Clinical Trial Results:
An adaptive Phase II study to evaluate the efficacy, pharmacodynamics, safety and tolerability of GSK2586184 in patients with mild to moderate systemic lupus erythematosus.
Summary


EudraCT number 
201200164541 
Trial protocol 
DE HU SE ES GR EE CZ PL 
Global end of trial date 
31 Mar 2014

Results information


Results version number 
v2(current) 
This version publication date 
26 Mar 2016

First version publication date 
01 Jul 2015

Other versions 
v1 
Version creation reason 

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 
JAK115919


Additional study identifiers


ISRCTN number 
  
US NCT number 
NCT01777256  
WHO universal trial number (UTN) 
  
Sponsors


Sponsor organisation name 
GlaxoSmithKline


Sponsor organisation address 
980 Great West Road, Brentford, Middlesex, United Kingdom,


Public contact 
GSK Response Center, GlaxoSmithKline, 1 8664357343,


Scientific contact 
GSK Response Center, GlaxoSmithKline, 1 8664357343,


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 
09 Jul 2014


Is this the analysis of the primary completion data? 
No


Global end of trial reached? 
Yes


Global end of trial date 
31 Mar 2014


Was the trial ended prematurely? 
Yes


General information about the trial


Main objective of the trial 
• To estimate the relationship between dose of GSK2586184 and pharmacodynamic effect on expression of selected messenger ribonucleic acid (mRNA) transcripts following 2 weeks of treatment in SLE patients
• To estimate the relationship between dose of GSK2586184 and clinical response as assessed by SELENA SLEDAI score following 12 weeks of treatment in SLE patients
• To evaluate the safety and tolerability of repeat doses of GSK2586184 in SLE patients.


Protection of trial subjects 
Not applicable


Background therapy 
  
Evidence for comparator 
  
Actual start date of recruitment 
05 Mar 2013


Long term followup planned 
No


Independent data monitoring committee (IDMC) involvement? 
No


Population of trial subjects


Number of subjects enrolled per country 

Country: Number of subjects enrolled 
Argentina: 3


Country: Number of subjects enrolled 
Czech Republic: 2


Country: Number of subjects enrolled 
Estonia: 3


Country: Number of subjects enrolled 
France: 3


Country: Number of subjects enrolled 
Greece: 6


Country: Number of subjects enrolled 
Hungary: 9


Country: Number of subjects enrolled 
Korea, Republic of: 1


Country: Number of subjects enrolled 
Peru: 14


Country: Number of subjects enrolled 
Poland: 9


Worldwide total number of subjects 
50


EEA total number of subjects 
32


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) 
50


From 65 to 84 years 
0


85 years and over 
0



Recruitment


Recruitment details 
  
Preassignment


Screening details 
Participants (par) with a clinical diagnosis of systemic lupus erythematosus (SLE) according to the American College of Rheumatology classification criteria were enrolled. Enrolled par with clinically active SLE were randomised in a 1:1:1:1:1 ratio to receive twice daily doses of GSK2586184 (50 milligram (mg), 100 mg, 200 mg, 400 mg) or placebo.  
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 
Carer, Assessor, Subject, Investigator, Monitor, Data analyst  
Arms


Are arms mutually exclusive 
Yes


Arm title

GSK2586184 50 mg BID  
Arm description 
Participants received a combination of 2 film coated tablets, so that each participant received a total of 50 milligram (mg) of GSK2586184, twice daily (BID) with food for 12 weeks.  
Arm type 
Experimental  
Investigational medicinal product name 
GSK2586184


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Tablet


Routes of administration 
Oral use


Dosage and administration details 
Either 50mg or 200mg oral tablets taken twice daily with food


Arm title

GSK2586184 100 mg BID  
Arm description 
Participants received a combination of 2 film coated tablets, so that each participant received a total of 100 mg of GSK2586184, BID with food for 12 weeks.  
Arm type 
Experimental  
Investigational medicinal product name 
GSK2586184


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Tablet


Routes of administration 
Oral use


Dosage and administration details 
Either 50mg or 200mg oral tablets taken twice daily with food


Arm title

GSK2586184 200 mg BID  
Arm description 
Participants received a combination of 2 film coated tablets, so that each participant received a total of 200 mg of GSK2586184, BID with food for 12 weeks.  
Arm type 
Experimental  
Investigational medicinal product name 
GSK2586184


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Tablet


Routes of administration 
Oral use


Dosage and administration details 
Either 50mg or 200mg oral tablets taken twice daily with food


Arm title

GSK2586184 400 mg BID  
Arm description 
Participants received a combination of 2 film coated tablets, so that each participant received a total of 400 mg of GSK2586184, BID with food for 12 weeks.  
Arm type 
Experimental  
Investigational medicinal product name 
GSK2586184


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Tablet


Routes of administration 
Oral use


Dosage and administration details 
Either 50mg or 200mg oral tablets taken twice daily with food


Arm title

Placebo  
Arm description 
Participants received a combination of 2 film coated tablets of GSK2586184 matching placebo, BID with food for 12 weeks.  
Arm type 
Placebo  
Investigational medicinal product name 
Placebo


Investigational medicinal product code 

Other name 

Pharmaceutical forms 
Tablet


Routes of administration 
Oral use


Dosage and administration details 
Placebo  Either 50mg or 200mg oral tablets taken twice daily with food





Baseline characteristics reporting groups


Reporting group title 
GSK2586184 50 mg BID


Reporting group description 
Participants received a combination of 2 film coated tablets, so that each participant received a total of 50 milligram (mg) of GSK2586184, twice daily (BID) with food for 12 weeks.  
Reporting group title 
GSK2586184 100 mg BID


Reporting group description 
Participants received a combination of 2 film coated tablets, so that each participant received a total of 100 mg of GSK2586184, BID with food for 12 weeks.  
Reporting group title 
GSK2586184 200 mg BID


Reporting group description 
Participants received a combination of 2 film coated tablets, so that each participant received a total of 200 mg of GSK2586184, BID with food for 12 weeks.  
Reporting group title 
GSK2586184 400 mg BID


Reporting group description 
Participants received a combination of 2 film coated tablets, so that each participant received a total of 400 mg of GSK2586184, BID with food for 12 weeks.  
Reporting group title 
Placebo


Reporting group description 
Participants received a combination of 2 film coated tablets of GSK2586184 matching placebo, BID with food for 12 weeks.  



End points reporting groups


Reporting group title 
GSK2586184 50 mg BID


Reporting group description 
Participants received a combination of 2 film coated tablets, so that each participant received a total of 50 milligram (mg) of GSK2586184, twice daily (BID) with food for 12 weeks.  
Reporting group title 
GSK2586184 100 mg BID


Reporting group description 
Participants received a combination of 2 film coated tablets, so that each participant received a total of 100 mg of GSK2586184, BID with food for 12 weeks.  
Reporting group title 
GSK2586184 200 mg BID


Reporting group description 
Participants received a combination of 2 film coated tablets, so that each participant received a total of 200 mg of GSK2586184, BID with food for 12 weeks.  
Reporting group title 
GSK2586184 400 mg BID


Reporting group description 
Participants received a combination of 2 film coated tablets, so that each participant received a total of 400 mg of GSK2586184, BID with food for 12 weeks.  
Reporting group title 
Placebo


Reporting group description 
Participants received a combination of 2 film coated tablets of GSK2586184 matching placebo, BID with food for 12 weeks. 


End point title 
Percentage Inhibition from Baseline of interferon (IFN) Transcriptional Biomarkers at Week 2  
End point description 
Mean reduction (40%) from Baseline of the IFN transcriptional signature biomarker was monitored at Week 2. Percentage (Per) inhibition (=[(Day x–Baseline)/Baseline]*100), was the Per reduction from baseline (Day1) and evaluated in any predesignated panels of genes i.e. Addenbrookes 1, Addenbrookes 2, JAK439, PD, Panel Stripping, Flare and Transcription. Analysis was performed using a repeated measures model with covariates of treatment, baseline, Day, Day by baseline and Day by treatment interactions. Only those Par available at the specified time points were analysed (n=X,X,X,X,X). Different Par may have been analysed at different time points, so the overall number of Par analysed reflects everyone in the Intent To Treat (ITT) Population i.e. Par randomised to treatment, received >=1 dose of study medication and had >=1 valid post dose assessment


End point type 
Primary


End point timeframe 
Baseline and Week 2




Notes [1]  ITT Population [2]  ITT Population [3]  ITT Population [4]  ITT Population [5]  ITT Population 

Statistical analysis title 
Analysis 1  
Comparison groups 
Placebo v GSK2586184 50 mg BID


Number of subjects included in analysis 
17


Analysis specification 
Prespecified


Analysis type 
superiority ^{[6]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
2.75


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
4.31  
upper limit 
9.81  
Notes [6]  Panel 1: Placebo vs GSK2586184 50 mg BID at Week 2 

Statistical analysis title 
Analysis 2  
Comparison groups 
Placebo v GSK2586184 100 mg BID


Number of subjects included in analysis 
19


Analysis specification 
Prespecified


Analysis type 
superiority ^{[7]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
1.55


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
5.19  
upper limit 
8.3  
Notes [7]  Panel 1: Placebo vs GSK2586184 100 mg BID at Week 2 

Statistical analysis title 
Analysis 3  
Comparison groups 
Placebo v GSK2586184 200 mg BID


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
superiority ^{[8]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
0.41


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
7.37  
upper limit 
6.56  
Notes [8]  Panel 1: Placebo vs GSK2586184 200 mg BID at Week 2 

Statistical analysis title 
Analysis 4  
Comparison groups 
Placebo v GSK2586184 400 mg BID


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
superiority ^{[9]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
5.39


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.46  
upper limit 
12.25  
Notes [9]  Panel 1: Placebo vs GSK2586184 400 mg BID at Week 2 

Statistical analysis title 
Analysis 5  
Comparison groups 
Placebo v GSK2586184 50 mg BID


Number of subjects included in analysis 
17


Analysis specification 
Prespecified


Analysis type 
superiority ^{[10]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
2.02


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
5.52  
upper limit 
9.56  
Notes [10]  Panel 2: Placebo vs GSK2586184 50 mg BID at Week 2 

Statistical analysis title 
Analysis 6  
Comparison groups 
Placebo v GSK2586184 100 mg BID


Number of subjects included in analysis 
19


Analysis specification 
Prespecified


Analysis type 
superiority ^{[11]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
1.34


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
5.86  
upper limit 
8.54  
Notes [11]  Panel 2: Placebo vs GSK2586184 100 mg BID at Week 2 

Statistical analysis title 
Analysis 7  
Comparison groups 
Placebo v GSK2586184 200 mg BID


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
superiority ^{[12]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
0.48


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
7.95  
upper limit 
6.99  
Notes [12]  Panel 2: Placebo vs GSK2586184 200 mg BID at Week 2 

Statistical analysis title 
Analysis 8  
Comparison groups 
Placebo v GSK2586184 400 mg BID


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
superiority ^{[13]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
4.78


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
2.55  
upper limit 
12.11  
Notes [13]  Panel 2: Placebo vs GSK2586184 400 mg BID at Week 2 

Statistical analysis title 
Analysis 9  
Comparison groups 
Placebo v GSK2586184 50 mg BID


Number of subjects included in analysis 
17


Analysis specification 
Prespecified


Analysis type 
superiority ^{[14]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
0.98


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
5.2  
upper limit 
7.16  
Notes [14]  Panel 3: Placebo vs GSK2586184 50 mg BID at Week 2 

Statistical analysis title 
Analysis 10  
Comparison groups 
Placebo v GSK2586184 100 mg BID


Number of subjects included in analysis 
19


Analysis specification 
Prespecified


Analysis type 
superiority ^{[15]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
0.76


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
5.13  
upper limit 
6.65  
Notes [15]  Panel 3: Placebo vs GSK2586184 100 mg BID at Week 2 

Statistical analysis title 
Analysis 11  
Comparison groups 
Placebo v GSK2586184 200 mg BID


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
superiority ^{[16]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
0.07


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
6.06  
upper limit 
6.19  
Notes [16]  Panel 3: Placebo vs GSK2586184 200 mg BID at Week 2 

Statistical analysis title 
Analysis 12  
Comparison groups 
Placebo v GSK2586184 400 mg BID


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
superiority ^{[17]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
4.02


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.99  
upper limit 
10.03  
Notes [17]  Panel 3: Placebo vs GSK2586184 400 mg BID at Week 2 

Statistical analysis title 
Analysis 13  
Comparison groups 
Placebo v GSK2586184 50 mg BID


Number of subjects included in analysis 
17


Analysis specification 
Prespecified


Analysis type 
superiority ^{[18]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
0.72


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
4.42  
upper limit 
5.87  
Notes [18]  Panel 4: Placebo vs GSK25865184 50 mg BID at Week 2 

Statistical analysis title 
Analysis 14  
Comparison groups 
Placebo v GSK2586184 100 mg BID


Number of subjects included in analysis 
19


Analysis specification 
Prespecified


Analysis type 
superiority ^{[19]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
0.57


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
4.32  
upper limit 
5.46  
Notes [19]  Panel 4: Placebo vs GSK2586184 100 mg BID at Week 2 

Statistical analysis title 
Analysis 15  
Comparison groups 
Placebo v GSK2586184 200 mg BID


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
superiority ^{[20]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
2.33


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
7.41  
upper limit 
2.76  
Notes [20]  Panel 4: Placebo vs GSK2586184 200 mg BID at Week 2 

Statistical analysis title 
Analysis 16  
Comparison groups 
Placebo v GSK2586184 400 mg BID


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
superiority ^{[21]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
2.99


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
2.01  
upper limit 
8  
Notes [21]  Panel 4: Placebo vs GSK2586184 400 mg BID at Week 2 

Statistical analysis title 
Analysis 17  
Comparison groups 
Placebo v GSK2586184 50 mg BID


Number of subjects included in analysis 
17


Analysis specification 
Prespecified


Analysis type 
superiority ^{[22]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
1.94


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
5.53  
upper limit 
9.42  
Notes [22]  Panel 5: Placebo vs GSK2586184 50 mg BID at Week 2 

Statistical analysis title 
Analysis 18  
Comparison groups 
Placebo v GSK2586184 100 mg BID


Number of subjects included in analysis 
19


Analysis specification 
Prespecified


Analysis type 
superiority ^{[23]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
1.28


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
5.85  
upper limit 
8.41  
Notes [23]  Panel 5: Placebo vs GSK2586184 100 mg BID at Week 2 

Statistical analysis title 
Analysis 19  
Comparison groups 
Placebo v GSK2586184 200 mg BID


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
superiority ^{[24]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
0.33


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
7.7  
upper limit 
7.04  
Notes [24]  Panel 5: Placebo vs GSK2586184 200 mg BID at Week 2 

Statistical analysis title 
Analysis 20  
Comparison groups 
Placebo v GSK2586184 400 mg BID


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
superiority ^{[25]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
5.8


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.45  
upper limit 
13.06  
Notes [25]  Panel 5: Placebo vs GSK2586184 400 mg BID at Week 2 

Statistical analysis title 
Analysis 21  
Comparison groups 
Placebo v GSK2586184 50 mg BID


Number of subjects included in analysis 
17


Analysis specification 
Prespecified


Analysis type 
superiority ^{[26]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
2.03


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
4.56  
upper limit 
8.61  
Notes [26]  Panel 6: Placebo vs GSK2586184 50 mg BID at Week 2 

Statistical analysis title 
Analysis 22  
Comparison groups 
Placebo v GSK2586184 100 mg BID


Number of subjects included in analysis 
19


Analysis specification 
Prespecified


Analysis type 
superiority ^{[27]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
1.58


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
4.71  
upper limit 
7.86  
Notes [27]  Panel 6: Placebo vs GSK2586184 100 mg BID at Week 2 

Statistical analysis title 
Analysis 23  
Comparison groups 
Placebo v GSK2586184 200 mg BID


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
superiority ^{[28]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
0.65


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
5.84  
upper limit 
7.15  
Notes [28]  Panel 6: Placebo vs GSK2586184 200 mg BID at Week 2 

Statistical analysis title 
Analysis 24  
Comparison groups 
Placebo v GSK2586184 400 mg BID


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
superiority ^{[29]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
5.93


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
0.46  
upper limit 
12.32  
Notes [29]  Panel 6: Placebo vs GSK2586184 400 mg BID at Week 2 

Statistical analysis title 
Analysis 25  
Comparison groups 
Placebo v GSK2586184 50 mg BID


Number of subjects included in analysis 
17


Analysis specification 
Prespecified


Analysis type 
superiority ^{[30]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
1.14


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.18  
upper limit 
3.45  
Notes [30]  Panel 7: Placebo vs GSK2586184 50 mg BID at Week 2 

Statistical analysis title 
Analysis 26  
Comparison groups 
Placebo v GSK2586184 100 mg BID


Number of subjects included in analysis 
19


Analysis specification 
Prespecified


Analysis type 
superiority ^{[31]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
0.06


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
2.3  
upper limit 
2.17  
Notes [31]  Panel 7: Placebo vs GSK2586184 100 mg BID at Week 2 

Statistical analysis title 
Analysis 27  
Comparison groups 
Placebo v GSK2586184 200 mg BID


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
superiority ^{[32]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
0.58


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
2.85  
upper limit 
1.68  
Notes [32]  Panel 7: Placebo vs GSK2586184 200 mg BID at Week 2 

Statistical analysis title 
Analysis 28  
Comparison groups 
Placebo v GSK2586184 400 mg BID


Number of subjects included in analysis 
18


Analysis specification 
Prespecified


Analysis type 
superiority ^{[33]}  
Method 

Parameter type 
Mean difference (final values)  
Point estimate 
0.84


Confidence interval 

level 
95%  
sides 
2sided


lower limit 
1.41  
upper limit 
3.09  
Notes [33]  Panel 7: Placebo vs GSK2586184 400 mg BID at Week 2 


End point title 
Change from Baseline of SELENA SLEDAI score at indicated timepoints up to Week 16. ^{[34]}  
End point description 
The Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) is a validated index for assessing SLE disease activity. It is a weighted index in which signs and symptoms, laboratory tests, and physician’s assessment for each of 9 organ systems are given a weighted score and summed, if present at the time of the visit or in the preceding 10 days. Modified version of SLEDAI is Safety of Estrogen in Lupus National Assessment (SELENA) SLEDAI where the maximum theoretical score for the SELENA SLEDAI was 105 with 0 indicating inactive disease. Baseline value is defined as Day 1 (predose) SELENA SLEDAI score. Only those Par available at the specified time points were analysed (represented by n=X,X,X,X,X in category titles). Different Par may have been analysed at different time points, so the overall number of Par analysed reflects everyone in the ITT Population.


End point type 
Primary


End point timeframe 
Baseline, Weeks 2, 4, 6, 8, 10, 12 and 16


Notes [34]  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: There were no statistics for this endpoint. 



Notes [35]  ITT Population. [36]  ITT Population. [37]  ITT Population. [38]  ITT Population. [39]  ITT Population. 

No statistical analyses for this end point 


End point title 
Change from Baseline in systolic blood pressure and diastolic blood pressure at the indicated time points up to Week 16 ^{[40]}  
End point description 
Change from Baseline in systolic blood pressure (BP) and diastolic BP is summarised for each postBaseline assessment up to Week 16. Change from Baseline was calculated as the individual postBaseline value minus the Baseline value. Baseline value is defined as the last Pretreatment value observed. Only those participants available at the specified time points were analysed (represented by n=X,X,X,X,X in category titles). Different participants may have been analysed at different time points, so the overall number of participants analysed reflects everyone in the ITT Population.


End point type 
Primary


End point timeframe 
Baseline, Weeks 2, 4, 6, 8, 10, 12 and 16


Notes [40]  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: There were no statistics for this endpoint. 



Notes [41]  ITT Population. “Not available (NA)” data is presented as “99999” [42]  ITT Population. “Not available (NA)” data is presented as “99999” [43]  ITT Population. “Not available (NA)” data is presented as “99999” [44]  ITT Population. “Not available (NA)” data is presented as “99999” [45]  ITT Population. “Not available (NA)” data is presented as “99999” 

No statistical analyses for this end point 


End point title 
Change from Baseline in heart rate at the indicated time points up to Week 16 ^{[46]}  
End point description 
Change from Baseline in sitting and supine heart rate is summarised for each postBaseline assessment up to Week 16. Change from Baseline was calculated as the individual postBaseline value minus the Baseline value. Baseline value is defined as the last Pretreatment value observed. Only those participants available at the specified time points were analysed (represented by n=X,X,X,X,X in category titles). Different participants may have been analysed at different time points, so the overall number of participants analysed reflects everyone in the ITT Population.


End point type 
Primary


End point timeframe 
Baseline, Weeks 2, 4, 6, 8, 10, 12 and 16


Notes [46]  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: There were no statistics for this endpoint. 



Notes [47]  ITT Population. “Not available (NA)” data is presented as “99999” [48]  ITT Population. “Not available (NA)” data is presented as “99999” [49]  ITT Population. “Not available (NA)” data is presented as “99999” [50]  ITT Population. “Not available (NA)” data is presented as “99999” [51]  ITT Population. “Not available (NA)” data is presented as “99999” 

No statistical analyses for this end point 


End point title 
Change from Baseline in temperature at the indicated time points up to Week 16 ^{[52]}  
End point description 
Change from Baseline in temperature is summarised for each postBaseline assessment up to Week 16. Change from Baseline was calculated as the individual postBaseline value minus the Baseline value. Baseline value is defined as the last Pretreatment value observed. Only those participants available at the specified time points were analysed (represented by n=X,X,X,X,X in category titles). Different participants may have been analysed at different time points, so the overall number of participants analysed reflects everyone in the ITT Population.


End point type 
Primary


End point timeframe 
Baseline, Weeks 2, 4, 6, 8, 10, 12 and 16


Notes [52]  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: There were no statistics for this endpoint. 



Notes [53]  ITT Population. “Not available (NA)” data is presented as “99999” [54]  ITT Population. “Not available (NA)” data is presented as “99999” [55]  ITT Population. “Not available (NA)” data is presented as “99999” [56]  ITT Population. “Not available (NA)” data is presented as “99999” [57]  ITT Population. “Not available (NA)” data is presented as “99999” 

No statistical analyses for this end point 


End point title 
Change from Baseline in albumin, globulin and protein at the indicated time points up to Week 16 ^{[58]}  
End point description 
Change from Baseline in the albumin, globulin and protein values are summarised for each postBaseline assessment until Week 16. Change from Baseline was calculated as the individual postBaseline value minus the Baseline value. Baseline value is defined as the last Pretreatment value observed. Only those participants available at the specified time points were analysed (represented by n=X,X,X,X,X in category titles). Different participants may have been analysed at different time points, so the overall number of participants analysed reflects everyone in the ITT Population.


End point type 
Primary


End point timeframe 
Baseline, Weeks 2, 3, 4, 5, 6, 8, 10, 12 and 16


Notes [58]  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: There were no statistics for this endpoint. 



Notes [59]  ITT Population. “Not available (NA)” data is presented as “99999” [60]  ITT Population. “Not available (NA)” data is presented as “99999” [61]  ITT Population. “Not available (NA)” data is presented as “99999” [62]  ITT Population. “Not available (NA)” data is presented as “99999” [63]  ITT Population. “Not available (NA)” data is presented as “99999” 

No statistical analyses for this end point 


End point title 
Change from Baseline in alkaline phosphatase, alanine amino transferase, aspartate amino transferase, creatine kinase, gamma glutamyl transferase and lactate dehydrogenase at the indicated time points up to Week 16 ^{[64]}  
End point description 
Change from Baseline in the alkaline phosphatase (ALP), alanine amino transferase (ALT), aspartate amino transferase (AST), creatine kinase (CK), gamma glutamyl transferase (GGT) and lactate dehydrogenase (LDH) values are summarised for each postBaseline assessment until Week 16. Change from Baseline was calculated as the individual postBaseline value minus the Baseline value. Baseline value is defined as the last Pretreatment value observed. Only those participants available at the specified time points were analysed (represented by n=X,X,X,X,X in category titles). Different participants may have been analysed at different time points, so the overall number of participants analysed reflects everyone in the ITT Population.


End point type 
Primary


End point timeframe 
Baseline, Weeks 2, 3, 4, 5, 6, 8, 10, 12 and 16


Notes [64]  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: There were no statistics for this endpoint. 



Notes [65]  ITT Population. “Not available (NA)” data is presented as “99999” [66]  ITT Population. “Not available (NA)” data is presented as “99999” [67]  ITT Population. “Not available (NA)” data is presented as “99999” [68]  ITT Population. “Not available (NA)” data is presented as “99999” [69]  ITT Population. “Not available (NA)” data is presented as “99999” 

No statistical analyses for this end point 


End point title 
Change from Baseline in anion gap, calcium, cholesterol, chloride, carbon dioxide, glucose, HDL cholesterol, potassium, LDL cholesterol, magnesium, phosphate, sodium, triglycerides, urea, VLDL cholesterol at the indicated time points up to Week 16. ^{[70]}  
End point description 
Change from Baseline in the anion gap, calcium, ionised calcium, cholesterol, chloride, carbon dioxide, glucose, high density lipoprotein (HDL) cholesterol (fasted and not fasted), potassium, low density lipoprotein (LDL) cholesterol (fasted and not fasted), magnesium, phosphate, sodium, triglycerides (fasted and not fasted), urea and very low density lipoprotein (VLDL) cholesterol values are summarised for each postBaseline assessment until Week 16. Change from Baseline was calculated as the individual postBaseline value minus the Baseline value. Baseline value is defined as the last Pretreatment value observed. Only those participants available at the specified time points were analysed (n=X,X,X,X,X). Different participants may have been analysed at different time points, so the overall number of participants analysed reflects everyone in the ITT Population.


End point type 
Primary


End point timeframe 
Baseline, Weeks 2, 3, 4, 5, 6, 8, 10, 12 and 16


Notes [70]  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: There were no statistics for this endpoint. 



Notes [71]  ITT Population. “Not available (NA)” data is presented as “99999” [72]  ITT Population. “Not available (NA)” data is presented as “99999” [73]  ITT Population. “Not available (NA)” data is presented as “99999” [74]  ITT Population. “Not available (NA)” data is presented as “99999” [75]  ITT Population. “Not available (NA)” data is presented as “99999” 

No statistical analyses for this end point 


End point title 
Change from Baseline in bilirubin, creatinine, iron binding capacity, iron and uric acid at the indicated time points up to Week 16 ^{[76]}  
End point description 
Change from Baseline in the bilirubin, direct and indirect bilirubin, creatinine, total iron binding capacity (TIBC), unsaturated iron binding capacity (UIBC), iron and uric acid values are summarised for each postBaseline assessment until Week 16. Change from Baseline was calculated as the individual postBaseline value minus the Baseline value. Baseline value is defined as the last Pretreatment value observed. Only those participants available at the specified time points were analysed (represented by n=X,X,X,X,X in category titles). Different participants may have been analysed at different time points, so the overall number of participants analysed reflects everyone in the ITT Population.


End point type 
Primary


End point timeframe 
Baseline, Weeks 2, 3, 4, 5, 6, 8, 10, 12 and 16


Notes [76]  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: There were no statistics for this endpoint. 



Notes [77]  ITT Population. “Not available (NA)” data is presented as “99999” [78]  ITT Population. “Not available (NA)” data is presented as “99999” [79]  ITT Population. “Not available (NA)” data is presented as “99999” [80]  ITT Population. “Not available (NA)” data is presented as “99999” [81]  ITT Population. “Not available (NA)” data is presented as “99999” 

No statistical analyses for this end point 


End point title 
Change from Baseline in albumin/globulin, BUN/creatinine and transferrin saturation at the indicated time points up to Week 16 ^{[82]}  
End point description 
Change from baseline in the albumin/globulin, blood urea nitrogen (BUN)/creatinine and transferrin saturation values are summarised for each postBaseline assessment until Week 16. Change from Baseline was calculated as the individual postBaseline value minus the Baseline value. Baseline value is defined as the last Pretreatment value observed. Only those participants available at the specified time points were analysed (represented by n=X,X,X,X,X in category titles). Different participants may have been analysed at different time points, so the overall number of participants analysed reflects everyone in the ITT Population.


End point type 
Primary


End point timeframe 
Baseline, Weeks 2, 3, 4, 5, 6, 8, 10, 12 and 16


Notes [82]  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: There were no statistics for this endpoint. 



Notes [83]  ITT Population. “Not available (NA)” data is presented as “99999” [84]  ITT Population. “Not available (NA)” data is presented as “99999” [85]  ITT Population. “Not available (NA)” data is presented as “99999” [86]  ITT Population. “Not available (NA)” data is presented as “99999” [87]  ITT Population. “Not available (NA)” data is presented as “99999” 

No statistical analyses for this end point 


End point title 
Change from Baseline in creatinine clearance at the indicated time points up to Week 16 ^{[88]}  
End point description 
Change from Baseline in the Creatinine Clearance values are summarised for each postBaseline assessment until Week 16. Change from Baseline was calculated as the individual postBaseline value minus the Baseline value. Baseline value is defined as the last Pretreatment value observed. Only those participants available at the specified time points were analysed (represented by n=X,X,X,X,X in category titles). Different participants may have been analysed at different time points, so the overall number of participants analysed reflects everyone in the ITT Population.


End point type 
Primary


End point timeframe 
Baseline, Weeks 2, 3, 4, 5, 6, 8, 10, 12 and 16


Notes [88]  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: There were no statistics for this endpoint. 



Notes [89]  ITT Population. “Not available (NA)” data is presented as “99999” [90]  ITT Population. “Not available (NA)” data is presented as “99999” [91]  ITT Population. “Not available (NA)” data is presented as “99999” [92]  ITT Population. “Not available (NA)” data is presented as “99999” [93]  ITT Population. “Not available (NA)” data is presented as “99999” 

No statistical analyses for this end point 


End point title 
Change from Baseline in basophils, eosinophils, lymphocytes, monocytes, neutrophils, neutrophils SG, platelets and leukocytes at the indicated time points up to Week 16 ^{[94]}  
End point description 
Change from Baseline in the basophils, eosinophils, lymphocytes, monocytes, neutrophils, neutrophils segmented (SG), platelets and leukocytes values are summarised for each postBaseline assessment until Week 16. Change from Baseline was calculated as the individual postBaseline value minus the Baseline value. Baseline value is defined as the last Pretreatment value observed. Only those participants available at the specified time points were analysed (represented by n=X,X,X,X,X in category titles). Different participants may have been analysed at different time points, so the overall number of participants analysed reflects everyone in the ITT Population.


End point type 
Primary


End point timeframe 
Baseline, Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12 and 16


Notes [94]  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: There were no statistics for this endpoint. 



Notes [95]  ITT Population [96]  ITT Population [97]  ITT Population [98]  ITT Population [99]  ITT Population 

No statistical analyses for this end point 


End point title 
Change from Baseline in basophils/leukocytes, eosinophils/leukocytes, lymphocytes/leukocytes, monocytes/leukocytes, neutrophils/leukocytes, neutrophils SG/leukocytes and EDW at the indicated time points up to Week 16 ^{[100]}  
End point description 
Change from Baseline in the basophils/leukocytes, eosinophils/leukocytes, lymphocytes/leukocytes, monocytes/leukocytes, neutrophils/leukocytes, neutrophils segmented (SG)/leukocytes and erythrocyte distribution width (EDW) values are summarised for each postBaseline assessment until Week 16. Change from Baseline was calculated as the individual postBaseline value minus the Baseline value. Baseline value is defined as the last Pretreatment value observed. Only those participants available at the specified time points were analysed (n=X,X,X,X,X). Different participants may have been analysed at different time points, so the overall number of participants analysed reflects everyone in the ITT Population.


End point type 
Primary


End point timeframe 
Baseline, Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12 and 16


Notes [100]  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: There were no statistics for this endpoint. 



Notes [101]  ITT Population [102]  ITT Population [103]  ITT Population [104]  ITT Population [105]  ITT Population 

No statistical analyses for this end point 


End point title 
Change from Baseline in erythrocytes and reticulocytes at the indicated time points up to Week 16 ^{[106]}  
End point description 
Change from Baseline in the erythrocyte and reticulocyte values are summarised for each postBaseline assessment until Week 16. Change from Baseline was calculated as the individual postBaseline value minus the Baseline value. Baseline value is defined as the last Pretreatment value observed. Only those participants available at the specified time points were analysed (represented by n=X,X,X,X,X in category titles). Different participants may have been analysed at different time points, so the overall number of participants analysed reflects everyone in the ITT Population.


End point type 
Primary


End point timeframe 
Baseline, Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12 and 16


Notes [106]  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: There were no statistics for this endpoint. 



Notes [107]  ITT Population [108]  ITT Population [109]  ITT Population [110]  ITT Population [111]  ITT Population 

No statistical analyses for this end point 


End point title 
Change from Baseline in hemoglobin and EMCHC at the indicated time points up to Week 16 ^{[112]}  
End point description 
Change from Baseline in the hemoglobin and erythrocyte mean corpuscular hemoglobin concentration (EMCHC) values are summarised for each postBaseline assessment until Week 16. Change from Baseline was calculated as the individual postBaseline value minus the Baseline value. Baseline value is defined as the last Pretreatment value observed. Only those participants available at the specified time points were analysed (represented by n=X,X,X,X,X in category titles). Different participants may have been analysed at different time points, so the overall number of participants analysed reflects everyone in the ITT Population.


End point type 
Primary


End point timeframe 
Baseline, Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12 and 16


Notes [112]  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: There were no statistics for this endpoint. 



Notes [113]  ITT Population [114]  ITT Population [115]  ITT Population [116]  ITT Population [117]  ITT Population 

No statistical analyses for this end point 


End point title 
Change from Baseline in EMCH at the indicated time points up to Week 16 ^{[118]}  
End point description 
Change from Baseline in the hemoglobin and erythrocyte mean corpuscular hemoglobin (EMCH) values are summarised for each postBaseline assessment until Week 16. Change from Baseline was calculated as the individual postBaseline value minus the Baseline value. Baseline value is defined as the last Pretreatment value observed. Only those participants available at the specified time points were analysed (represented by n=X,X,X,X,X in category titles). Different participants may have been analysed at different time points, so the overall number of participants analysed reflects everyone in the ITT Population.


End point type 
Primary


End point timeframe 
Baseline, Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12 and 16


Notes [118]  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: There were no statistics for this endpoint. 



Notes [119]  ITT Population. [120]  ITT Population. [121]  ITT Population. [122]  ITT Population. [123]  ITT Population. 

No statistical analyses for this end point 


End point title 
Change from Baseline in EMCV and MPV at the indicated time points up to Week 16 ^{[124]}  
End point description 
Change from Baseline in the erythrocyte mean corpuscular volume (EMCV) and mean platelet volume (MPV) values are summarised for each postBaseline assessment until Week 16. Change from Baseline was calculated as the individual postBaseline value minus the Baseline value. Baseline value is defined as the last Pretreatment value observed. Only those participants available at the specified time points were analysed (represented by n=X,X,X,X,X in category titles). Different participants may have been analysed at different time points, so the overall number of participants analysed reflects everyone in the ITT Population.


End point type 
Primary


End point timeframe 
Baseline, Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12 and 16


Notes [124]  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: There were no statistics for this endpoint. 



Notes [125]  ITT Population [126]  ITT Population [127]  ITT Population [128]  ITT Population [129]  ITT Population 

No statistical analyses for this end point 


End point title 
Change from Baseline in hematocrit and reticulocytes/erythrocytes at the indicated time points up to Week 16 ^{[130]}  
End point description 
Change from Baseline in the hematocrit and reticulocytes/erythrocytes values are summarised for each postBaseline assessment until Week 16. Change from Baseline was calculated as the individual postBaseline value minus the Baseline value. Baseline value is defined as the last Pretreatment value observed. Only those participants available at the specified time points were analysed (represented by n=X,X,X,X,X in category titles). Different participants may have been analysed at different time points, so the overall number of participants analysed reflects everyone in the ITT Population.


End point type 
Primary


End point timeframe 
Baseline, Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12 and 16


Notes [130]  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: There were no statistics for this endpoint. 



Notes [131]  ITT Population [132]  ITT Population [133]  ITT Population [134]  ITT Population [135]  ITT Population 

No statistical analyses for this end point 


End point title 
Number of participants with urinalysis data at the indicated time points up to Week 16 ^{[136]}  
End point description 
Number of participants with negative and positives (trace, +, ++ and +++) data for urine glucose (UGLU), urine ketones (UKET) and urine occult blood (UOB) are summarised for each postBaseline assesment until Week 16. Urinalysis was performed by dipstick method. Baseline value is defined as the last Pretreatment value observed. Only those participants available at the specified time points were analysed (represented by n=X,X,X,X,X in category titles). A value of 99999 indicates no participants were analyzed therefore there is no data for this time point.


End point type 
Primary


End point timeframe 
Baseline, Weeks 1, 2, 3, 4, 5, 6, 8, 10, 12 and 16


Notes [136]  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: There were no statistics for this endpoint. 

