (Week 1)

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[18]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.88

Confidence interval

level

80%

sides

2-sided

lower limit

-1.21

upper limit

-0.54

Variability estimate

Standard error of the mean

Dispersion value

0.26

Notes
[18] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: ASP7962 vs. Placebo (Week 2)

Statistical analysis description

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.132 ^[19]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.28

Confidence interval

level

90%

sides

2-sided

lower limit

-0.69

upper limit

0.13

Variability estimate

Standard error of the mean

Dispersion value

0.25

Notes
[19] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo (Week 2)

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.005 ^[20]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.77

Confidence interval

level

80%

sides

2-sided

lower limit

-1.16

upper limit

-0.39

Variability estimate

Standard error of the mean

Dispersion value

0.3

Notes
[20] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: ASP7962 vs. Placebo (Week 4)

Statistical analysis description

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.335 ^[21]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.12

Confidence interval

level

90%

sides

2-sided

lower limit

-0.58

upper limit

0.34

Variability estimate

Standard error of the mean

Dispersion value

0.28

Notes
[21] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo (Week 4)

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.007 ^[22]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.83

Confidence interval

level

80%

sides

2-sided

lower limit

-1.26

upper limit

-0.4

Variability estimate

Standard error of the mean

Dispersion value

0.33

Notes
[22] - One-sided P-value for pairwise treatment comparison with placebo.

Secondary: Change from Baseline to Weeks 1, 2 and 4 in WOMAC Stiffness Subscale Score

Top of page

End point title

Change from Baseline to Weeks 1, 2 and 4 in WOMAC Stiffness Subscale Score

End point description

WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The stiffness subscale contains two questions that ask about stiffness during the last 48 hours caused by the arthritis. A negative change indicated a reduction/improvement from baseline. The analysis population was the FAS. N is the number of participants with data available at baseline and at each time point that were included in the analysis.

End point type

Secondary

End point timeframe

Baseline and Weeks 1, 2, and 4

End point values	Placebo	ASP7962	Naproxen
Number of subjects analysed	79	81	42
Units: units on a scale
least squares mean (standard error)
Week 1 [N=76, 79, 42]	-1.20 ( 0.18 )	-1.24 ( 0.18 )	-2.11 ( 0.25 )
Week 2 [N=75, 80, 41]	-1.32 ( 0.19 )	-1.52 ( 0.19 )	-2.39 ( 0.26 )
Week 4 [N=75, 77, 39]	-1.66 ( 0.20 )	-1.83 ( 0.20 )	-2.81 ( 0.28 )

Difference: ASP7962 vs. Placebo (Week 1)

Statistical analysis description

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.439 ^[23]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.04

Confidence interval

level

90%

sides

2-sided

lower limit

-0.46

upper limit

0.38

Variability estimate

Standard error of the mean

Dispersion value

0.25

Notes
[23] - One-sided P-value for pairwise treatment comparison with placebo..

Difference: Naproxen vs. Placebo (Week 1)

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002 ^[24]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.9

Confidence interval

level

80%

sides

2-sided

lower limit

-1.3

upper limit

-0.51

Variability estimate

Standard error of the mean

Dispersion value

0.3

Notes
[24] - One-sided P-value for pairwise treatment comparison with placebo..

Difference: ASP7962 vs. Placebo (Week 2)

Statistical analysis description

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.217 ^[25]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.21

Confidence interval

level

90%

sides

2-sided

lower limit

-0.65

upper limit

0.23

Variability estimate

Standard error of the mean

Dispersion value

0.27

Notes
[25] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo (Week 2)

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[26]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-1.08

Confidence interval

level

80%

sides

2-sided

lower limit

-1.49

upper limit

-0.67

Variability estimate

Standard error of the mean

Dispersion value

0.32

Notes
[26] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: ASP7962 vs. Placebo (Week 4)

Statistical analysis description

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.278 ^[27]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.17

Confidence interval

level

90%

sides

2-sided

lower limit

-0.64

upper limit

0.3

Variability estimate

Standard error of the mean

Dispersion value

0.28

Notes
[27] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo (Week 4)

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[28]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-1.16

Confidence interval

level

80%

sides

2-sided

lower limit

-1.6

upper limit

-0.71

Variability estimate

Standard error of the mean

Dispersion value

0.34

Notes
[28] - One-sided P-value for pairwise treatment comparison with placebo.

Secondary: Change from Baseline to Weeks 1, 2 and 4 in WOMAC Total Score

Top of page

End point title

Change from Baseline to Weeks 1, 2 and 4 in WOMAC Total Score

End point description

WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The total score is the sum of scores from pain, physical function and stiffness subscales. Total score ranges from 0 to 30. A negative change indicated a reduction/improvement from baseline. The analysis population was the FAS. N is the number of participants with data available at baseline and at each time point that were included in the analysis.

End point type

Secondary

End point timeframe

Baseline and Weeks 1, 2, and 4

End point values	Placebo	ASP7962	Naproxen
Number of subjects analysed	79	81	42
Units: units on a scale
least squares mean (standard error)
Week 1 [N=76, 79, 42]	-3.30 ( 0.48 )	-3.50 ( 0.47 )	-5.84 ( 0.64 )
Week 2 [N=75, 80, 41]	-3.63 ( 0.52 )	-4.50 ( 0.52 )	-6.11 ( 0.71 )
Week 4 [N=75, 77, 39]	-5.02 ( 0.58 )	-5.54 ( 0.57 )	-7.66 ( 0.79 )

Difference: ASP7962 vs. Placebo (Week 1)

Statistical analysis description

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.379 ^[29]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.2

Confidence interval

level

90%

sides

2-sided

lower limit

-1.3

upper limit

0.89

Variability estimate

Standard error of the mean

Dispersion value

0.66

Notes
[29] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo (Week 1)

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[30]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-2.54

Confidence interval

level

80%

sides

2-sided

lower limit

-3.56

upper limit

-1.53

Variability estimate

Standard error of the mean

Dispersion value

0.79

Notes
[30] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: ASP7962 vs. Placebo (Week 2)

Statistical analysis description

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.117 ^[31]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.88

Confidence interval

level

90%

sides

2-sided

lower limit

-2.09

upper limit

0.34

Variability estimate

Standard error of the mean

Dispersion value

0.73

Notes
[31] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo (Week 2)

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003 ^[32]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-2.48

Confidence interval

level

80%

sides

2-sided

lower limit

-3.61

upper limit

-1.36

Variability estimate

Standard error of the mean

Dispersion value

0.87

Notes
[32] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: ASP7962 vs. Placebo (Week 4)

Statistical analysis description

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.261 ^[33]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.52

Confidence interval

level

90%

sides

2-sided

lower limit

-1.86

upper limit

0.82

Variability estimate

Standard error of the mean

Dispersion value

0.81

Notes
[33] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo (Week 4)

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004 ^[34]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-2.64

Confidence interval

level

80%

sides

2-sided

lower limit

-3.89

upper limit

-1.39

Variability estimate

Standard error of the mean

Dispersion value

0.97

Notes
[34] - One-sided P-value for pairwise treatment comparison with placebo.

Secondary: Change from Baseline to Weeks 1, 2 and 4 in WOMAC Walking Pain Score

Top of page

End point title

Change from Baseline to Weeks 1, 2 and 4 in WOMAC Walking Pain Score

End point description

WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The walking pain score is based on question 1 of the questionnaire on pain when walking on a flat surface. A negative change indicated a reduction/improvement from baseline. The analysis population was the FAS. N is the number of participants with data available at baseline and at each time point that were included in the analysis.

End point type

Secondary

End point timeframe

Baseline and Weeks 1, 2, and 4

End point values	Placebo	ASP7962	Naproxen
Number of subjects analysed	79	81	42
Units: units on a scale
least squares mean (standard error)
Week 1 [N=76, 79, 42]	-0.91 ( 0.20 )	-0.90 ( 0.19 )	-1.80 ( 0.26 )
Week 2 [N=75, 80, 41]	-0.95 ( 0.21 )	-1.33 ( 0.21 )	-1.92 ( 0.28 )
Week 4 [N=75, 77, 39]	-1.56 ( 0.23 )	-1.78 ( 0.22 )	-2.52 ( 0.31 )

Difference: ASP7962 vs. Placebo (Week 1)

Statistical analysis description

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.518 ^[35]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

0.01

Confidence interval

level

90%

sides

2-sided

lower limit

-0.44

upper limit

0.46

Variability estimate

Standard error of the mean

Dispersion value

0.27

Notes
[35] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo (Week 1)

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003 ^[36]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.89

Confidence interval

level

80%

sides

2-sided

lower limit

-1.31

upper limit

-0.48

Variability estimate

Standard error of the mean

Dispersion value

0.32

Notes
[36] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: ASP7962 vs. Placebo (Week 2)

Statistical analysis description

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

equivalence

P-value

= 0.101 ^[37]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.38

Confidence interval

level

90%

sides

2-sided

lower limit

-0.86

upper limit

0.11

Variability estimate

Standard error of the mean

Dispersion value

0.29

Notes
[37] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo (Week 2)

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003 ^[38]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.97

Confidence interval

level

80%

sides

2-sided

lower limit

-1.42

upper limit

-0.52

Variability estimate

Standard error of the mean

Dispersion value

0.35

Notes
[38] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: ASP7962 vs. Placebo (Week 4)

Statistical analysis description

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.243 ^[39]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.22

Confidence interval

level

90%

sides

2-sided

lower limit

-0.74

upper limit

0.3

Variability estimate

Standard error of the mean

Dispersion value

0.32

Notes
[39] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo (Week 4)

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.006 ^[40]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.96

Confidence interval

level

80%

sides

2-sided

lower limit

-1.45

upper limit

-0.47

Variability estimate

Standard error of the mean

Dispersion value

0.38

Notes
[40] - One-sided P-value for pairwise treatment comparison with placebo.

Secondary: Change from Baseline to Weeks 1, 2, 3, 4 and EOT in Mean Daily Average Pain Score Assessed by the Numerical Rating Scale

Top of page

End point title

Change from Baseline to Weeks 1, 2, 3, 4 and EOT in Mean Daily Average Pain Score Assessed by the Numerical Rating Scale

End point description

The NRS is an 11-point scale used to capture the participant’s average pain in the last 24 hours on a daily basis. This scale is composed of a single question and the score ranges from 0 to 10, where 0 anchors “no pain” and 10 anchors “pain as bad as you can imagine." The mean daily average NRS pain score was derived from the daily index knee pain ratings recorded by participants in an electronic diary (e-diary) on the last 4 days prior to randomization. A negative change indicated a reduction/improvement from baseline. The analysis population was the FAS. N is the number of participants with data available at baseline and at each time point that were included in the analysis. The EOT value was defined as the last available postbaseline measurement within the treatment period.

End point type

Secondary

End point timeframe

Baseline and Weeks 1, 2, 3, 4 and EOT (up to 4 weeks)

End point values	Placebo	ASP7962	Naproxen
Number of subjects analysed	79	81	42
Units: units on a scale
least squares mean (standard error)
Week 1 [N=78, 81, 42]	-0.61 ( 0.15 )	-0.58 ( 0.15 )	-1.38 ( 0.21 )
Week 2 [N=77, 81, 42]	-1.17 ( 0.17 )	-0.96 ( 0.17 )	-1.96 ( 0.23 )
Week 3 [N=77, 80, 41]	-1.40 ( 0.19 )	-1.20 ( 0.19 )	-2.22 ( 0.26 )
Week 4 [N=77, 80, 40]	-1.59 ( 0.20 )	-1.42 ( 0.19 )	-2.26 ( 0.27 )
EOT [N=78, 81, 42]	-1.60 ( 0.19 )	-1.49 ( 0.19 )	-2.30 ( 0.26 )

Difference: ASP7962 vs. Placebo (Week 1)

Statistical analysis description

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.555 ^[41]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

0.03

Confidence interval

level

90%

sides

2-sided

lower limit

-0.32

upper limit

0.38

Variability estimate

Standard error of the mean

Dispersion value

0.21

Notes
[41] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo (Week 1)

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001 ^[42]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.77

Confidence interval

level

80%

sides

2-sided

lower limit

-1.1

upper limit

-0.44

Variability estimate

Standard error of the mean

Dispersion value

0.25

Notes
[42] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: ASP7962 vs. Placebo (Week 2)

Statistical analysis description

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.807 ^[43]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

0.21

Confidence interval

level

90%

sides

2-sided

lower limit

-0.19

upper limit

0.6

Variability estimate

Standard error of the mean

Dispersion value

0.24

Notes
[43] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo (Week 2)

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003 ^[44]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.79

Confidence interval

level

80%

sides

2-sided

lower limit

-1.16

upper limit

-0.42

Variability estimate

Standard error of the mean

Dispersion value

0.29

Notes
[44] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: ASP7962 vs. Placebo (Week 3)

Statistical analysis description

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.775 ^[45]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

0.2

Confidence interval

level

90%

sides

2-sided

lower limit

-0.24

upper limit

0.64

Variability estimate

Standard error of the mean

Dispersion value

0.26

Notes
[45] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo (Week 3)

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.005 ^[46]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.83

Confidence interval

level

80%

sides

2-sided

lower limit

-1.24

upper limit

-0.42

Variability estimate

Standard error of the mean

Dispersion value

0.32

Notes
[46] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: ASP7962 vs. Placebo (Week 4)

Statistical analysis description

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.734 ^[47]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

0.17

Confidence interval

level

90%

sides

2-sided

lower limit

-0.28

upper limit

0.63

Variability estimate

Standard error of the mean

Dispersion value

0.28

Notes
[47] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo (Week 4)

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.023 ^[48]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.67

Confidence interval

level

80%

sides

2-sided

lower limit

-1.1

upper limit

-0.24

Variability estimate

Standard error of the mean

Dispersion value

0.33

Notes
[48] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: ASP7962 vs. Placebo (EOT)

Statistical analysis description

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.653 ^[49]

Method

ANCOVA

Parameter type

LSM Difference

Point estimate

0.11

Confidence interval

level

90%

sides

2-sided

lower limit

-0.34

upper limit

0.55

Variability estimate

Standard error of the mean

Dispersion value

0.27

Notes
[49] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo (EOT)

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.016 ^[50]

Method

ANCOVA

Parameter type

LSM Difference

Point estimate

-0.71

Confidence interval

level

80%

sides

2-sided

lower limit

-1.13

upper limit

-0.29

Variability estimate

Standard error of the mean

Dispersion value

0.33

Notes
[50] - One-sided P-value for pairwise treatment comparison with placebo.

Secondary: Change from Baseline Patient Global Assessment (PGA) at Weeks 1, 2, 4 and EOT

Top of page

End point title

Change from Baseline Patient Global Assessment (PGA) at Weeks 1, 2, 4 and EOT

End point description

The PGA is an 11-point NRS scale used to capture the participant’s overall impression at the time of the assessment in the index knee. This is a single question and the score ranges from 0 to 10, where 0 anchors “very good” and 10 anchors “very poor.” A negative change indicated a reduction/improvement from baseline. The analysis population was the FAS. N is the number of participants with data available at baseline and at each time point that were included in the analysis. The EOT value was defined as the last available postbaseline measurement within the treatment period.

End point type

Secondary

End point timeframe

Baseline and Weeks 1, 2, 4 and EOT (up to 4 weeks)

End point values	Placebo	ASP7962	Naproxen
Number of subjects analysed	79	81	42
Units: units on a scale
least squares mean (standard error)
Week 1 [N=75, 79, 42]	-1.15 ( 0.20 )	-1.27 ( 0.19 )	-1.71 ( 0.26 )
Week 2 [N=74, 80, 41]	-1.25 ( 0.21 )	-1.55 ( 0.20 )	-2.02 ( 0.28 )
Week 4 [N=73, 77, 39]	-1.57 ( 0.24 )	-1.97 ( 0.23 )	-2.43 ( 0.32 )
EOT [N=78, 81, 42]	-1.56 ( 0.23 )	-1.99 ( 0.22 )	-2.48 ( 0.31 )

Difference: ASP7962 vs. Placebo (Week 1)

Statistical analysis description

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.324 ^[51]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.13

Confidence interval

level

90%

sides

2-sided

lower limit

-0.58

upper limit

0.33

Variability estimate

Standard error of the mean

Dispersion value

0.27

Notes
[51] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo (Week 1)

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.042 ^[52]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.57

Confidence interval

level

80%

sides

2-sided

lower limit

-0.98

upper limit

-0.15

Variability estimate

Standard error of the mean

Dispersion value

0.33

Notes
[52] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: ASP7962 vs. Placebo (Week 2)

Statistical analysis description

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.148 ^[53]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.3

Confidence interval

level

90%

sides

2-sided

lower limit

-0.78

upper limit

0.17

Variability estimate

Standard error of the mean

Dispersion value

0.29

Notes
[53] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo (Week 2)

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.013 ^[54]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.77

Confidence interval

level

80%

sides

2-sided

lower limit

-1.22

upper limit

-0.33

Variability estimate

Standard error of the mean

Dispersion value

0.35

Notes
[54] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: ASP7962 vs. Placebo (Week 4)

Statistical analysis description

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.112 ^[55]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.4

Confidence interval

level

90%

sides

2-sided

lower limit

-0.95

upper limit

0.14

Variability estimate

Standard error of the mean

Dispersion value

0.33

Notes
[55] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo (Week 4)

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.015 ^[56]

Method

Mixed-effect model, Repeated measures

Parameter type

LSM Difference

Point estimate

-0.87

Confidence interval

level

80%

sides

2-sided

lower limit

-1.38

upper limit

-0.36

Variability estimate

Standard error of the mean

Dispersion value

0.4

Notes
[56] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: ASP7962 vs. Placebo (EOT)

Statistical analysis description

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.088 ^[57]

Method

ANCOVA

Parameter type

LSM Difference

Point estimate

-0.44

Confidence interval

level

90%

sides

2-sided

lower limit

-0.97

upper limit

0.1

Variability estimate

Standard error of the mean

Dispersion value

0.32

Notes
[57] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo (EOT)

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.009 ^[58]

Method

ANCOVA

Parameter type

LSM Difference

Point estimate

-0.92

Confidence interval

level

80%

sides

2-sided

lower limit

-1.42

upper limit

-0.42

Variability estimate

Standard error of the mean

Dispersion value

0.39

Notes
[58] - One-sided P-value for pairwise treatment comparison with placebo.

Secondary: Percentage of Participants who Achieved ≥ 30% Decrease from Baseline to EOT in WOMAC Pain Subscale Score

Top of page

End point title

Percentage of Participants who Achieved ≥ 30% Decrease from Baseline to EOT in WOMAC Pain Subscale Score

End point description

Percentage of participants who had a reduction from baseline to EOT in WOMAC pain subscale score of ≥ 30% is reported. WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The pain subscale contains five questions that ask about pain during the last 48 hours caused by arthritis in the index knee. The analysis population was the FAS. Only participants with data at baseline or EOT were included in the analysis. The EOT value was defined as the last available postbaseline measurement within the treatment period.

End point type

Secondary

End point timeframe

Baseline and EOT (up to 4 weeks)

End point values	Placebo	ASP7962	Naproxen
Number of subjects analysed	79	81	42
Units: percentage of participants
number (confidence interval 90%)	43 (33.6 to 52.9)	53.1 (43.4 to 62.6)	64.3 (50.5 to 76.5)

Difference: ASP7962 vs. Placebo

Statistical analysis description

Differences of the percentages were calculated by subtracting the percentage of placebo group from the percentage of the active treatment group. Confidence interval for each treatment group and the difference of the percentage was an exact unconditional confidence interval based on Santner-Snell approach.

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.133 ^[59]

Method

Fisher exact

Parameter type

Percentage Difference

Point estimate

Confidence interval

level

90%

sides

2-sided

lower limit

-3.2

upper limit

23.2

Notes
[59] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.021 ^[60]

Method

Fisher exact

Parameter type

Percentage Difference

Point estimate

21.2

Confidence interval

level

80%

sides

2-sided

lower limit

8.8

upper limit

33.1

Notes
[60] - One-sided P-value for pairwise treatment comparison with placebo.

Secondary: Percentage of Participants who Achieved ≥ 50% Decrease from Baseline to EOT in WOMAC Pain Subscale Score

Top of page

End point title

Percentage of Participants who Achieved ≥ 50% Decrease from Baseline to EOT in WOMAC Pain Subscale Score

End point description

Percentage of participants who had a reduction from baseline to EOT in WOMAC pain subscale score of ≥ 50% is reported. WOMAC is a tri-dimensional, self-administered, patient-centered health status questionnaire designed to capture the elements of pain, stiffness and physical function in participants with OA of the knee and/or hip joints. The questionnaire consists of 24 questions, which are divided into three subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question is scored using 11-point NRS scale ranging from 0 (none) to 10 (extreme). The pain subscale contains five questions that ask about pain during the last 48 hours caused by arthritis in the index knee. The analysis population was the FAS. Only participants with data at baseline or EOT were included in the analysis. The EOT value was defined as the last available postbaseline measurement within the treatment period.

End point type

Secondary

End point timeframe

Baseline and EOT (up to 4 weeks)

End point values	Placebo	ASP7962	Naproxen
Number of subjects analysed	79	81	42
Units: percentage of participants
number (confidence interval 90%)	22.8 (15.3 to 31.9)	32.1 (23.6 to 41.7)	45.2 (32.0 to 59.0)

Difference: ASP7962 vs. Placebo

Statistical analysis description

Comparison groups

Placebo v ASP7962

Number of subjects included in analysis

160

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.127 ^[61]

Method

Fisher exact

Parameter type

Percentage Difference

Point estimate

9.3

Confidence interval

level

90%

sides

2-sided

lower limit

-3.7

upper limit

22.2

Notes
[61] - One-sided P-value for pairwise treatment comparison with placebo.

Difference: Naproxen vs. Placebo

Statistical analysis description

Comparison groups

Placebo v Naproxen

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.01 ^[62]

Method

Fisher exact

Parameter type

Percentage Difference

Point estimate

22.5

Confidence interval

level

80%

sides

2-sided

lower limit

10.1

upper limit

34.3

Notes
[62] - One-sided P-value for pairwise treatment comparison with placebo.

Secondary: Number of Participants with Treatment-Emergent Adverse Events

Top of page

End point title

Number of Participants with Treatment-Emergent Adverse Events

End point description

A TEAE was defined as an adverse event (AE) which started or worsened after the first dose of study drug until 30 days after taking the last dose of study drug. This included abnormal laboratory tests, vital signs or electrocardiogram data that were defined as AEs if the abnormality induced clinical signs or symptoms, required active intervention, interruption or discontinuation of study drug or was clinically significant in the investigator's opinion. The analysis population was the safety analysis set (SAF), which consisted of all randomized participants who took at least 1 dose of double-blind study drug.

End point type

Secondary

End point timeframe

From first dose of study drug up to 30 days after last dose of study drug (up to 8 weeks)

End point values	Placebo	ASP7962	Naproxen
Number of subjects analysed	85	85	42
Units: participants
TEAE	24	31	13
Drug-related TEAE	10	8	7
Serious TEAE	0	1	0
Drug-related serious TEAE	0	0	0
Deaths	0	0	0
TEAE leading to withdrawal of treatment	3	3	2
Drug-related TEAE leading to treatment withdrawal	3	1	2
Joint-related TEAE	1	3	2
Neurological-related TEAE	2	4	0
Hepatic-related TEAE	0	0	1

No statistical analyses for this end point

Secondary: Number of Participants with an Affirmative Response in Columbia – Suicide Severity Rating Scale (C-SSRS): Suicidal Ideation

Top of page

End point title

Number of Participants with an Affirmative Response in Columbia – Suicide Severity Rating Scale (C-SSRS): Suicidal Ideation

End point description

C-SSRS is a questionnaire used for suicide assessment. The data presented are the number of participants with an affirmative ("YES") response to questions: (1) Wish to be dead; (2) Non-specific active suicidal thoughts; (3) Active suicidal ideation with any methods (not plan) without intent to act; (4) Active suicidal ideation with some intent to act, without specific plan; and (5) Active suicidal ideation with specific plan and intent. The participant’s worst finding in the treatment period or follow-up period is reported. The analysis population was the SAF. N is the number of participants with data available at each time point.

End point type

Secondary

End point timeframe

From first dose of study drug up to end of study (up to 8 weeks)

End point values	Placebo	ASP7962	Naproxen
Number of subjects analysed	85	85	42
Units: participants
Treatment period [N=79, 82, 42]	0	0	0
Follow-up period [N=77, 81, 42]	0	1	0

No statistical analyses for this end point

Secondary: Number of Participants with an Affirmative Response in C-SSRS: Suicidal Behavior

Top of page

End point title

Number of Participants with an Affirmative Response in C-SSRS: Suicidal Behavior

End point description

C-SSRS is a questionnaire used for suicide assessment. The data presented are the number of participants with an affirmative ("YES") response to questions: (1) Preparatory acts or behavior; (2) Aborted attempt; (3) Interrupted attempt; (4) Actual attempt; and (5) Completed suicide. The participant’s worst finding in the treatment period or follow-up period is reported. The analysis population was the SAF. N is the number of participants with data available at each time point.

End point type

Secondary

End point timeframe

From first dose of study drug up to end of study (up to 8 weeks)

End point values	Placebo	ASP7962	Naproxen
Number of subjects analysed	85	85	42
Units: participants
Treatment period [N=79, 82, 42]	0	0	0
Follow-up period [N=77, 81, 42]	0	0	0

No statistical analyses for this end point

Secondary: Number of Participants with an Affirmative Response in C-SSRS: Suicidal Ideation or Behavior

Top of page

End point title

Number of Participants with an Affirmative Response in C-SSRS: Suicidal Ideation or Behavior

End point description

C-SSRS is a questionnaire used for suicide assessment. The data presented are the number of participants with an affirmative ("YES") response to any one of the ten suicidal ideation and behavior questions. The participant’s worst finding in the treatment period or follow-up period is reported. The analysis population was the SAF. N is the number of participants with data available at each time point.

End point type

Secondary

End point timeframe

From first dose of study drug up to end of study (up to 8 weeks)

End point values	Placebo	ASP7962	Naproxen
Number of subjects analysed	85	85	42
Units: participants
Treatment period [N=79, 82, 42]	0	0	0
Follow-up period [N=77, 81, 42]	0	1	0

No statistical analyses for this end point

Secondary: Number of Participants with an Affirmative Response in C-SSRS: Self-injurious Behavior without Suicidal Intent

Top of page

End point title

Number of Participants with an Affirmative Response in C-SSRS: Self-injurious Behavior without Suicidal Intent

End point description

C-SSRS is a questionnaire used for suicide assessment. The data presented are the number of participants with an affirmative ("YES") response to the question "Has subject engaged in Non-Suicidal Self-Injurious Behavior?" The participant’s worst finding in the treatment period or follow-up period is reported. The analysis population was the SAF. N is the number of participants with data available at each time point.

End point type

Secondary

End point timeframe

From first dose of study drug up to end of study (up to 8 weeks)

End point values	Placebo	ASP7962	Naproxen
Number of subjects analysed	85	85	42
Units: participants
Treatment period [N=79, 82, 42]	0	1	0
Follow-up period [N=77, 81, 42]	0	1	0

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

From first dose of study drug up to 30 days after last dose of study drug (up to 8 weeks)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.1

Reporting group title

Placebo

Reporting group description

Participants received placebo orally twice daily for a period of 4 weeks.

Reporting group title

Naproxen

Reporting group description

Participants received 500 mg of Naproxen orally twice daily for 4 weeks.

Reporting group title

ASP7962

Reporting group description

Participants received 100 mg of ASP7962 orally twice daily for 4 weeks.

Serious adverse events	Placebo	Naproxen	ASP7962
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 85 (0.00%)	0 / 42 (0.00%)	1 / 85 (1.18%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 85 (0.00%)	0 / 42 (0.00%)	1 / 85 (1.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 4%

Non-serious adverse events	Placebo	Naproxen	ASP7962
Total subjects affected by non serious adverse events
subjects affected / exposed	8 / 85 (9.41%)	5 / 42 (11.90%)	8 / 85 (9.41%)
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	4 / 85 (4.71%)	0 / 42 (0.00%)	4 / 85 (4.71%)
occurrences all number	9	0	4
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 85 (0.00%)	2 / 42 (4.76%)	0 / 85 (0.00%)
occurrences all number	0	2	0
Abdominal pain upper
subjects affected / exposed	1 / 85 (1.18%)	2 / 42 (4.76%)	2 / 85 (2.35%)
occurrences all number	1	2	2
Constipation
subjects affected / exposed	0 / 85 (0.00%)	2 / 42 (4.76%)	0 / 85 (0.00%)
occurrences all number	0	2	0
Infections and infestations
Nasopharyngitis
subjects affected / exposed	4 / 85 (4.71%)	0 / 42 (0.00%)	3 / 85 (3.53%)
occurrences all number	4	0	3

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

06 Nov 2015

The substantial changes include: 1) The procedure for obtaining radiographic images was changed. A radiograph image of the index knee was added to the follow-up period to assess for potential changes in the index knee poststudy drug treatment. The requirement for a lateral view of hips was removed because it was considered not essential to the assessment of the progression of hip OA. 2) Inclusion Criteria 12 and 14 were revised. The list of highly effective forms of birth control was updated, and Inclusion Criteria 12 and 14 were updated to reflect current recommendations by the Clinical Trials Facilitation Group related to contraception in clinical trials. 3) The gastrointestinal protective strategy was expanded, adding explicit language to state that gastroprotective agents could be used at the investigators’ discretion, considering the risk of serious gastrointestinal toxicity of naproxen, especially in older adults and patients treated with low dose aspirin for cardioprophylaxis. 4) Text was added regarding the absence of any evaluation of the test drug's phototoxic potential because specific phototoxicity studies have not been conducted for ASP7962. Although ASP7962 did not contain typical phototoxic structural moieties and the nonclinical data did not indicate a photosafety concern, based on the absorption peak at 305 nm, a phototoxicity potential for ASP7962 could not be excluded. Nonsubstantial changes were made: 1) To update Sponsor contact information 2) To update footnote in schedule of assessments 3) To update Appendix 12.6.

26 Jul 2016

The substantial changes include: (continued from above) 5) Specification for exclusion of participants with severe knee malalignment or another jointrelated condition was updated. Due to the change of Inclusion Criterion 4, it was considered relevant to add severe malalignment to the exclusion criteria. Although malalignment does not appear to be an independent risk factor for RPOA, out of an abundance of caution, the Osteo IAC members recommended that patients with severe malalignment be excluded from the study. This was assessed through centrally read radiographs as well as clinical evaluation of the participant. It was recommended that, in case of acute subchondral insufficiency fracture, additional medical evaluation would be required before considering a participant for enrollment into this study. 6) The specification for exclusion of participants with specific shoulder medical history was updated. Based on a few cases of RPOA of the shoulder reported in the anti-NGF programs, there was a theoretical concern of RPOA of the shoulder. However, there is a lack of evidence to indicate which participants this might affect. As a history of conditions, such as rotator cuff diseases, was expected to be common among the patients, these types of condition were not to prohibit enrollment. 7) Exclusion Criterion12 was revised, stating that participants with intolerance or hypersensitivity to tramadol were allowed to enter the study if the participants accepted to limiting rescue medication to paracetamol. 8) Exclusion Criterion 17 was revised to allow the enrollment of participants with a history of cardiovascular disease whose condition was stable. Unexplained syncope was removed from the exclusion criterion. PR interval was increased from 210 to 240 ms.

26 Jul 2016

The substantial changes include: (continued from above) 9) Exclusion Criterion 21 was revised, removing hepatitis B core antibodies (anti-HBc) test result from the exclusion criterion. HBsAg was considered a sufficient serologic test to assess presence of infection. A positive test result for anti-HBc in the presence of negative HBsAg suggests immunity due to natural infection. Active disease would be associated with increased liver tests and would be excluded due to Exclusion Criterion 19. 10) Exclusion Criterion 23 was revised, limiting the exclusion of participants having previously received antibodies to NGF to 3 months prior to screening. A 3-month washout was considered sufficient not to interfere with any study endpoints or cause any safety concerns. 11) Exclusion Criterion 23 and Prohibited Medications and Nonmedication Therapies were revised, reducing the use of intraarticular local anesthetics from 12 months to 3 months before screening. The reason was that there is no evidence that participants undergoing local anesthetic injection, such as lidocaine during a related single injection procedure, are at high risk of presentation of clinical chondral toxicity. 12) The strength and use of cytochrome P450 inducers were specified, adding "strong" to cytochrome P450 inducers and "regularly" to be consistent with the wording of Exclusion Criterion 32. 13) Study design was slightly revised, adding a section to allow reevaluation of participants who were not eligible under Version 2.0 of the protocol, but would be eligible based on the revised inclusion and exclusion criteria in Version 3.0 of the protocol. In case new radiographic assessments were deemed inappropriate, this was to be discussed first with the Medical Monitor. 14) Laboratory assessments were modified, deleting benzodiazepines from drug and alcohol urine screening. Assessment of benzodiazepine use was not considered to impact participant safety or adherence to the protocol.

26 Jul 2016

Nonsubstantial changes were made: (continued from above) 1) To update the contact details of key study personnel 2) To update the abbreviations list 3) To extend the planned study period 4) To update the planned number of study centers 5) To clarify the process for radiographic imaging 6) To update the order of the secondary safety endpoints 7) To update the statistical presentation of treatment-emergent adverse events (TEAEs) 8) To add text regarding educational material for participants 9) To update the schedule of assessments 10) To update the Hospital Anxiety and Depression Scale (HADS) 11) To update the physical examination section 12) To update the Neuropathic Pain Symptom Inventory (NPSI) 13) To update the reporting of serious adverse events (SAEs) 14) To update the analysis of exploratory endpoints 15) To update the statistical section on physical examination 16) To delete a reference 17) To update the table of questionnaires 18) To include minor administrative-type changes.

26 Jul 2016

The substantial changes include: 1) Inclusion Criterion 2 was revised, increasing the upper age limit from 75 to 80 years to allow participants aged 76 to 80 years to be entered in the study. The reason was that OA becomes increasingly prevalent with aging, and symptomatic OA affects many in their eighth decade. There was no evidence that ASP7962 should benefit older individuals to a lesser extent than those who are younger. 2) Inclusion Criterion 8 was removed. This inclusion criterion required participants to have a mean daily index knee average pain score between ≥ 4 and ≤ 9 (on a 0 to10 NRS). Pain criteria to enter the study were thus limited to the well-established WOMAC criteria for pain that are the standard for OA pain studies. 3) Inclusion Criterion 6 was revised. The Kellgren-Lawrence grade at screening (based on central reading) was increased such that participants with Kellgren-Lawrence grade 4 were included as well. After a review of publically available information from the anti-NGF monoclonal antibody programs and discussion with external experts and key opinion leaders (with expertise in rheumatology, radiology and RPOA), the exclusion of Kellgren-Lawrence grade 4 was considered unnecessary as there was no evidence suggesting an increased risk of RPOA with Kellgren-Lawrence grade 4. 4) Exclusion Criterion 4 was revised. If a participant was stable, treated and not experiencing clinical signs of concomitant diseases, the participant could be suitable as this should not impact safety or assessments within the study. For participants with diabetes mellitus, attaining a target HbA1c of < 6.5% to 7% can be challenging. For some participants the risks of intensive glycemic control may have outweighed the benefits and a less strict HbA1c cutoff seemed reasonable provided that, in the investigator’s judgment, the participant was clinically stable. HbA1c was increased from 7.1% to 8.0% to allow a less strict surrogate for diabetes control.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Phase 2a, Randomized, Double-blind, Placebo- and Naproxen-controlled, Parallel-group Study to Assess the Analgesic Efficacy of ASP7962 in Patients With Pain Due to Osteoarthritis of the Knee

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from Baseline to Week 4 in Western Ontario and McMaster Universities Arthritis Index (WOMAC) Pain Subscale Score

Primary: Change from Baseline to Week 4 in Western Ontario and McMaster Universities Arthritis Index (WOMAC) Pain Subscale Score

Secondary: Change from Baseline to End of Treatment (EOT) in WOMAC Pain Subscale Score

Secondary: Change from Baseline to End of Treatment (EOT) in WOMAC Pain Subscale Score

Secondary: Change from Baseline to EOT in WOMAC Physical Function Subscale Score

Secondary: Change from Baseline to EOT in WOMAC Physical Function Subscale Score

Secondary: Change from Baseline to EOT in WOMAC Stiffness Subscale Score

Secondary: Change from Baseline to EOT in WOMAC Stiffness Subscale Score

Secondary: Change from Baseline to EOT in WOMAC Total Score

Secondary: Change from Baseline to EOT in WOMAC Total Score

Secondary: Change from Baseline to EOT in WOMAC Walking Pain Score

Secondary: Change from Baseline to EOT in WOMAC Walking Pain Score

Secondary: Change from Baseline to Weeks 1 and 2 in WOMAC Pain Subscale Score

Secondary: Change from Baseline to Weeks 1 and 2 in WOMAC Pain Subscale Score

Secondary: Change from Baseline to Weeks 1, 2 and 4 in WOMAC Physical Function Subscale Score

Secondary: Change from Baseline to Weeks 1, 2 and 4 in WOMAC Physical Function Subscale Score

Secondary: Change from Baseline to Weeks 1, 2 and 4 in WOMAC Stiffness Subscale Score

Secondary: Change from Baseline to Weeks 1, 2 and 4 in WOMAC Stiffness Subscale Score

Secondary: Change from Baseline to Weeks 1, 2 and 4 in WOMAC Total Score

Secondary: Change from Baseline to Weeks 1, 2 and 4 in WOMAC Total Score

Secondary: Change from Baseline to Weeks 1, 2 and 4 in WOMAC Walking Pain Score

Secondary: Change from Baseline to Weeks 1, 2 and 4 in WOMAC Walking Pain Score

Secondary: Change from Baseline to Weeks 1, 2, 3, 4 and EOT in Mean Daily Average Pain Score Assessed by the Numerical Rating Scale

Secondary: Change from Baseline to Weeks 1, 2, 3, 4 and EOT in Mean Daily Average Pain Score Assessed by the Numerical Rating Scale

Secondary: Change from Baseline Patient Global Assessment (PGA) at Weeks 1, 2, 4 and EOT

Secondary: Change from Baseline Patient Global Assessment (PGA) at Weeks 1, 2, 4 and EOT

Secondary: Percentage of Participants who Achieved ≥ 30% Decrease from Baseline to EOT in WOMAC Pain Subscale Score

Secondary: Percentage of Participants who Achieved ≥ 30% Decrease from Baseline to EOT in WOMAC Pain Subscale Score

Secondary: Percentage of Participants who Achieved ≥ 50% Decrease from Baseline to EOT in WOMAC Pain Subscale Score

Secondary: Percentage of Participants who Achieved ≥ 50% Decrease from Baseline to EOT in WOMAC Pain Subscale Score

Secondary: Number of Participants with Treatment-Emergent Adverse Events

Secondary: Number of Participants with Treatment-Emergent Adverse Events

Secondary: Number of Participants with an Affirmative Response in Columbia – Suicide Severity Rating Scale (C-SSRS): Suicidal Ideation

Secondary: Number of Participants with an Affirmative Response in Columbia – Suicide Severity Rating Scale (C-SSRS): Suicidal Ideation

Secondary: Number of Participants with an Affirmative Response in C-SSRS: Suicidal Behavior

Secondary: Number of Participants with an Affirmative Response in C-SSRS: Suicidal Behavior

Secondary: Number of Participants with an Affirmative Response in C-SSRS: Suicidal Ideation or Behavior

Secondary: Number of Participants with an Affirmative Response in C-SSRS: Suicidal Ideation or Behavior

Secondary: Number of Participants with an Affirmative Response in C-SSRS: Self-injurious Behavior without Suicidal Intent

Secondary: Number of Participants with an Affirmative Response in C-SSRS: Self-injurious Behavior without Suicidal Intent

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 2a, Randomized, Double-blind, Placebo- and Naproxen-controlled, Parallel-group Study to Assess the Analgesic Efficacy of ASP7962 in Patients With Pain Due to Osteoarthritis of the Knee