Clinical Trial Results:
A Two Part Protocol Using Double Blind Placebo Control to Assess the Safety, Tolerability, and Pharmacokinetics of Single Escalating Intraarticular Doses Followed by Assessment of Efficacy, Safety, Tolerability and Pharmacokinetics of a Single Intraarticular Dose of the TrkA Inhibitor, GZ389988A, in Patients With Painful Osteoarthritis of the Knee
Summary


EudraCT number 
201400480534 
Trial protocol 
DE 
Global end of trial date 
13 Sep 2017

Results information


Results version number 
v1(current) 
This version publication date 
27 Sep 2018

First version publication date 
27 Sep 2018

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


Trial identification


Sponsor protocol code 
TDU13828 – ACT13830


Additional study identifiers


ISRCTN number 
  
US NCT number 
NCT02424942  
WHO universal trial number (UTN) 
U111111630806  
Other trial identifiers 
NCT Number for Part 2 Study (ACT13830): NCT02845271  
Sponsors


Sponsor organisation name 
Genzyme, a Sanofi Company


Sponsor organisation address 
500 Kendall Street, Cambridge, MA , United States, 02142


Public contact 
Trial Transparency Team, Sanofi aventis recherche & développement , contactUS@sanofi.com


Scientific contact 
Trial Transparency Team, Sanofi aventis recherche & développement, contactUS@sanofi.com


Paediatric regulatory details


Is trial part of an agreed paediatric investigation plan (PIP) 
No


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


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


Results analysis stage


Analysis stage 
Final


Date of interim/final analysis 
21 Dec 2017


Is this the analysis of the primary completion data? 
No


Global end of trial reached? 
Yes


Global end of trial date 
13 Sep 2017


Was the trial ended prematurely? 
No


General information about the trial


Main objective of the trial 
To assess in subjects with painful osteoarthritis (OA) of the knee:
 Part 1: The tolerability and safety of GZ389988A after ascending single intraarticular (IA) doses.
 The pharmacokinetic (PK) parameters of GZ389988A after ascending single IA doses.
 To obtain preliminary pharmacodynamics (PD) evaluation of GZ389988A after ascending single IA doses.
 Part 2: The efficacy of a single IA dose of GZ389988A versus placebo.
 The tolerability and safety of a single IA dose of GZ389988A.
 The PK parameters of a single IA dose of GZ389988A.


Protection of trial subjects 
Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the SanofiAventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.


Background therapy 
  
Evidence for comparator 
  
Actual start date of recruitment 
17 Apr 2015


Long term followup planned 
Yes


Long term followup rationale 
Safety  
Long term followup duration 
3 Months  
Independent data monitoring committee (IDMC) involvement? 
No


Population of trial subjects


Number of subjects enrolled per country 

Country: Number of subjects enrolled 
Germany: 132


Worldwide total number of subjects 
132


EEA total number of subjects 
132


Number of subjects enrolled per age group 

In utero 
0


Preterm newborn  gestational age < 37 wk 
0


Newborns (027 days) 
0


Infants and toddlers (28 days23 months) 
0


Children (211 years) 
0


Adolescents (1217 years) 
0


Adults (1864 years) 
81


From 65 to 84 years 
51


85 years and over 
0



Recruitment


Recruitment details 
Study was conducted at a single center in Germany. A total of 28 subjects were randomized and treated between 17 April 2015 and 13 July 2016 in Part 1 and a total of 104 subjects were randomized and treated between 22 July 2016 and 13 September 2017 in Part 2 .  
Preassignment


Screening details 
Part 1 consisted of 5 ascending dose levels of GZ389988A to determine maximum tolerated dose (MTD). For confirmation of MTD, the dose level of dose 3 and 4 were duplicated in 4 additional subjects with the same staggered dosing. Part 2 of the study was conducted at the MTD analyzed in Part 1.  
Period 1


Period 1 title 
Overall Study (overall period)


Is this the baseline period? 
Yes  
Allocation method 
Randomised  controlled


Blinding used 
Double blind  
Roles blinded 
Subject, Investigator  
Blinding implementation details 
For Part 2 of the study, GZ389988A and placebo were administered by a qualified orthopedic surgeon, supported by a nurse, both of whom were unblinded and not otherwise involved in the study (apart from identifying potential subjects for the study and taking synovial fluid samples).


Arms


Are arms mutually exclusive 
Yes


Arm title

Part 1: Placebo  
Arm description 
Subjects received single dose of placebo (matched to GZ389988A) IA injection on Day 1. Data was pooled for all subjects who received placebo in Part1 and reported in this arm.  
Arm type 
Placebo  
Investigational medicinal product name 
Placebo


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Solvent for parenteral use


Routes of administration 
Intraarticular use


Dosage and administration details 
Subjects received single dose of placebo (matched to GZ389988A) IA injection in the knee joint on Day 1. To ensure safety conditions, dosing of each subject was staggered such that only one subject was dosed per day.


Arm title

Part 1: GZ389988A Dose 1  
Arm description 
Subjects received single dose of GZ389988A dose 1 IA injection on Day 1.  
Arm type 
Experimental  
Investigational medicinal product name 
GZ389988A


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Suspension for injection


Routes of administration 
Intraarticular use


Dosage and administration details 
Subjects received single dose of GZ389988A dose 1 IA injection in the knee joint on Day 1. To ensure safety conditions, dosing of each subject was staggered such that only one subject was dosed per day.


Arm title

Part 1: GZ389988A Dose 2  
Arm description 
Subjects received single dose of GZ389988A dose 2 injection on Day 1.  
Arm type 
Experimental  
Investigational medicinal product name 
GZ389988A


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Suspension for injection


Routes of administration 
Intraarticular use


Dosage and administration details 
Subjects received single dose of GZ389988A dose 2 IA injection in the knee joint on Day 1. To ensure safety conditions, dosing of each subject was staggered such that only one subject was dosed per day.


Arm title

Part 1: GZ389988A Dose 3  
Arm description 
Subjects received single dose of GZ389988A dose 3 IA injection on Day 1.  
Arm type 
Experimental  
Investigational medicinal product name 
GZ389988A


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Suspension for injection


Routes of administration 
Intraarticular use


Dosage and administration details 
Subjects received single dose of GZ389988A dose 3 IA injection in the knee joint on Day 1. To ensure safety conditions, dosing of each subject was staggered such that only one subject was dosed per day.


Arm title

Part 1: GZ389988A Dose 4  
Arm description 
Subjects received single dose of GZ389988A dose 4 IA injection on Day 1.  
Arm type 
Experimental  
Investigational medicinal product name 
GZ389988A


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Suspension for injection


Routes of administration 
Intraarticular use


Dosage and administration details 
Subjects received single dose of GZ389988A dose 4 IA injection in the knee joint on Day 1. To ensure safety conditions, dosing of each subject was staggered such that only one subject was dosed per day.


Arm title

Part 1: GZ389988A Dose 5  
Arm description 
Subjects received single dose of GZ389988A dose 5 IA injection on Day 1.  
Arm type 
Experimental  
Investigational medicinal product name 
GZ389988A


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Suspension for injection


Routes of administration 
Intraarticular use


Dosage and administration details 
Subjects received single dose of GZ389988A dose 5 IA injection in the knee joint on Day 1. To ensure safety conditions, dosing of each subject was staggered such that only one subject was dosed per day.


Arm title

Part 2: Placebo  
Arm description 
Subjects received single IA dose of placebo (matched to GZ389988A) injection on Day 1.  
Arm type 
Placebo  
Investigational medicinal product name 
Placebo


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Solvent for parenteral use


Routes of administration 
Intraarticular use


Dosage and administration details 
Subjects received single dose of placebo (matched to GZ389988A) IA injection in the knee joint on Day 1.


Arm title

Part 2: GZ389988A Dose 4 from Part 1  
Arm description 
Subjects received single IA dose of GZ389988A on Day 1 at dose 4 confirmed in Part 1.  
Arm type 
Experimental  
Investigational medicinal product name 
GZ389988A


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Suspension for injection


Routes of administration 
Intraarticular use


Dosage and administration details 
Subjects received single dose of GZ389988A at dose 4 IA injection in the knee joint on Day 1.





Baseline characteristics reporting groups


Reporting group title 
Part 1: Placebo


Reporting group description 
Subjects received single dose of placebo (matched to GZ389988A) IA injection on Day 1. Data was pooled for all subjects who received placebo in Part1 and reported in this arm.  
Reporting group title 
Part 1: GZ389988A Dose 1


Reporting group description 
Subjects received single dose of GZ389988A dose 1 IA injection on Day 1.  
Reporting group title 
Part 1: GZ389988A Dose 2


Reporting group description 
Subjects received single dose of GZ389988A dose 2 injection on Day 1.  
Reporting group title 
Part 1: GZ389988A Dose 3


Reporting group description 
Subjects received single dose of GZ389988A dose 3 IA injection on Day 1.  
Reporting group title 
Part 1: GZ389988A Dose 4


Reporting group description 
Subjects received single dose of GZ389988A dose 4 IA injection on Day 1.  
Reporting group title 
Part 1: GZ389988A Dose 5


Reporting group description 
Subjects received single dose of GZ389988A dose 5 IA injection on Day 1.  
Reporting group title 
Part 2: Placebo


Reporting group description 
Subjects received single IA dose of placebo (matched to GZ389988A) injection on Day 1.  
Reporting group title 
Part 2: GZ389988A Dose 4 from Part 1


Reporting group description 
Subjects received single IA dose of GZ389988A on Day 1 at dose 4 confirmed in Part 1.  



End points reporting groups


Reporting group title 
Part 1: Placebo


Reporting group description 
Subjects received single dose of placebo (matched to GZ389988A) IA injection on Day 1. Data was pooled for all subjects who received placebo in Part1 and reported in this arm.  
Reporting group title 
Part 1: GZ389988A Dose 1


Reporting group description 
Subjects received single dose of GZ389988A dose 1 IA injection on Day 1.  
Reporting group title 
Part 1: GZ389988A Dose 2


Reporting group description 
Subjects received single dose of GZ389988A dose 2 injection on Day 1.  
Reporting group title 
Part 1: GZ389988A Dose 3


Reporting group description 
Subjects received single dose of GZ389988A dose 3 IA injection on Day 1.  
Reporting group title 
Part 1: GZ389988A Dose 4


Reporting group description 
Subjects received single dose of GZ389988A dose 4 IA injection on Day 1.  
Reporting group title 
Part 1: GZ389988A Dose 5


Reporting group description 
Subjects received single dose of GZ389988A dose 5 IA injection on Day 1.  
Reporting group title 
Part 2: Placebo


Reporting group description 
Subjects received single IA dose of placebo (matched to GZ389988A) injection on Day 1.  
Reporting group title 
Part 2: GZ389988A Dose 4 from Part 1


Reporting group description 
Subjects received single IA dose of GZ389988A on Day 1 at dose 4 confirmed in Part 1. 


End point title 
Part 1: Number of Subjects With any TreatmentEmergent Adverse Events (TEAE) ^{[1]} ^{[2]}  
End point description 
Any untoward medical occurrence in a subject who received investigational medicinal product (IMP) was considered an adverse event (AE) without regard to possibility of causal relationship with this treatment. TEAEs: AEs that occurred or worsened during the ontreatment period (time from the first dose of study medication administration up to the end of study [EOS] visit). Analysis was performed on safety population which included all subjects who were exposed to study drug administration.


End point type 
Primary


End point timeframe 
From first dose of GZ389988A administration up to Day 84 (EOS)


Notes [1]  No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Since analysis is descriptive in nature, statistical data could not be provided. [2]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was evaluated for Part 1 only. 



No statistical analyses for this end point 


End point title 
Part 2: Change From Baseline Average Over 4 Weeks (up to Day 28) in Weekly Mean score of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A1 Pain Subscore (Walking Pain) Collected Daily in the Target Knee ^{[3]}  
End point description 
WOMAC index(VAS 3.1):health status measure questionnaire:24questions(Q)of 3subscales:pain(5Q),stiffness(2Q),physical function(17Q).Each Q measured on 0(no pain)100(maximal pain)visual analog scale(VAS).WOMAC A1(measure of pain during walking on flat surface)was part of pain subscale from WOMAC index.Weekly mean score of WOMAC A1,defined as average of daily measurements over the week was calculated for each week.Statistical analysis was done on the change from baseline in weekly mean score calculated for each week.Negative change=improvement.Analysis performed on Modified intenttotreat(mITT)population included all randomized subjects exposed to study treatment,without any major/critical deviations related to diagnosis of primary knee OA or rescue medication other than those allowed,and for whom any WOMAC A1 pain subscore from electronic Diary(eDiary)as measured by the VAS were considered evaluable at baseline,with atleast 1 post baseline assessment after single IA injection.


End point type 
Primary


End point timeframe 
Baseline, Day 1 to 28


Notes [3]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was evaluated for Part 2 only. 



Statistical analysis title 
Over 4 weeks: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0441 ^{[4]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least Squares Mean Difference  
Point estimate 
7.4865


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
14.7065  
upper limit 
0.2665  
Variability estimate 
Standard error of the mean


Dispersion value 
4.3476


Notes [4]  Specified onesided Pvalue. 


End point title 
Part 1: Maximum Plasma Concentration (Cmax) of GZ389988A ^{[5]}  
End point description 
Cmax was defined as maximum plasma concentration of GZ389988A. Analysis was performed on PK population which included all subjects without any major deviations related to study drug administration, and for whom any PK parameters were available.


End point type 
Secondary


End point timeframe 
Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 144, 312, 480, 648, 984, 1320, 1656, and 1992 hours postdose on Day 1


Notes [5]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Subjects treated with placebo were not included in the analysis of PK parameters. 



No statistical analyses for this end point 


End point title 
Part 1: Area Under the PlasmaDrugConcentration Versus Time Curve From Time Zero to Last Quantifiable Concentration (AUClast) of GZ389988A ^{[6]}  
End point description 
AUClast was defined as area under the plasmadrugconcentration versus time curve calculated using the trapezoidal method from time zero to the real time tlast where tlast was the time corresponding to the last concentration above the limit of quantification, Clast. Analysis was performed on PK population.


End point type 
Secondary


End point timeframe 
Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 144, 312, 480, 648, 984, 1320, 1656, and 1992 hours postdose on Day 1


Notes [6]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Subjects treated with placebo were not included in the analysis of PK parameters. 



No statistical analyses for this end point 


End point title 
Part 1: Area Under the PlasmaDrugConcentration Versus Time Curve From Time Zero to Infinity (AUCinf) of GZ389988A ^{[7]}  
End point description 
AUCinf was defined as area under the plasmadrugconcentration versus time curve from time zero extrapolated to infinity. Values with percentage of extrapolation >30% were not reported. Analysis was performed on PK population. Number of subjects analyzed=subjects with available data for this endpoint. Here, 999 represents that SD was not calculated as data was available only for two subjects.


End point type 
Secondary


End point timeframe 
Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 144, 312, 480, 648, 984, 1320, 1656, and 1992 hours postdose on Day 1


Notes [7]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Subjects treated with placebo were not included in the analysis of PK parameters. 



Notes [8]  Since a loglinear terminal phase could not be determined and/or extrapolated area was >30%. 

No statistical analyses for this end point 


End point title 
Part 1: Terminal HalfLife (t1/2z) of GZ389988A ^{[9]}  
End point description 
t1/2z was defined as time measured for the plasma concentration of GZ389988A to decrease by one half. Analysis was performed on PK population. Here, 999 represents that data was not calculated as data was available only for two subjects.


End point type 
Secondary


End point timeframe 
Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 144, 312, 480, 648, 984, 1320, 1656, and 1992 hours postdose on Day 1


Notes [9]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Subjects treated with placebo were not included in the analysis of PK parameters. 



No statistical analyses for this end point 


End point title 
Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of GZ389988A ^{[10]}  
End point description 
Tmax was defined as time to reach Cmax. Analysis was performed on PK population.


End point type 
Secondary


End point timeframe 
Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 144, 312, 480, 648, 984, 1320, 1656, and 1992 hours postdose on Day 1


Notes [10]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Subjects treated with placebo were not included in the analysis of PK parameters. 



No statistical analyses for this end point 


End point title 
Part 1: Apparent Volume of Distribution (Vz/F) of GZ389988A ^{[11]}  
End point description 
Vz/F was defined as apparent terminal phase plasma volume of distribution, and was calculated as: Dose/AUC*λz. Analysis was performed on PK population. Number of subjects analyzed=subjects with available data for this endpoint. Here, 999 represents that data was not calculated as data was available only for two subjects.


End point type 
Secondary


End point timeframe 
Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 144, 312, 480, 648, 984, 1320, 1656, and 1992 hours postdose on Day 1


Notes [11]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Subjects treated with placebo were not included in the analysis of PK parameters. 



Notes [12]  Since loglinear terminal phase could not be determined &/or extrapolated area was >30%. 

No statistical analyses for this end point 


End point title 
Part 1: Apparent Total Body Clearance(CL/F) of GZ389988A ^{[13]}  
End point description 
CL/F was defined as apparent total body clearance of a drug from the plasma, and was calculated as: Dose/AUC. Analysis was performed on PK population. Number of subjects analyzed=subjects with available data for this endpoint. Here, 999 represents that data was not calculated as data was available only for two subjects.


End point type 
Secondary


End point timeframe 
Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 144, 312, 480, 648, 984, 1320, 1656, and 1992 hours postdose on Day 1


Notes [13]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Subjects treated with placebo were not included in the analysis of PK parameters. 



Notes [14]  Since loglinear terminal phase could not be determined &/or extrapolated area was >30%. 

No statistical analyses for this end point 


End point title 
Part 1: Synovial Fluid Concentrations of GZ389988A ^{[15]}  
End point description 
Analysis was performed on PK population. Number of subjects analyzed=subjects with available data for this endpoint. Here 'n' signifies number of subjects with available data for specified category for each arm respectively. 9999 represents that data was not calculated as data was below lower limit of quantification (0.1 ng/mL). 999 represents standard deviation could not be calculated due to single evaluable subject.


End point type 
Secondary


End point timeframe 
Predose, at anytime on Day 28 and Day 84


Notes [15]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Synovial fluid concentrations were only collected for subjects who received placebo, GZ389988A Dose 4 and Dose 5. 



No statistical analyses for this end point 


End point title 
Part 1: Change from Baseline in WOMAC Total Score at Day 7, 14, 21, 28, 42, 56, 70 and 84 ^{[16]}  
End point description 
WOMAC index is health status measure questionnaire of twentyfour questions comprising of 3 subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question was measured on a 100millimeter (mm) visual analogue scale (VAS) ranging from 0=no pain to 100=maximal pain. Total score was sum of the 3 subscale scores, giving total score range of 0 to 2400 mm where higher scores indicated higher level of pain, stiffness and physical function. The change from baseline in WOMAC total score was calculated at each specified visit (Day 7, 14, 21, 28, 42, 56, 70, and 84). Analysis was performed on PD population which included all subjects without any major/critical deviations or AEs that would impact the PD response, and for whom any WOMAC subscores as measured by the 100mm VAS were considered evaluable at baseline and at least 1 postbaseline measurements.


End point type 
Secondary


End point timeframe 
Baseline, Day 7, 14, 21, 28, 42, 56, 70 and 84


Notes [16]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was evaluated for Part 1 only. 



No statistical analyses for this end point 


End point title 
Part 1: Change From Baseline in WOMAC Pain Subscore at Day 7, 14, 21, 28, 42, 56, 70 and 84 ^{[17]}  
End point description 
WOMAC index is health status measure questionnaire of twentyfour questions comprising of 3 subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question was measured on a 100mm VAS ranging from 0=no pain to 100=maximal pain. WOMAC pain subscore was sum of 5 questions with score ranging from 0 to 500 mm, where higher score indicated higher level of pain. The change from baseline in WOMAC pain subscore was calculated at each specified visit (Day 7, 14, 21, 28, 42, 56, 70, and 84). Analysis was performed on PD population.


End point type 
Secondary


End point timeframe 
Baseline, Day 7, 14, 21, 28, 42, 56, 70 and 84


Notes [17]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was evaluated for Part 1 only. 



No statistical analyses for this end point 


End point title 
Part 1: Change From Baseline in WOMAC A1 Subscore (Walking Pain) at Day 7, 14, 21, 28, 42, 56, 70 and 84 ^{[18]}  
End point description 
WOMAC A1 (measure of pain during walking on a flat surface) was part of the pain subscale (question 1) from the WOMAC index. WOMAC A1 was measured on a 100 mm VAS ranging from 0 to 100, where higher score indicated the higher level of pain. The change from baseline in WOMAC A1 subscore was calculated at each specified visit (Day 7, 14, 21, 28, 42, 56, 70, and 84). Analysis was performed on PD population.


End point type 
Secondary


End point timeframe 
Baseline, Day 7, 14, 21, 28, 42, 56, 70 and 84


Notes [18]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was evaluated for Part 1 only. 



Statistical analysis title 
Up to Day 28: GZ389988A Dose 1 vs Placebo  
Statistical analysis description 
Analysis was performed using linear mixed effect model with corresponding baseline as covariate and dose, week, weekbydose interaction and gender as fixed effects.


Comparison groups 
Part 1: GZ389988A Dose 1 v Part 1: Placebo


Number of subjects included in analysis 
10


Analysis specification 
Prespecified


Analysis type 
superiority  
Method 

Parameter type 
Least squares mean difference  
Point estimate 
11.9984


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
22.6588  
upper limit 
46.6557  
Statistical analysis title 
Up to Day 28: GZ389988A Dose 2 vs Placebo  
Statistical analysis description 
Analysis was performed using linear mixed effect model with corresponding baseline as covariate and dose, week, weekbydose interaction and gender as fixed effects.


Comparison groups 
Part 1: GZ389988A Dose 2 v Part 1: Placebo


Number of subjects included in analysis 
10


Analysis specification 
Prespecified


Analysis type 
superiority  
Method 

Parameter type 
Least squares mean difference  
Point estimate 
24.1031


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
11.8636  
upper limit 
60.0698  
Statistical analysis title 
Up to Day 28: GZ389988A Dose 3 vs Placebo  
Statistical analysis description 
Analysis was performed using linear mixed effect model with corresponding baseline as covariate and dose, week, weekbydose interaction and gender as fixed effects.


Comparison groups 
Part 1: GZ389988A Dose 3 v Part 1: Placebo


Number of subjects included in analysis 
13


Analysis specification 
Prespecified


Analysis type 
superiority  
Method 

Parameter type 
Least squares mean difference  
Point estimate 
19.0405


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
46.943  
upper limit 
8.8621  
Statistical analysis title 
Up to Day 28: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
Analysis was performed using linear mixed effect model with corresponding baseline as covariate and dose, week, weekbydose interaction and gender as fixed effects.


Comparison groups 
Part 1: GZ389988A Dose 4 v Part 1: Placebo


Number of subjects included in analysis 
13


Analysis specification 
Prespecified


Analysis type 
superiority  
Method 

Parameter type 
Least squares mean difference  
Point estimate 
4.6515


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
23.6359  
upper limit 
32.939  
Statistical analysis title 
Up to Day 28: GZ389988A Dose 5 vs Placebo  
Statistical analysis description 
Analysis was performed using linear mixed effect model with corresponding baseline as covariate and dose, week, weekbydose interaction and gender as fixed effects.


Comparison groups 
Part 1: GZ389988A Dose 5 v Part 1: Placebo


Number of subjects included in analysis 
9


Analysis specification 
Prespecified


Analysis type 
superiority  
Method 

Parameter type 
Least squares mean difference  
Point estimate 
4.069


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
46.0989  
upper limit 
37.9609  
Statistical analysis title 
Up to Day 84: GZ389988A Dose 1 vs Placebo  
Statistical analysis description 
Analysis was performed using linear mixed effect model with corresponding baseline as covariate and dose, week, weekbydose interaction and gender as fixed effects.


Comparison groups 
Part 1: GZ389988A Dose 1 v Part 1: Placebo


Number of subjects included in analysis 
10


Analysis specification 
Prespecified


Analysis type 
superiority  
Method 

Parameter type 
Least squares mean difference  
Point estimate 
13.5698


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
20.9287  
upper limit 
48.0684  
Statistical analysis title 
Up to Day 84: GZ389988A Dose 2 vs Placebo  
Statistical analysis description 
Analysis was performed using linear mixed effect model with corresponding baseline as covariate and dose, week, weekbydose interaction and gender as fixed effects.


Comparison groups 
Part 1: GZ389988A Dose 2 v Part 1: Placebo


Number of subjects included in analysis 
10


Analysis specification 
Prespecified


Analysis type 
superiority  
Method 

Parameter type 
Least squares mean difference  
Point estimate 
22.9246


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
12.8893  
upper limit 
58.7384  
Statistical analysis title 
Up to Day 84: GZ389988A Dose 3 vs Placebo  
Statistical analysis description 
Analysis was performed using linear mixed effect model with corresponding baseline as covariate and dose, week, weekbydose interaction and gender as fixed effects.


Comparison groups 
Part 1: GZ389988A Dose 3 v Part 1: Placebo


Number of subjects included in analysis 
13


Analysis specification 
Prespecified


Analysis type 
superiority  
Method 

Parameter type 
Least squares mean difference  
Point estimate 
15.5315


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
43.306  
upper limit 
12.2429  
Statistical analysis title 
Up to Day 84: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
Analysis was performed using linear mixed effect model with corresponding baseline as covariate and dose, week, weekbydose interaction and gender as fixed effects.


Comparison groups 
Part 1: GZ389988A Dose 4 v Part 1: Placebo


Number of subjects included in analysis 
13


Analysis specification 
Prespecified


Analysis type 
superiority  
Method 

Parameter type 
Least squares mean difference  
Point estimate 
3.8271


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
24.334  
upper limit 
31.9882  
Statistical analysis title 
Up to Day 84: GZ389988A Dose 5 vs Placebo  
Statistical analysis description 
Analysis was performed using linear mixed effect model with corresponding baseline as covariate and dose, week, weekbydose interaction and gender as fixed effects.


Comparison groups 
Part 1: GZ389988A Dose 5 v Part 1: Placebo


Number of subjects included in analysis 
9


Analysis specification 
Prespecified


Analysis type 
superiority  
Method 

Parameter type 
Least squares mean difference  
Point estimate 
3.0649


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
38.7884  
upper limit 
44.9183 


End point title 
Part 1: Change From Baseline in WOMAC Stiffness Subscore at Day 7, 14, 21, 28, 42, 56, 70 and 84 ^{[19]}  
End point description 
WOMAC index is health status measure questionnaire of twentyfour questions comprising 3 subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question was measured on a 100mm VAS ranging from 0=no pain to 100=maximal pain. Stiffness was defined as a sensation of decreased ease of movement in the index joint. WOMAC stiffness subscore was sum of 2
questions with score ranging from 0 to 200 mm, where higher score indicated higher level of stiffness. The change from baseline in WOMAC stiffness subscore was calculated at each specified visit (Day 7, 14, 21, 28, 42, 56, 70, and 84). Analysis was performed on PD population.


End point type 
Secondary


End point timeframe 
Baseline, Day 7, 14, 21, 28, 42, 56, 70 and 84


Notes [19]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was evaluated for Part 1 only. 



No statistical analyses for this end point 


End point title 
Part 1: Change From Baseline in WOMAC Physical Function Subscore at Day 7, 14, 21, 28, 42, 56, 70 and 84 ^{[20]}  
End point description 
WOMAC index is health status measure questionnaire of twentyfour questions comprising of 3 subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question was measured on a 100mm VAS ranging from 0=no pain to 100=maximal pain. WOMAC physical function subscore was sum of 17 questions with score ranging from 0 to 1700 mm, where higher score indicated higher level of physical function. The change from baseline in WOMAC physical subscore was calculated at each specified visit (Day 7, 14, 21, 28, 42, 56, 70, and 84). Analysis was performed on PD population.


End point type 
Secondary


End point timeframe 
Baseline, Day 7, 14, 21, 28, 42, 56, 70 and 84


Notes [20]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was evaluated for Part 1 only. 



No statistical analyses for this end point 


End point title 
Part 2: Change From Baseline Average Over 12 Weeks (up to Day 84) in Weekly Mean score of WOMAC A1 Pain Subscore (Walking Pain) Collected Daily in the Target Knee ^{[21]}  
End point description 
WOMAC A1 (Question 1 of the pain subscale of WOMAC index) was used to measure the amount of pain in the target knee while walking on a flat surface during last 24 hours. It was measured daily on a 0100 VAS ranging from 0=no pain to 100=maximal pain, where higher score indicated the higher intensity of pain. The weekly mean score of WOMAC A1 pain subscore, defined as average of daily measurements over the week were calculated for each week. The statistical analysis was done on the change from baseline score calculated at each week. Analysis was performed on mITT population.


End point type 
Secondary


End point timeframe 
Baseline, Days 1 to 84


Notes [21]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was evaluated for Part 2 only. 



Statistical analysis title 
Over 12 weeks: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0636 ^{[22]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
6.7807


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
14.1019  
upper limit 
0.5405  
Variability estimate 
Standard error of the mean


Dispersion value 
4.4096


Notes [22]  Specified onesided Pvalue. 


End point title 
Part2:Change From Baseline Average Over Days 1to7(1 Week),1to14(2 Weeks),1to21(3 Weeks),1to42(6 Weeks),1to56(8 Weeks), and 1to70(10 Weeks) in Weekly Mean Score of WOMAC A1 Pain Subscore (Walking Pain) Collected Daily in the Target Knee ^{[23]}  
End point description 
WOMAC A1 (Question 1 of the pain subscale of WOMAC index) was used to measure the amount of pain in the target knee while walking on a flat surface during last 24 hours. It was measured daily on a 0100 VAS ranging from 0=no pain to 100=maximal pain, where higher score indicated the higher intensity of pain. The weekly mean score of WOMAC A1 pain subscore, defined as average of daily measurements over the week were calculated for each week. The statistical analysis was done on the change from baseline score calculated at each week. Analysis was performed on mITT population.


End point type 
Secondary


End point timeframe 
Baseline, Days 1 to 7, 1 to 14, 1 to 21, 1 to 42, 1 to 56, and 1 to 70


Notes [23]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was evaluated for Part 2 only. 



Statistical analysis title 
Over Days 1 to 7: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.4133 ^{[24]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
1.0488


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
8.9906  
upper limit 
6.8929  
Variability estimate 
Standard error of the mean


Dispersion value 
4.7714


Notes [24]  Specified onesided Pvalue. 

Statistical analysis title 
Over Days 1 to 14: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1062 ^{[25]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
5.7737


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.4134  
upper limit 
1.866  
Variability estimate 
Standard error of the mean


Dispersion value 
4.5975


Notes [25]  Specified onesided Pvalue. 

Statistical analysis title 
Over Days 1 to 21: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0638 ^{[26]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
6.7766


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
14.1001  
upper limit 
0.5469  
Variability estimate 
Standard error of the mean


Dispersion value 
4.4092


Notes [26]  Specified onesided Pvalue. 

Statistical analysis title 
Over Days 1 to 42: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0412 ^{[27]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
7.5751


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
14.7424  
upper limit 
0.4079  
Variability estimate 
Standard error of the mean


Dispersion value 
4.3167


Notes [27]  Specified onesided Pvalue. 

Statistical analysis title 
Over Days 1 to 56: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0489 ^{[28]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
7.2329


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
14.4193  
upper limit 
0.0464  
Variability estimate 
Standard error of the mean


Dispersion value 
4.3284


Notes [28]  Specified onesided Pvalue. 

Statistical analysis title 
Over Days 1 to 70: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0546 ^{[29]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
7.0565


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
14.3054  
upper limit 
0.1923  
Variability estimate 
Standard error of the mean


Dispersion value 
4.366


Notes [29]  Specified onesided Pvalue. 


End point title 
Part2:Change From Baseline at Day 7(Week 1),14(Week 2),21(Week 3),28(Week 4),35(Week 5),42(Week 6),49(Week 7),56(Week 8),63(Week 9),70(Week 10),77(Week 11) and 84(Week 12) in Weekly Mean WOMAC A1 Pain Subscore (Walking Pain) Collected Daily in Target Knee ^{[30]}  
End point description 
WOMAC A1 (Question 1 of the pain subscale of WOMAC index) was used to measure the amount of pain in the target knee while walking on a flat surface during last 24 hours. It was measured daily on a 0100 VAS ranging from 0=no pain to 100=maximal pain, where higher score indicated the higher intensity of pain. The weekly mean score of WOMAC A1 pain subscore, defined as average of daily measurements over the week were calculated for each week. The statistical analysis was done on the change from baseline score calculated at each week. Analysis was performed on mITT population. Here, “Number analyzed”(n)=number of subjects with available data at specified time point for each dose respectively.


End point type 
Secondary


End point timeframe 
Baseline, Day 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, and 84


Notes [30]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was evaluated for Part 2 only. 



Statistical analysis title 
At Day 7: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.4133 ^{[31]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
1.0488


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
8.9906  
upper limit 
6.8929  
Variability estimate 
Standard error of the mean


Dispersion value 
4.7714


Notes [31]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 14: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.016 ^{[32]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
10.4986


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
18.5104  
upper limit 
2.4867  
Variability estimate 
Standard error of the mean


Dispersion value 
4.8241


Notes [32]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 21: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0247 ^{[33]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
8.7824


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
16.1122  
upper limit 
1.4527  
Variability estimate 
Standard error of the mean


Dispersion value 
4.4159


Notes [33]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 28: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0185 ^{[34]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
9.6161


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
17.1703  
upper limit 
2.062  
Variability estimate 
Standard error of the mean


Dispersion value 
4.5517


Notes [34]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 35: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0308 ^{[35]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
8.5393


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
16.0423  
upper limit 
1.0363  
Variability estimate 
Standard error of the mean


Dispersion value 
4.5216


Notes [35]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 42: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.074 ^{[36]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
6.9655


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
14.8971  
upper limit 
0.9661  
Variability estimate 
Standard error of the mean


Dispersion value 
4.78


Notes [36]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 49: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0901 ^{[37]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
6.4318


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
14.3434  
upper limit 
1.4798  
Variability estimate 
Standard error of the mean


Dispersion value 
4.7678


Notes [37]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 56: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1064 ^{[38]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
5.9804


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.8986  
upper limit 
1.9379  
Variability estimate 
Standard error of the mean


Dispersion value 
4.7717


Notes [38]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 63: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1127 ^{[39]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
6.005


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
14.1785  
upper limit 
2.1685  
Variability estimate 
Standard error of the mean


Dispersion value 
4.9253


Notes [39]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 70: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0895 ^{[40]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
6.6973


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
14.9124  
upper limit 
1.5179  
Variability estimate 
Standard error of the mean


Dispersion value 
4.9504


Notes [40]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 77: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1227 ^{[41]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
5.8185


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
14.0838  
upper limit 
2.4468  
Variability estimate 
Standard error of the mean


Dispersion value 
4.9805


Notes [41]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 84: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1674 ^{[42]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.9849


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.5217  
upper limit 
3.5519  
Variability estimate 
Standard error of the mean


Dispersion value 
5.144


Notes [42]  Specified onesided Pvalue. 


End point title 
Part2:Change From Baseline Average Over Days 1to7(1 Week),1to14(2 Weeks),1to21(3 Weeks), 1to28(4 Weeks),1to42(6 Weeks),1to56(8 Weeks),1to70(10 Weeks) and 1to84(12 Weeks) in Weekly Mean Overall Knee Pain Scores Collected Daily in Target Knee ^{[43]}  
End point description 
Overall knee pain was measured daily in target knee on a 0100 VAS ranging from 0=no pain to 100=maximal pain, where higher score indicated the higher level of pain. The weekly mean score of overall Knee pain score, defined as average of daily measurements over the week were calculated for each week. The statistical analysis was done on the change from baseline score calculated at each week. Analysis was performed on mITT population.


End point type 
Secondary


End point timeframe 
Baseline, Days 1 to 7, 1 to 14, 1 to 21, 1 to 28, 1 to 42, 1 to 56, 1 to 70, and 1 to 84


Notes [43]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was evaluated for Part 2 only. 



Statistical analysis title 
Over Days 1 to 7: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.4278 ^{[44]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
0.8672


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
8.7645  
upper limit 
7.0301  
Variability estimate 
Standard error of the mean


Dispersion value 
4.7477


Notes [44]  Specified onesided Pvalue. 

Statistical analysis title 
Over Days 1 to 14: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1371 ^{[45]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
5.1538


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
12.9374  
upper limit 
2.6299  
Variability estimate 
Standard error of the mean


Dispersion value 
4.686


Notes [45]  Specified onesided Pvalue. 

Statistical analysis title 
Over Days 1 to 21: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0974 ^{[46]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
5.9658


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.554  
upper limit 
1.6224  
Variability estimate 
Standard error of the mean


Dispersion value 
4.5699


Notes [46]  Specified onesided Pvalue. 

Statistical analysis title 
Over Days 1 to 28: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0665 ^{[47]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
6.8641


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
14.3885  
upper limit 
0.6603  
Variability estimate 
Standard error of the mean


Dispersion value 
4.5319


Notes [47]  Specified onesided Pvalue. 

Statistical analysis title 
Over Days 1 to 42: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0597 ^{[48]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
7.0995


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
14.6032  
upper limit 
0.4041  
Variability estimate 
Standard error of the mean


Dispersion value 
4.5199


Notes [48]  Specified onesided Pvalue. 

Statistical analysis title 
Over Days 1 to 56: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0736 ^{[49]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
6.6255


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
14.1561  
upper limit 
0.9051  
Variability estimate 
Standard error of the mean


Dispersion value 
4.5362


Notes [49]  Specified onesided Pvalue. 

Statistical analysis title 
Over Days 1 to 70: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0859 ^{[50]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
6.3097


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.9222  
upper limit 
1.3027  
Variability estimate 
Standard error of the mean


Dispersion value 
4.5856


Notes [50]  Specified onesided Pvalue. 

Statistical analysis title 
Over Days 1 to 84: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0957 ^{[51]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
6.0927


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.7823  
upper limit 
1.5969  
Variability estimate 
Standard error of the mean


Dispersion value 
4.6321


Notes [51]  Specified onesided Pvalue. 


End point title 
Part2:Change From Baseline at Day 7(Week 1),14(Week 2),21(Week 3),28(Week 4),35(Week 5),42(Week 6),49(Week 7),56(Week 8),63(Week 9),70(Week 10),77(Week 11) and 84(Week 12) in Weekly Mean Score of Overall Knee Pain Collected Daily ^{[52]}  
End point description 
Overall knee pain was measured daily on a 0100 VAS ranging from 0=no pain to 100=maximal pain, where higher score indicated the higher level of pain. The weekly mean score of Overall knee pain, defined as average of daily measurements over the week were calculated for each week. The statistical analysis was done on the change from baseline score calculated at each week. Analysis was performed on mITT population. Here, “n”= number of subjects with available data at specified time point.


End point type 
Secondary


End point timeframe 
Baseline, Day 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, and 84


Notes [52]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was evaluated for Part 2 only. 



Statistical analysis title 
At Day 7: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.4278 ^{[53]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
0.8672


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
8.7645  
upper limit 
7.0301  
Variability estimate 
Standard error of the mean


Dispersion value 
4.7477


Notes [53]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 14: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0315 ^{[54]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
9.4404


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
17.7768  
upper limit 
1.1039  
Variability estimate 
Standard error of the mean


Dispersion value 
5.0205


Notes [54]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 21: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0559 ^{[55]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
7.5898


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
15.442  
upper limit 
0.2623  
Variability estimate 
Standard error of the mean


Dispersion value 
4.7309


Notes [55]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 28: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0249 ^{[56]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
9.559


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
17.5526  
upper limit 
1.5655  
Variability estimate 
Standard error of the mean


Dispersion value 
4.8167


Notes [56]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 35: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0354 ^{[57]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
8.7348


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
16.6783  
upper limit 
0.7912  
Variability estimate 
Standard error of the mean


Dispersion value 
4.7869


Notes [57]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 42: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1022 ^{[58]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
6.4061


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
14.7298  
upper limit 
1.9176  
Variability estimate 
Standard error of the mean


Dispersion value 
5.0162


Notes [58]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 49: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1331 ^{[59]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
5.5676


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.8315  
upper limit 
2.6962  
Variability estimate 
Standard error of the mean


Dispersion value 
4.9802


Notes [59]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 56: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1686 ^{[60]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.8392


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.169  
upper limit 
3.4906  
Variability estimate 
Standard error of the mean


Dispersion value 
5.02


Notes [60]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 63: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1853 ^{[61]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.6959


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.3618  
upper limit 
3.9701  
Variability estimate 
Standard error of the mean


Dispersion value 
5.2226


Notes [61]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 70: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1514 ^{[62]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
5.3973


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
14.0448  
upper limit 
3.2501  
Variability estimate 
Standard error of the mean


Dispersion value 
5.2113


Notes [62]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 77: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1634 ^{[63]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
5.187


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.925  
upper limit 
3.551  
Variability estimate 
Standard error of the mean


Dispersion value 
5.2659


Notes [63]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 84: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1845 ^{[64]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.8286


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.7105  
upper limit 
4.0534  
Variability estimate 
Standard error of the mean


Dispersion value 
5.3526


Notes [64]  Specified onesided Pvalue. 


End point title 
Part 2: Change From Baseline Average Over Days 1to7(1 Week),1to14(2 Weeks),1to21(3 Weeks), 1to28(4 Weeks),1to42(6 Weeks),1to56(8 Weeks),1to70(10 Weeks) and 1to84(12 Weeks) in WOMAC A1 Pain Subscore (Walking Pain) Over Last 48 Hours (hrs) at Each Visit ^{[65]}  
End point description 
WOMAC A1 (Question 1 of the pain subscale of WOMAC index) was used to measure the amount of pain in the target knee while walking on a flat surface during last 48 hours. It was measured daily on a 0100 VAS ranging from 0=no pain to 100=maximal pain, where higher score indicated the higher intensity of pain. The statistical analysis was done on the change from baseline score (calculated as average of daily measurements over the week) for each week. Analysis was performed on mITT population.


End point type 
Secondary


End point timeframe 
Baseline, Days 1 to 7, 1 to 14, 1 to 21, 1 to 28, 1 to 42, 1 to 56, 1 to 70, and 1 to 84


Notes [65]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was evaluated for Part 2 only. 



Statistical analysis title 
Over Days 1 to 7: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1572 ^{[66]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
5.0039


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.2235  
upper limit 
3.2156  
Variability estimate 
Standard error of the mean


Dispersion value 
4.9481


Notes [66]  Specified onesided Pvalue. 

Statistical analysis title 
Over Days 1 to 14: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1166 ^{[67]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
5.6819


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.5459  
upper limit 
2.1821  
Variability estimate 
Standard error of the mean


Dispersion value 
4.7369


Notes [67]  Specified onesided Pvalue. 

Statistical analysis title 
Over Days 1 to 21: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0951 ^{[68]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
6.1021


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.7836  
upper limit 
1.5795  
Variability estimate 
Standard error of the mean


Dispersion value 
4.6273


Notes [68]  Specified onesided Pvalue. 

Statistical analysis title 
Over Days 1 to 28: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0893 ^{[69]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
6.229


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.8622  
upper limit 
1.4042  
Variability estimate 
Standard error of the mean


Dispersion value 
4.5981


Notes [69]  Specified onesided Pvalue. 

Statistical analysis title 
Over Days 1 to 42: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1044 ^{[70]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
5.8475


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.5218  
upper limit 
1.8268  
Variability estimate 
Standard error of the mean


Dispersion value 
4.6229


Notes [70]  Specified onesided Pvalue. 

Statistical analysis title 
Over Days 1 to 56: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1194 ^{[71]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
5.4778


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.1512  
upper limit 
2.1956  
Variability estimate 
Standard error of the mean


Dispersion value 
4.6222


Notes [71]  Specified onesided Pvalue. 

Statistical analysis title 
Over Days 1 to 70: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.126 ^{[72]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
5.3373


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.0285  
upper limit 
2.3538  
Variability estimate 
Standard error of the mean


Dispersion value 
4.6328


Notes [72]  Specified onesided Pvalue. 

Statistical analysis title 
Over Days 1 to 84: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1386 ^{[73]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
5.1214


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
12.9041  
upper limit 
2.6613  
Variability estimate 
Standard error of the mean


Dispersion value 
4.6879


Notes [73]  Specified onesided Pvalue. 


End point title 
Part2:Change From Baseline in WOMAC A1 Pain Subscore (Walking Pain) at Days 7(Week 1),14(Week 2),21(Week 3),28(Week 4),42(Week 6),56(Week 8),70(Week 10) and 84(Week 12) as Measured by the VAS 0100 Over the Last 48 Hours at Each Visit ^{[74]}  
End point description 
WOMAC A1 (Question 1 of the pain subscale of WOMAC index) was used to measure the amount of pain in the target knee while walking on a flat surface during last 48 hours. It was measured daily on a 0100 VAS ranging from 0=no pain to 100=maximal pain, where higher score indicated the higher intensity of pain. The change from baseline in WOMAC A1 Pain subscore was calculated at each specified visit (Day 7, 14, 21, 28, 42, 56, 70, and 84). Analysis was performed on mITT population. Here, “n” = number of subjects with available data at specified timepoints.


End point type 
Secondary


End point timeframe 
Baseline, Day 7, 14, 21, 28, 42, 56, 70, and 84


Notes [74]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was evaluated for Part 2 only. 



Statistical analysis title 
At Day 7: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1572 ^{[75]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
5.0039


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.2235  
upper limit 
3.2156  
Variability estimate 
Standard error of the mean


Dispersion value 
4.9481


Notes [75]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 14: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1052 ^{[76]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
6.3599


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
14.7348  
upper limit 
2.015  
Variability estimate 
Standard error of the mean


Dispersion value 
5.0453


Notes [76]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 21: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0811 ^{[77]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
6.9424


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
15.1275  
upper limit 
1.2426  
Variability estimate 
Standard error of the mean


Dispersion value 
4.9325


Notes [77]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 28: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0964 ^{[78]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
6.6099


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
14.9774  
upper limit 
1.7575  
Variability estimate 
Standard error of the mean


Dispersion value 
5.0425


Notes [78]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 42: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.2073 ^{[79]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.3214


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.0767  
upper limit 
4.4338  
Variability estimate 
Standard error of the mean


Dispersion value 
5.2765


Notes [79]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 56: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.2419 ^{[80]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
3.6291


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
12.201  
upper limit 
4.9428  
Variability estimate 
Standard error of the mean


Dispersion value 
5.1657


Notes [80]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 70: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1971 ^{[81]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.4945


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.2108  
upper limit 
4.2217  
Variability estimate 
Standard error of the mean


Dispersion value 
5.2526


Notes [81]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 84: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.263 ^{[82]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
3.6099


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.0243  
upper limit 
5.8045  
Variability estimate 
Standard error of the mean


Dispersion value 
5.6726


Notes [82]  Specified onesided Pvalue. 


End point title 
Part2:Change From Baseline Average Over Days1to7(1Week),1to14(2Weeks),1to21(3Weeks), 1to28(4Weeks),1to42(6Weeks),1to56(8Weeks),1to70(10Weeks),1to84(12Weeks)in WOMAC Index total,Pain,Stiffness,Physical Function Subscale Scores Over Last 48hrs at Each Visit ^{[83]}  
End point description 
WOMAC index is health status measure questionnaire of twentyfour questions comprising of 3 subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question was measured on a 0100 VAS ranging from 0=minimum to 100=maximum during last 48 hours. Higher score= higher intensity of pain, worse physical function and higher level of stiffness respectively. A total WOMAC index score and a WOMAC subscore for each dimension were calculated as an average of each item concerned. The statistical analysis was done on the change from baseline score (calculated as average of daily measurements over the week), for each week. Analysis was performed on mITT population.


End point type 
Secondary


End point timeframe 
Baseline, Days 1 to 7, 1 to 14, 1 to 21 , 1 to 28, 1 to 42, 1 to 56, 1 to 70, and 1 to 84


Notes [83]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was evaluated for Part 2 only. 



Statistical analysis title 
Days1 to 7:WOMAC indexGZ389988A Dose4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.3059 ^{[84]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
2.3186


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
9.8826  
upper limit 
5.2454  
Variability estimate 
Standard error of the mean


Dispersion value 
4.5517


Notes [84]  Specified onesided Pvalue. 

Statistical analysis title 
Days1to14:WOMAC indexGZ389988A Dose4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1743 ^{[85]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
3.8525


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
10.6463  
upper limit 
2.9413  
Variability estimate 
Standard error of the mean


Dispersion value 
4.0913


Notes [85]  Specified onesided Pvalue. 

Statistical analysis title 
Days1to21:WOMAC indexGZ389988A Dose4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1121 ^{[86]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.8151


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
11.3523  
upper limit 
1.7221  
Variability estimate 
Standard error of the mean


Dispersion value 
3.9374


Notes [86]  Specified onesided Pvalue. 

Statistical analysis title 
Days1to28:WOMAC indexGZ389988A Dose4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0915 ^{[87]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
5.246


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
11.7414  
upper limit 
1.2494  
Variability estimate 
Standard error of the mean


Dispersion value 
3.9124


Notes [87]  Specified onesided Pvalue. 

Statistical analysis title 
Days1to42:WOMAC indexGZ389988A Dose4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0961 ^{[88]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
5.1574


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
11.6798  
upper limit 
1.365  
Variability estimate 
Standard error of the mean


Dispersion value 
3.9286


Notes [88]  Specified onesided Pvalue. 

Statistical analysis title 
Days1to56:WOMAC indexGZ389988A Dose4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1037 ^{[89]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.9987


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
11.5389  
upper limit 
1.5414  
Variability estimate 
Standard error of the mean


Dispersion value 
3.9393


Notes [89]  Specified onesided Pvalue. 

Statistical analysis title 
Days1to70:WOMAC indexGZ389988A Dose4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.107 ^{[90]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.9427


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
11.5054  
upper limit 
1.62  
Variability estimate 
Standard error of the mean


Dispersion value 
3.9528


Notes [90]  Specified onesided Pvalue. 

Statistical analysis title 
Days1to84:WOMAC indexGZ389988A Dose4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1152 ^{[91]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.8086


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
11.4247  
upper limit 
1.8076  
Variability estimate 
Standard error of the mean


Dispersion value 
3.9849


Notes [91]  Specified onesided Pvalue. 

Statistical analysis title 
Days1to7:WOMAC painGZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1446 ^{[92]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.9447


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
12.6514  
upper limit 
2.762  
Variability estimate 
Standard error of the mean


Dispersion value 
4.6389


Notes [92]  Specified onesided Pvalue. 

Statistical analysis title 
Days1to14:WOMAC painGZ389988A Dose4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0694 ^{[93]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
6.31


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.3288  
upper limit 
0.7089  
Variability estimate 
Standard error of the mean


Dispersion value 
4.2274


Notes [93]  Specified onesided Pvalue. 

Statistical analysis title 
Days1to21:WOMAC painGZ389988A Dose4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0517 ^{[94]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
6.8205


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.7103  
upper limit 
0.0692  
Variability estimate 
Standard error of the mean


Dispersion value 
4.15


Notes [94]  Specified onesided Pvalue. 

Statistical analysis title 
Days1to28:WOMAC painGZ389988A Dose4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0433 ^{[95]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
7.1525


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
14.0125  
upper limit 
0.2924  
Variability estimate 
Standard error of the mean


Dispersion value 
4.1321


Notes [95]  Specified onesided Pvalue. 

Statistical analysis title 
Days1to42:WOMAC painGZ389988A Dose4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0518 ^{[96]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
6.8339


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.7423  
upper limit 
0.0745  
Variability estimate 
Standard error of the mean


Dispersion value 
4.1612


Notes [96]  Specified onesided Pvalue. 

Statistical analysis title 
Days1to56:WOMAC painGZ389988A Dose4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0601 ^{[97]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
6.5504


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.4896  
upper limit 
0.3888  
Variability estimate 
Standard error of the mean


Dispersion value 
4.1796


Notes [97]  Specified onesided Pvalue. 

Statistical analysis title 
Days1to70:WOMAC painGZ389988A Dose4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0646 ^{[98]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
6.421


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.3882  
upper limit 
0.5461  
Variability estimate 
Standard error of the mean


Dispersion value 
4.1964


Notes [98]  Specified onesided Pvalue. 

Statistical analysis title 
Days1to84:WOMAC painGZ389988A Dose4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0701 ^{[99]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
6.3033


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.3433  
upper limit 
0.7368  
Variability estimate 
Standard error of the mean


Dispersion value 
4.2402


Notes [99]  Specified onesided Pvalue. 

Statistical analysis title 
Days1to7:WOMAC stiffnessGZ389988A Dose4vsPlacebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.2799  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
2.6283


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
10.0893  
upper limit 
4.8328  
Variability estimate 
Standard error of the mean


Dispersion value 
4.4902


Statistical analysis title 
Day1to14:WOMAC stiffnessGZ389988A Dose4vsPlacebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.169 ^{[100]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
3.9332


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
10.7165  
upper limit 
2.8502  
Variability estimate 
Standard error of the mean


Dispersion value 
4.0855


Notes [100]  Specified onesided Pvalue. 

Statistical analysis title 
Day1to21:WOMAC stiffnessGZ389988A Dose4vsPlacebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1402 ^{[101]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.3027


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
10.8849  
upper limit 
2.2795  
Variability estimate 
Standard error of the mean


Dispersion value 
3.9648


Notes [101]  Specified onesided Pvalue. 

Statistical analysis title 
Day1to28:WOMAC stiffnessGZ389988A Dose4vsPlacebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1374 ^{[102]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.277


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
10.7429  
upper limit 
2.189  
Variability estimate 
Standard error of the mean


Dispersion value 
3.8948


Notes [102]  Specified onesided Pvalue. 

Statistical analysis title 
Day1to42:WOMAC stiffnessGZ389988A Dose4vsPlacebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1513 ^{[103]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.048


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
10.5339  
upper limit 
2.4379  
Variability estimate 
Standard error of the mean


Dispersion value 
3.9068


Notes [103]  Specified onesided Pvalue. 

Statistical analysis title 
Day1to56:WOMAC stiffnessGZ389988A Dose4vsPlacebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1756 ^{[104]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
3.6711


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
10.1782  
upper limit 
2.8361  
Variability estimate 
Standard error of the mean


Dispersion value 
3.9195


Notes [104]  Specified onesided Pvalue. 

Statistical analysis title 
Day1to70:WOMAC stiffnessGZ389988A Dose4vsPlacebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1948 ^{[105]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
3.4073


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
9.9535  
upper limit 
3.139  
Variability estimate 
Standard error of the mean


Dispersion value 
3.9429


Notes [105]  Specified onesided Pvalue. 

Statistical analysis title 
Day1to84:WOMAC stiffnessGZ389988A Dose4vsPlacebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.2026 ^{[106]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
3.3333


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
9.9551  
upper limit 
3.2886  
Variability estimate 
Standard error of the mean


Dispersion value 
3.9883


Notes [106]  Specified onesided Pvalue. 

Statistical analysis title 
Day1to7:WOMAC physical functionGZ389988A/Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.4007 ^{[107]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
1.2069


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
9.1559  
upper limit 
6.742  
Variability estimate 
Standard error of the mean


Dispersion value 
4.7829


Notes [107]  Specified onesided Pvalue. 

Statistical analysis title 
Day1to14:WOMAC physical functionGZ389988A/Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.2549 ^{[108]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
2.8295


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
9.9312  
upper limit 
4.2721  
Variability estimate 
Standard error of the mean


Dispersion value 
4.2764


Notes [108]  Specified onesided Pvalue. 

Statistical analysis title 
Day1to21:WOMAC physical functionGZ389988A/Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1644 ^{[109]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
3.9991


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
10.7655  
upper limit 
2.7673  
Variability estimate 
Standard error of the mean


Dispersion value 
4.0753


Notes [109]  Specified onesided Pvalue. 

Statistical analysis title 
Day1to28:WOMAC physical functionGZ389988A/Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.133 ^{[110]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.5148


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
11.2162  
upper limit 
2.1867  
Variability estimate 
Standard error of the mean


Dispersion value 
4.0364


Notes [110]  Specified onesided Pvalue. 

Statistical analysis title 
Day1to42:WOMAC physical functionGZ389988A/Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1333 ^{[111]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.5115


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
11.2161  
upper limit 
2.1931  
Variability estimate 
Standard error of the mean


Dispersion value 
4.0383


Notes [111]  Specified onesided Pvalue. 

Statistical analysis title 
Day1to56:WOMAC physical functionGZ389988A/Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1384 ^{[112]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.416


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
11.12  
upper limit 
2.2879  
Variability estimate 
Standard error of the mean


Dispersion value 
4.0379


Notes [112]  Specified onesided Pvalue. 

Statistical analysis title 
Day1to70:WOMAC physical functionGZ389988A/Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1392 ^{[113]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.4066


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
11.1187  
upper limit 
2.3054  
Variability estimate 
Standard error of the mean


Dispersion value 
4.0427


Notes [113]  Specified onesided Pvalue. 

Statistical analysis title 
Day1to84:WOMAC physical functionGZ389988A/Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1487 ^{[114]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.261


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
11.0134  
upper limit 
2.4914  
Variability estimate 
Standard error of the mean


Dispersion value 
4.067


Notes [114]  Specified onesided Pvalue. 


End point title 
Part2:Change From Baseline at Days 7(Week 1),14(Week 2),21(Week 3),28(Week 4),42(Week 6),56(Week 8),70(Week 10) and 84(Week 12) in WOMAC Index Total, Pain, Stiffness, and Physical Function Subscores Over the Last 48 Hours at Each Visit ^{[115]}  
End point description 
WOMAC index is health status measure questionnaire of twentyfour questions comprising of 3 subscales: pain (5 questions), stiffness (2 questions) and physical function (17 questions). Each question was measured on a 0100 VAS ranging from 0=minimum to 100=maximum over last 48 hours. A total WOMAC index score and a WOMAC subscore for each dimension were calculated as an average of each item concerned. The change from baseline in all subscores were calculated at each specified visit (Day 7, 14, 21, 28, 42, 56, 70, and 84). Analysis was performed on mITT population. Here, “n” = number of subjects with available data at specified timepoints.


End point type 
Secondary


End point timeframe 
Baseline, Days 7, 14, 21, 28, 42, 56, 70, and 84


Notes [115]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was evaluated for Part 2 only. 



Statistical analysis title 
At Day 7: WOMAC index GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.3059  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
2.3186


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
9.8826  
upper limit 
5.2454  
Variability estimate 
Standard error of the mean


Dispersion value 
4.5517


Statistical analysis title 
At Day 14:WOMAC index GZ389988A Dose4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0929  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
5.3864


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
12.1001  
upper limit 
1.3274  
Variability estimate 
Standard error of the mean


Dispersion value 
4.0438


Statistical analysis title 
At Day 21:WOMAC index GZ389988A Dose4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0489  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
6.7403


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.4366  
upper limit 
0.044  
Variability estimate 
Standard error of the mean


Dispersion value 
4.0344


Statistical analysis title 
At Day 28:WOMAC index GZ389988A Dose4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0636  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
6.5386


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.5968  
upper limit 
0.5195  
Variability estimate 
Standard error of the mean


Dispersion value 
4.2529


Statistical analysis title 
At Day 42:WOMAC index GZ389988A Dose4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.14  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.8031


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
12.1439  
upper limit 
2.5378  
Variability estimate 
Standard error of the mean


Dispersion value 
4.4233


Statistical analysis title 
At Day 56:WOMAC index GZ389988A Dose4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.172  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.2053


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
11.5475  
upper limit 
3.1369  
Variability estimate 
Standard error of the mean


Dispersion value 
4.4238


Statistical analysis title 
At Day 70:WOMAC index GZ389988A Dose4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1526  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.6067


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
12.0255  
upper limit 
2.8121  
Variability estimate 
Standard error of the mean


Dispersion value 
4.47


Statistical analysis title 
At Day 84:WOMAC index GZ389988A Dose4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.2043  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
3.8696


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
11.6091  
upper limit 
3.87  
Variability estimate 
Standard error of the mean


Dispersion value 
4.663


Statistical analysis title 
At Day 7:WOMAC painGZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1446  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.9447


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
12.6514  
upper limit 
2.762  
Variability estimate 
Standard error of the mean


Dispersion value 
4.6389


Statistical analysis title 
At Day 14:WOMAC painGZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0365  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
7.6752


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
14.7089  
upper limit 
0.6415  
Variability estimate 
Standard error of the mean


Dispersion value 
4.2368


Statistical analysis title 
At Day 21:WOMAC painGZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0396  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
7.8417


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
15.1836  
upper limit 
0.4998  
Variability estimate 
Standard error of the mean


Dispersion value 
4.4236


Statistical analysis title 
At Day 28:WOMAC painGZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0369  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
8.1483


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
15.6366  
upper limit 
0.6601  
Variability estimate 
Standard error of the mean


Dispersion value 
4.512


Statistical analysis title 
At Day 42:WOMAC painGZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1212  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
5.5599


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.4087  
upper limit 
2.289  
Variability estimate 
Standard error of the mean


Dispersion value 
4.7293


Statistical analysis title 
At Day 56:WOMAC painGZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.14  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
5.1329


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
12.9761  
upper limit 
2.7103  
Variability estimate 
Standard error of the mean


Dispersion value 
4.7255


Statistical analysis title 
At Day 70:WOMAC painGZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1189  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
5.6445


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.5353  
upper limit 
2.2464  
Variability estimate 
Standard error of the mean


Dispersion value 
4.7541


Statistical analysis title 
At Day 84:WOMAC painGZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1392  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
5.4791


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.826  
upper limit 
2.8679  
Variability estimate 
Standard error of the mean


Dispersion value 
5.0288


Statistical analysis title 
At Day7:WOMAC stiffnessGZ389988A Dose4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.2799  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
2.6283


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
10.0893  
upper limit 
4.8328  
Variability estimate 
Standard error of the mean


Dispersion value 
4.4902


Statistical analysis title 
At Day14:WOMAC stiffnessGZ389988A Dose4vsPlacebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1066  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
5.2381


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
12.1806  
upper limit 
1.7044  
Variability estimate 
Standard error of the mean


Dispersion value 
4.1812


Statistical analysis title 
At Day21:WOMAC stiffnessGZ389988A Dose4vsPlacebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1179  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
5.0418


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
12.0581  
upper limit 
1.9744  
Variability estimate 
Standard error of the mean


Dispersion value 
4.2272


Statistical analysis title 
At Day28:WOMAC stiffnessGZ389988A Dose4vsPlacebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1588  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.1996


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
11.1391  
upper limit 
2.7398  
Variability estimate 
Standard error of the mean


Dispersion value 
4.1817


Statistical analysis title 
At Day42:WOMAC stiffnessGZ389988A Dose4vsPlacebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects


Comparison groups 
Part 2: Placebo v Part 2: GZ389988A Dose 4 from Part 1


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.2429  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
3.1323


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
10.5647  
upper limit 
4.3  
Variability estimate 
Standard error of the mean


Dispersion value 
4.4787


Statistical analysis title 
At Day56:WOMAC stiffnessGZ389988A Dose4vsPlacebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.3465  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
1.7862


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
9.2753  
upper limit 
5.7029  
Variability estimate 
Standard error of the mean


Dispersion value 
4.5121


Statistical analysis title 
At Day70:WOMAC stiffnessGZ389988A Dose4vsPlacebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.347  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
1.8246


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
9.5019  
upper limit 
5.8526  
Variability estimate 
Standard error of the mean


Dispersion value 
4.6255


Statistical analysis title 
At Day84:WOMAC stiffnessGZ389988A Dose4vsPlacebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.2825  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
2.815


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
10.9068  
upper limit 
5.2767  
Variability estimate 
Standard error of the mean


Dispersion value 
4.875


Statistical analysis title 
At Day7:WOMAC physical functionGZ389988A/Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.4007  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
1.2069


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
9.1559  
upper limit 
6.742  
Variability estimate 
Standard error of the mean


Dispersion value 
4.7829


Statistical analysis title 
Day14:WOMAC physical functionGZ389988A/Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1456  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.4521


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
11.4195  
upper limit 
2.5153  
Variability estimate 
Standard error of the mean


Dispersion value 
4.1965


Statistical analysis title 
Day21:WOMAC physical functionGZ389988A/Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0618  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
6.3382


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.1144  
upper limit 
0.4379  
Variability estimate 
Standard error of the mean


Dispersion value 
4.0825


Statistical analysis title 
Day28:WOMAC physical functionGZ389988A/Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0828  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
6.0618


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
13.2662  
upper limit 
1.1425  
Variability estimate 
Standard error of the mean


Dispersion value 
4.341


Statistical analysis title 
Day42:WOMAC physical functionGZ389988A/Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1587  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.4985


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
11.9303  
upper limit 
2.9334  
Variability estimate 
Standard error of the mean


Dispersion value 
4.4781


Statistical analysis title 
Day56:WOMAC physical functionGZ389988A/Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.19  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
3.9385


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
11.3538  
upper limit 
3.4768  
Variability estimate 
Standard error of the mean


Dispersion value 
4.4678


Statistical analysis title 
Day70:WOMAC physical functionGZ389988A/Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1684  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.3503


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
11.8315  
upper limit 
3.131  
Variability estimate 
Standard error of the mean


Dispersion value 
4.5077


Statistical analysis title 
Day84:WOMAC physical functionGZ389988A/Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.2454  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
3.2417


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
11.0232  
upper limit 
4.5398  
Variability estimate 
Standard error of the mean


Dispersion value 
4.6883



End point title 
Part 2: Change From Baseline in Patient Global Assessment (PGA) of Disease Status Average Over Days 1 to 7 (1 Week), 1 to 14 (2 Weeks), 1 to 21 (3 Weeks), 1 to 28 (4 Weeks), 1 to 42 (6 Weeks), 1 to 56 (8 Weeks), 1 to 70 (10 Weeks) and 1 to 84 (12 Weeks) ^{[116]}  
End point description 
The PGA was used by subjects to rate the disease (osteoarthritis) status of the target knee. Subjects provided their response on a 0100 VAS ranging from 0 (very well) to 100 (very poor), where higher scores indicated very poor condition of the knee. The statistical analysis was done on the change from baseline score (calculated as average of daily measurements over the week) for each week. Analysis was performed on mITT population. Here, "number of subjects analysed"= subjects with available data for this endpoint.


End point type 
Secondary


End point timeframe 
Baseline, Days 1 to 7, 1 to 14, 1 to 21, 1 to 28, 1 to 42, 1 to 56, 1 to 70, and 1 to 84


Notes [116]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was evaluated for Part 2 only. 



Statistical analysis title 
Over Days 1 to 7: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
101


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.4051 ^{[117]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
1.1405


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
9.0084  
upper limit 
6.7274  
Variability estimate 
Standard error of the mean


Dispersion value 
4.7344


Notes [117]  Specified onesided Pvalue. 

Statistical analysis title 
Over Days 1 to 14: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
101


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.2328 ^{[118]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
3.1124


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
10.1667  
upper limit 
3.9419  
Variability estimate 
Standard error of the mean


Dispersion value 
4.2484


Notes [118]  Specified onesided Pvalue. 

Statistical analysis title 
Over Days 1 to 21: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
101


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1445 ^{[119]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.3705


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
11.178  
upper limit 
2.437  
Variability estimate 
Standard error of the mean


Dispersion value 
4.0999


Notes [119]  Specified onesided Pvalue. 

Statistical analysis title 
Over Days 1 to 28: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
101


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1113 ^{[120]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
5.0002


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
11.7651  
upper limit 
1.7647  
Variability estimate 
Standard error of the mean


Dispersion value 
4.0742


Notes [120]  Specified onesided Pvalue. 

Statistical analysis title 
Over Days 1 to 42: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
101


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1376 ^{[121]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.4486


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
11.1802  
upper limit 
2.283  
Variability estimate 
Standard error of the mean


Dispersion value 
4.0539


Notes [121]  Specified onesided Pvalue. 

Statistical analysis title 
Over Days 1 to 56: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
101


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1553 ^{[122]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.1185


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
10.8277  
upper limit 
2.5906  
Variability estimate 
Standard error of the mean


Dispersion value 
4.0402


Notes [122]  Specified onesided Pvalue. 

Statistical analysis title 
Over Days 1 to 70: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
101


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1523 ^{[123]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.1926


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
10.94  
upper limit 
2.5549  
Variability estimate 
Standard error of the mean


Dispersion value 
4.0631


Notes [123]  Specified onesided Pvalue. 

Statistical analysis title 
Over Days 1 to 84: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
101


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1519 ^{[124]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.2237


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
11.0094  
upper limit 
2.5621  
Variability estimate 
Standard error of the mean


Dispersion value 
4.086


Notes [124]  Specified onesided Pvalue. 


End point title 
Part 2: Change From Baseline in PGA of Disease Status at Each Visit (Days 7, 14, 21, 28, 42, 56, 70 and 84) ^{[125]}  
End point description 
The PGA was used by subjects to rate the disease (osteoarthritis) status of the target knee. Subjects provided their response on a 0100 VAS ranging from 0 (very well) to 100 (very poor), where higher scores indicated very poor condition of the knee. The change from baseline in all subscores were calculated at each specified visit (Day 7, 14, 21, 28, 42, 56, 70, and 84). Analysis was performed on mITT population. Here, “n” = number of subjects with available data at specified time point.


End point type 
Secondary


End point timeframe 
Baseline, Day 7, 14, 21, 28, 42, 56, 70, and 84


Notes [125]  The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was evaluated for Part 2 only. 



Statistical analysis title 
At Day 7: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.4051 ^{[126]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
1.1405


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
9.0084  
upper limit 
6.7274  
Variability estimate 
Standard error of the mean


Dispersion value 
4.7344


Notes [126]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 14: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1241 ^{[127]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
5.0843


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
12.3511  
upper limit 
2.1825  
Variability estimate 
Standard error of the mean


Dispersion value 
4.3762


Notes [127]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 21: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0612 ^{[128]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
6.8866


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
14.2264  
upper limit 
0.4532  
Variability estimate 
Standard error of the mean


Dispersion value 
4.4216


Notes [128]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 28: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.0701 ^{[129]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
6.8894


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
14.581  
upper limit 
0.8022  
Variability estimate 
Standard error of the mean


Dispersion value 
4.6342


Notes [129]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 42: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.3141 ^{[130]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
2.2422


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
9.9037  
upper limit 
5.4192  
Variability estimate 
Standard error of the mean


Dispersion value 
4.6156


Notes [130]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 56: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.2968 ^{[131]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
2.4682


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
10.1217  
upper limit 
5.1853  
Variability estimate 
Standard error of the mean


Dispersion value 
4.6108


Notes [131]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 70: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1717 ^{[132]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.6369


Confidence interval 

level 
90%  
sides 
2sided


lower limit 
12.7232  
upper limit 
3.4495  
Variability estimate 
Standard error of the mean


Dispersion value 
4.8706


Notes [132]  Specified onesided Pvalue. 

Statistical analysis title 
At Day 84: GZ389988A Dose 4 vs Placebo  
Statistical analysis description 
The linear mixed effect model included the corresponding baseline as covariate and treatment, week, weekbytreatment interaction and gender as fixed effects.


Comparison groups 
Part 2: GZ389988A Dose 4 from Part 1 v Part 2: Placebo


Number of subjects included in analysis 
104


Analysis specification 
Prespecified


Analysis type 
superiority  
Pvalue 
= 0.1847 ^{[133]}  
Method 
Linear Mixed Effect Model  
Parameter type 
Least squares mean difference  
Point estimate 
4.4412


Confidence interval 

level 
90%  
sides 