Clinical trial NCT04744207
Conditions: Systemic Sclerosis
Sponsor: Gesynta Pharma AB
Start date: 2020-12-29; Completion date: 2022-06-15
Enrollment: 94 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to determine the safety, and evaluate the efficacy of GS-248 versus placebo on Raynaud's Phenomenon (RP) in subjects with Systemic Sclerosis (SSc).

Detailed description:
The primary objective of this study is to determine the safety, and evaluate the efficacy of GS-248 versus placebo on Raynaud's Phenomenon (RP) in subjects with Systemic Sclerosis (SSc).

This is a randomized, double-blind, placebo-controlled study conducted in multiple sites in 4 countries in Europe. Approximately 80 subjects will be randomized in a 1:1 allocation to receive either GS-248 (120 mg) or placebo once daily. The study will comprise an enrolment period, a treatment period, and a follow-up period, with a total of 5 study visits over approximately 10 weeks.

Arms: arm 1: GS-248, capsule, 120 mg, once daily for 4 weeks arm 2: placebo, capsule, once daily for 4 weeks
Interventions: intervention 1: GS-248 intervention 2: Placebo
Intervention descriptions: intervention 1: 120 mg, capsule, once daily for 4 weeks intervention 2: capsule, once daily for 4 weeks

Protocol documents:
Prot_000.pdf: 
 
 
Title:  
 
A Phase II, randomized, multi-center, placebo-controlled, double-blind study 
investigate the safety of GS-248, and efficacy on Raynaud’s phenomenon (RP) 
peripheral vascular blood flow, in subjects with systemic sclerosis (SSc) 
Protocol:
Version 5.0, dated 10 December 2021 
SAP: 
Version 2.0, dared 19 July 2022 
NCT: 
04744207 
 


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The study will be conducted according to the protocol and in compliance with Good
Clinical Practice (GCP), with the Declaration of Helsinki, and with other applicable
regulatory requirements.
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   
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       
  
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   
      
       
     
  


 
 






























































Objectives
Primary:




Endpoints

Primary Efficacy:





Key secondary efficacy:



















Safety Endpoints:








.
Exploratory efficacy:





















.
Secondary:





Secondary:






























Exploratory:








ex
vivo.




















Exploratory:






ex vivo 
.





















































































































Subjects with signs of other autoimmune diseases (e.g.
Sjögren’s syndrome, myositis, rheumatoid arthritis) could be
included if SSc is the dominating phenotype.



or



























or 




















Note: Subjects could be included if they have been treated
with a stable dose of mycophenolic acid during 4 weeks prior
to study entry.


































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

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








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

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





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
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
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





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
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
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
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
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ex vivo
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
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
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
and 
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



Note: Subjects who have been treated with a stable dose of
mycophenolic acid during 1 month prior to Visit 1 could
continue that dose during the study.
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

Note: Use of topical or inhaled corticosteroids is allowed
throughout the study.
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


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











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


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


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

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


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



































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
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
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
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


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
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


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
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
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
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


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



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







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




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
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
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
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












6.2.1.1
Definitions.........................................................................35








6.2.1.2
Recording Adverse Events ................................................36
6.2.1.3
Responsibilities of the Investigator...................................37
6.2.1.4
Responsibilities of the Sponsor.........................................38


6.2.2.1
Responsibilities of the Investigator...................................38
6.2.2.2
Responsibilities of the Sponsor.........................................39




6.2.4.1
Responsibilities of the Investigator...................................39

























































































































































































































































































































































1.1.1
Indication









































































in vitro in vivo 


















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

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













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


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



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






















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
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
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
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
Primary:




Primary Efficacy:



Key secondary efficacy:












Exploratory efficacy:









.

Safety Endpoints:






.
Secondary:



Secondary:




























Exploratory:





ex vivo.




















Exploratory:




ex vivo 
.






































1























qd: once daily












































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













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









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










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

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
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







Subjects with signs of other autoimmune diseases (e.g. Sjögren’s syndrome,
myositis, rheumatoid arthritis) could be included if SSc is the dominating
phenotype.































or



.














Note: Subjects could be included if they have been treated with a stable dose
of mycophenolic acid during 4 weeks prior to Visit 1.































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

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







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


















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
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

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










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

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








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
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

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

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
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
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





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








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



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




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

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







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






















5.2.1
Continued Access to Study Intervention After the End of the Study



















































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










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












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
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
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


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





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

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
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







































































6.1.1
Primary Efficacy Endpoint



6.1.2
Key Secondary Efficacy Endpoints















6.1.3
Secondary Efficacy Endpoints














6.1.4
Exploratory Efficacy Endpoints



















6.2.1
Adverse Events
6.2.1.1
Definitions


































































































6.2.1.2
Recording Adverse Events














































6.2.1.3
Responsibilities of the Investigator





























(e.g., changes to study treatment, other treatment given and
follow up tests



(the relationship to the study treatment[s]
and study procedures)























6.2.1.4
Responsibilities of the Sponsor



6.2.2
Evaluation of Adverse Events
6.2.2.1
Responsibilities of the Investigator
















6.2.2.2
Responsibilities of the Sponsor



6.2.3
Outcome of Events





















6.2.4
Notifying of Adverse Events
6.2.4.1
Responsibilities of the Investigator






















































6.2.4.2
Responsibilities of the Sponsor






6.2.5
Laboratory Parameters














o

o

o



















































































6.2.6
Vital Signs








.








6.2.7
Electrocardiograms














6.2.8
Physical Examinations













6.3.1
Pharmacokinetics






























6.3.2
Pharmacodynamics



ex vivo 










































7.1.1
Screening (Visit 1)




















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

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
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


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

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
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
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
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
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
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
7.1.2
Baseline Visit (Visit 2)




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
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
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








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
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
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
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
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
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
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

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
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
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
o

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
o

o

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

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
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
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
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

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
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
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
o

7.1.3
Visit 3



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
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
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
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
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
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
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
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
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
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








o

o

o



o

7.1.4
End of Treatment, Week 4 (Visit 4)
























o

o

o

o

o

o


o

o



o

o

o

o

o

7.1.5
Follow-up (and/or Early Termination) Visit (Visit 5)















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




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









o

o



o

7.1.6
Study Conduct During a COVID-19 Outbreak














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

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

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

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
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




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

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



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
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


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




























8.1.1
Disposition of Subjects





8.1.2
Protocol Deviations




8.1.3
Analysis Populations




























































8.5.1
Primary Efficacy Endpoint Analysis

























8.5.2
Key Secondary Efficacy Endpoints Analysis








8.5.3
Exploratory and Secondary Efficacy Endpoints Analysis






















































ex vivo.




























8.10.1 Handling of Dropouts and Missing Data














8.10.2 Rules for Excluding Subjects from Analysis




































































9.3.1
Deviations from the Protocol



































10.3.1 eCRF System








10.3.2 List of Subjects (subject identification log)






10.3.3 Source Data




















10.3.4 Investigator Site File / Regulatory Binder






















































































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



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




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
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

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
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
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
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






















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

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



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
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
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
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
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
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
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




























































































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
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
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

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


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
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

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


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
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
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
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


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


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
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
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

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

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

































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


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
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


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





















































j.














p.










(time window +/- 5 minutes, exact time recorded in eCRF)



































































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

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


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
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– 


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
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





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




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

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
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
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
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
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




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
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













Preparation for cold challenge














Cold challenge protocol

























Thermography



























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






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










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





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

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
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
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

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
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





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

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









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




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



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
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


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



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

















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















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
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

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


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



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
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










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




































































AA-metabolites (PGEM,
PGIM, TXM)




































































Anticentromere
Anti–topoisomerase I
Anti–RNA polymerase III












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

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










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





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


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
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












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



























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










































































Considering all the ways in which Raynaud’s symptoms affect you, compared to the start of
treatment, how do you rate your Raynaud’s currently?”

much better

a little better

no change

a little worse

much worse.












































































aprepitant
A04A
Antiemetics and antinauseants
dronedarone
C01B
Class 1 and 3 antiarrhythmic drugs
conivaptan
C03
Diuretics
diltiazem
C08
Calcium channel blockers
verapamil
C08
Calcium channel blockers
ciprofloxacin
J01
Antibacterial drugs
clarithromycin
J01
Antibacterial drugs
erythromycin
J01
Antibacterial drugs
telithromycin
J01
Antibacterial drugs
troleandomycin
J01
Antibacterial drugs
fluconazole
J02
Antibacterial drugs
itraconazole
J02
Antimycotic drugs
ketoconazole
J02
Antimycotic drugs
posaconazole
J02
Antimycotic drugs
voriconazole
J02
Antimycotic drugs
cyclosporine
J04
Antimycobacterials
boceprevir,
J05
Antiviral drugs
cobicistat,
J05
Antiviral drugs
danoprevir and ritonavir
J05
Antiviral drugs
elvitegravir and ritonavir
J05
Antiviral drugs
indinavir and ritonavir
J05
Antiviral drugs
lopinavir and ritonavir
J05
Antiviral drugs
nelfinavir
J05
Antiviral drugs
paritaprevir and ritonavir and
(combative and/or dasabuvir)
J05
Antiviral drugs
ritonavir
J05
Antiviral drugs
saquinavir and ritonavir
J05
Antiviral drugs
telaprevir
J05
Antiviral drugs
tipranavir and ritonavir
J05
Antiviral drugs
crizotinib
L01
Antineoplastic drugs
idelalisib
L01
Antineoplastic drugs
imatinib
L01
Antineoplastic drugs
tofisopam
N05
Psycholeptics
fluvoxamine
N06A
Antidepressants
nefazodone
N06A
Antidepressants
grapefruit juice
More information available from: https://www.fda.gov/drugs/drug-interactions-
labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-
inducers

SAP_001.pdf: 
 
 
Title:  
 
A Phase II, randomized, multi-center, placebo-controlled, double-blind study 
investigate the safety of GS-248, and efficacy on Raynaud’s phenomenon (RP) 
peripheral vascular blood flow, in subjects with systemic sclerosis (SSc) 
Protocol:
Version 5.0, dated 10 December 2021 
SAP: 
Version 2.0, dated 19 July 2022 
NCT: 
04744207 
 


FRM/BS/001.03
Version 5.0, Effective Sep-2020
Statistical Analysis Plan Version 2.0
Page 1 of 2
Sponsor
Gesynta Pharma AB
Protocol No
GS-2001
CONFIDENTIAL
Statistical Analysis Plan (SAP)
Sponsor:
Gesynta Pharma AB
Study Title:
A Phase II, randomized, multi-center, placebo-controlled, double-
blind study to investigate the safety of GS-248, and efficacy on 
Raynaud’s phenomenon (RP) and peripheral vascular blood flow, 
in subjects with systemic sclerosis (SSc)
Protocol
Version/Date:
Final v5.0, 10-December-2021
SAP
Version/Date:
Final Blinded SAP GS-2001 V2.0, 19-Jul-2022
Supersedes SAP Ver-
sion:
Final 1.0
Appendices
(external documents):
1.
List of Tables, Listing, Figures (TLFs)
Approval
The Trial Statistician hereby confirms that the SAP was prepared in conformance with the pro-
cedures and principles set forth in the indicated protocol version and all established relevant
guidelines. 
Name
Affiliation, Function
Signature:
Date:
Gonnie van Osta, 
Consultant/Ergomed Trial Statistician
By signing hereafter, I confirm that this Statistical Analysis Plan adequately describes the sta-
tistical analyses to be performed in the context of this study.
Name
Affiliation, Function
Signature:
Date:
Jan Kowalski,
Gesynta Pharma AB


FRM/BS/001.03
Version 5.0, Effective Sep-2020
Statistical Analysis Plan Version 2.0
Page 2 of 3
Sponsor
Gesynta Pharma AB
Protocol No
GS-2001
CONFIDENTIAL
Revision history
SAP Version
Version date
Reason(s) for change
0.1
23-Mar-2021
1st draft for sponsor review
0.2
7-Aug-2021
2nd draft for sponsor review
0.3
30-Sept-2021
3rd draft after discussion with sponsor
0.4
11-Oct-2021
4th version for sponsor review
0.5
15-Oct-2021
5th version for sponsor review
1.0
18-Oct-2021
Final version for sponsor sign-off
1.1
8-Jul-2022
Draft updated SAP prior to unblinding
2.0
19-Jul-2022
Final SAP prior to unblinding


FRM/BS/001.03
Version 5.0, Effective Sep-2020
Statistical Analysis Plan Version 2.0
Page 3 of 4
Sponsor
Gesynta Pharma AB
Protocol No
GS-2001
CONFIDENTIAL
TABLE OF CONTENTS
LIST OF ABBREVIATIONS...............................................................................................6
1 Study information..............................................................................................................8
1.1 Primary objective.............................................................................................................. 8
1.2 Secondary objective.......................................................................................................... 8
1.3 Exploratory objective........................................................................................................ 9
1.4 Study design...................................................................................................................... 9
1.5 Planned sample size........................................................................................................ 10
2 General Information.........................................................................................................11
2.1 Background details ......................................................................................................... 11
2.2 Deviations from the trial protocol with regard to statistical analyses............................. 11
2.3 Individual protocol deviations ........................................................................................ 11
3 Analysis Populations........................................................................................................ 12
3.1 Screened Set.................................................................................................................... 12
3.2 Randomized Set .............................................................................................................. 12
3.3 Full Analysis Set............................................................................................................. 12
3.4 Per-protocol Set .............................................................................................................. 12
3.5 Safety Analysis Set ......................................................................................................... 12
3.6 PK Analysis Set .............................................................................................................. 12
4 Statistical Analyses .......................................................................................................... 12
4.1 Conventions .................................................................................................................... 13
4.1.1
Baseline definition ................................................................................................. 13
4.1.2
Missing data........................................................................................................... 13
4.1.3
Study day definition............................................................................................... 13
4.1.4
Completion of study definition.............................................................................. 13
4.1.5
End of Study definition.......................................................................................... 13
4.1.6
Window date .......................................................................................................... 13
4.2 Demographic and other background data ....................................................................... 13
4.3 Disposition...................................................................................................................... 14
4.4 Analysis Sets................................................................................................................... 14
4.5 IMP exposure, compliance ............................................................................................. 15
4.6 Medical history, physical examination ........................................................................... 15
4.7 Prior and concomitant medication .................................................................................. 15
5 Efficacy ............................................................................................................................ 16
5.1 Primary endpoint: Mean change from baseline to week 4 in number of Raynaud’s 
Phenomenon (RP) attacks..................................................................................................... 16
5.1.1
Diary: Number of RP attacks................................................................................. 16
5.1.2
Derivation of the mean change from baseline to week 4 number of RP attacks ... 17
5.1.3
Missing value imputation of primary endpoint...................................................... 17
5.1.4
Descriptive statistics .............................................................................................. 18
5.1.5
Statistical inference on Mean change in number of RP attacks............................. 18
5.1.6
Robustness ............................................................................................................. 18
5.2 Key Secondary endpoints ............................................................................................... 19
5.2.1
Mean change from baseline to week 4 in pain experienced during RP attacks..... 19
5.2.2
Mean change from baseline to week 4 in the Raynaud’s Condition Score (RCS) 20


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5.2.3
Mean change from baseline to week 4 in the cumulative and mean duration of RP 
attacks
20
5.3 Exploratory objectives and endpoints............................................................................. 21
5.3.1
Patient Global Impression of Change at week 4.................................................... 21
5.3.2
Physician Global Impression of Change at week 4. .............................................. 21
5.3.3
Mean change in ASRAP Questionnaire score from baseline to week 4................ 21
5.3.4
Mean change from baseline to week 4 in peripheral blood flow prior to cold 
challenge and IMP administration ........................................................................................ 22
5.3.5
Mean change in peripheral blood flow from pre-IMP to post-IMP administration at 
Visit 2
22
5.3.6
Mean change in recovery of peripheral blood flow after cold challenge from pre-
IMP to post-IMP administration at Visit 2 ........................................................................... 22
5.3.7
Mean change from baseline to week 4 in recovery of peripheral blood flow after 
cold challenge. ...................................................................................................................... 23
5.3.8
Mean change of maximum daily pain score for RP attacks................................... 23
5.4 Subgroup analysis........................................................................................................... 23
6 Pharmacokinetic Endpoints analysis ..............................................................................23
7 Pharmacodynamic analysis..............................................................................................24
7.1.1
Percentage change in PGE2 level in whole blood ex vivo from baseline to week 4.
24
7.1.2
Percentage change in levels of PGEM, PGIM and TXM (AA-metabolites) in urine 
from baseline to week 4. ....................................................................................................... 24
7.1.3
Percentage change in levels of biomarkers in blood/plasma from baseline to week 
4. 24
7.1.4
Expression of platelet surface markers. ................................................................. 25
7.1.5
Change in microvascular volume from baseline to week 4 (D-OCT) ................... 25
8 Safety................................................................................................................................25
8.1 Adverse events................................................................................................................ 25
8.2 Deaths, serious adverse events and other significant adverse events ............................. 27
8.3 Vital signs ....................................................................................................................... 27
8.4 ECG ................................................................................................................................ 27
8.4.1
Descriptive statistics .............................................................................................. 28
8.4.2
QTc prolongation................................................................................................... 28
8.4.3
ECG categorical data ............................................................................................. 29
8.4.4
Listings................................................................................................................... 29
8.5 Laboratory variables ....................................................................................................... 29
8.5.1
Continuous laboratory data:................................................................................... 29
8.5.2
Qualitative laboratory data:.................................................................................... 30
8.6 Interim analyses .............................................................................................................. 30
9 Quality Control................................................................................................................30
10 Derivations and Transformations.................................................................................30
10.1
Formulas for derived variables.................................................................................. 30
10.2
Transformations to be applied................................................................................... 30
11 References ...................................................................................................................... 31
12 Standards used in Preparation of Statistical Outputs..................................................32
12.1
Programming ............................................................................................................. 32
12.2
Layout........................................................................................................................ 32


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12.3
Headers, Titles and Footnotes ................................................................................... 32
12.4
General Conventions ................................................................................................. 33
Appendices..........................................................................................................................35
1. List of Tables, Listings, Figures ..................................................................................... 35
2. List of Efficacy Endpoints .............................................................................................. 35


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LIST OF ABBREVIATIONS
Abbreviation
Description
AE
Adverse Event
ANCOVA
Analysis of Covariance
ASRAP
Assessment of Scleroderma-associated Raynaud's Phenomenon
ATC
Anatomic, Therapeutic, Chemical (Classification System for Drugs)
AUC
Area under the Curve
BMI
Body Mass Index
BP
Blood Pressure
CI
Confidence Interval
CRF
Case Report Form
CSR
Clinical Study Report
DDD
Distal Dorsal Difference
DMP
Data Management Plan
DRM
Data Review Meeting
DVP
Data Validation Plan
ECG
Electrocardiogram
FACS
Fluorescence-activated cell sorting
FAS
Full Analysis Set
ICH
International Council for Harmonisation
IMP
Investigational Medicinal Product
LN
Natural Log
LSmeans
Least Squares Means
MCP
Multiple Comparisons Procedure
MedDRA
Medical Dictionary for Regulatory Activities
MNAR
Missing not at random
PD
Pharmacodynamics
PK
Pharmacokinetics
PP
Per-protocol
PPS
Per-protocol Set
PT
Preferred Term
RCS
Raynaud's Condition Score
RP
Raynaud's Phenomenon
SAE
Serious Adverse Event
SAS
Safety Analysis Set
SAP
Statistical Analysis Plan
SAS®
Statistical Analysis Software Package
SD
Standard Deviation
SOC
System Organ Class
SOP
Standard Operating Procedure
SP
Statistical Programmer
SSC
Systemic sclerosis
TEAE
Treatment Emergent Adverse Event


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TLFs
Tables, Listings, Figures
TS
Trial Statistician


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1 STUDY INFORMATION
1.1 Primary objective
Objectives
Endpoints
Primary:
To determine the safety and efficacy of 
GS-248 versus placebo on RP in sub-
jects with SSc.
EFFICACY
Primary Efficacy:
Mean change from baseline to week 4 in 
the number of Raynaud’s Phenomenon 
attacks per week.
Key secondary efficacy:
Mean change from baseline to week 
4 in the Raynaud’s Condition Score 
(RCS).
Mean change from baseline to week 
4 in the cumulative duration of Ray-
naud’s Phenomenon attacks.
Mean change from baseline to week 
4 in pain experienced during RP at-
tacks.
Exploratory efficacy:
Patient Global Impression of Change 
at week 4.
Physician Global Impression of 
Change at week 4. 
Mean change in ASRAP Question-
naire score from baseline to week 4.
SAFETY
Safety Endpoints:
Incidence of Adverse events.
Incidence of Serious Adverse 
Events.
Clinical laboratory and vital signs.
1.2 Secondary objective
Table 1.1: Study Objectives and Endpoints
Objectives
Endpoints
Secondary:
Secondary:
Mean change from baseline to week 
4 in peripheral blood flow prior to 


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Objectives
Endpoints
To determine the efficacy of GS-248 on 
peripheral vascular blood flow in sub-
jects with SSc and RP.
cold challenge and IMP administra-
tion. 
Mean change in peripheral blood 
flow from pre-IMP to post-IMP ad-
ministration at Visit 2.
Mean change in recovery of periph-
eral blood flow after cold challenge 
from pre-IMP to post-IMP admin-
istration at Visit 2.
Mean change from baseline to week 
4 in recovery of peripheral blood 
flow after cold challenge.
1.3 Exploratory objective
Objectives
Endpoints
Exploratory:
To explore the PK of GS-248.
To explore the efficacy of GS-248 
on PGE2 formation in whole blood 
ex vivo.
To explore the efficacy of GS-248 
on formation of arachidonic acid 
metabolites.
To explore the efficacy of GS-248 
on inflammation and endothelial 
dysfunction.
To explore the efficacy of GS-248 
on platelet activation.
To explore the efficacy of GS-248 
on microvascular volume.
To collect blood and urine for poten-
tial future analysis of inflammatory 
biomarkers and endothelial dysfunc-
tion (results will be reported at a 
later date).
Exploratory:
GS-248 levels in plasma.
Change in PGE2 level in whole 
blood ex vivo from baseline to week 
4.
Change in levels of PGEM, PGIM 
and TXM in urine from baseline to 
week 4.
Change in levels of biomarkers in 
blood/plasma from baseline to week 
4.
Expression of platelet surface mark-
ers.
Change in microvascular volume 
from baseline to week 4.
1.4 Study design
This is a randomised, double-blind, placebo-controlled study conducted in multiple sites in 4 
countries in Europe. Approximately 80 subjects will be randomised in a 1:1 allocation to re-
ceive either GS-248 (120 mg) or placebo daily, stratified to any of the 3 strata of background 


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vasodilatory treatment (Ca-blockers, PDE-5 inhibitors or no background vasodilatory treat-
ment), with approximately 40 subjects in each treatment group.
The study will comprise a run-in/enrolment period, a treatment period, and a follow-up period, 
with a total of 5 study visits.
Figure 1
GS-248 (120 mg) qd oral (N=40)
Placebo qd oral (N=40)
Day
-21 to 
-14
1
15(±2)
28(-2/+1)
42-49
Visit
1
2
3
4
5
Screening/ 
Run-in
Randomization/
Start Treatment
Treatment/analyses
End of Treatment
Follow-up/ 
Final Visit
Study assessments of thermography and pharmacodynamics will be conducted at preselected 
sites based on availability of technology.
The flowchart/schedule of events (several pages) can be found in Appendix 2-4 of the protocol. 
1.5 Planned sample size
Power calculation for the primary efficacy endpoint is based on a two-sided t-test for independent sam-
ples with a type-I error rate. Calculations assumed a mean change from baseline to week 4 of 12.0 for 
the active treatment arm versus 4.0 for the placebo arm, and a common standard deviation of 10.0 with 
a planned power of 80%.
Power calculations reveal that 26 subjects per group are needed to meet the power goal. To allow for a 
drop-out rate of 10%, and some margin for uncertainty in the assumption of variation in the power 
calculation assumed, approximately 80 subjects will be enrolled and randomised into this study.
An estimated 50 subjects will be assessed for the secondary endpoint of mean change in peripheral 
blood flow using thermography and cold challenge.


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2 GENERAL INFORMATION
2.1 Background details
All study data will be transferred to a SAS database (version 9.4 or later) for statistical analysis 
purposes. Data will be imported from a Data Capture System Viedoc and External Data Ven-
dors Lablytica Life Science, University of Manchester, Dr Del Galdo at Chapel Allerton Hos-
pital and Medicover via validated SAS programs.
The SAP will be finalized before database lock and unblinding after agreement with the Spon-
sor on subject disposition and coding.
2.2 Deviations from the trial protocol with regard to statistical analyses
The following deviations from the protocol were identified as being important for the statisti-
cal analysis:
Definition of FAS population was changed to include all randomised and treated subjects. And 
the requirement to have eligible data at visit 4 was removed.
Original text in protocol v4.0: The Full Analysis Set (FAS) includes all subjects who 
were randomized, received at least one dose of IMP and have evaluable data on the 
primary endpoint at visit 4.
The revised definition in the SAP: The Full Analysis Set (FAS), consists of all subjects 
that were randomised and received at least one dose of IMP. 
Definition of PK Analysis Set (PKAS) was changed to include GS-248 treated patients only: 
Original text in protocol v4.0: The PK Analysis Set (PKAS) consists of all subjects 
who received at least one dose of IMP within 30 hours before a blood sample for GS-
248 bioanalysis was taken.
The revised definition in the SAP: The PK Analysis Set (PKAS) consists of all subjects 
who received at least one dose of GS-248 within 30 hours before a blood sample for 
GS-248 bioanalysis was taken.
2.3 Individual protocol deviations
In the course of the study, all protocol deviations will be collected, and during a Blind Data 
Review Meeting (BDRM) with the sponsor, protocol deviations and the consequences regard-
ing the analysis populations and statistical analysis will be assessed. 
The following protocol deviations may affect the evaluation of subject data and will be con-
sidered for exclusion from the Per-Protocol analysis:
Violation of inclusion/exclusion criteria
Not receiving the medication to which the subject was randomized
Use of prohibited concomitant medication
Non-compliance with protocol procedures
Less than 80% compliance with IMP intake


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Any subjects or data values excluded from analysis will be identified, along with their reason 
for exclusion. A complete listing of documented and derived protocol deviations and the judg-
ment for assessment of subject disposition (i.e. analysis population membership) will be signed 
before database lock.
3 ANALYSIS POPULATIONS
3.1 Screened Set 
The Screened Set consists of all subjects that were screened for the study by signing the In-
formed Consent Document. Non-randomized subjects in the screened set, will be considered 
screening failures.
3.2 Randomized Set
The Randomized Set includes all subjects who were randomized. 
3.3 Full Analysis Set
The Full Analysis Set (FAS) includes all subjects who were randomized and received at least 
one dose of the IMP. 
3.4 Per-protocol Set
The Per-Protocol Set (PPS) includes all subjects of the FAS who had no major protocol devi-
ations in a way that might affect the evaluation of the effect of the study drug(s) on the primary 
endpoint as determined during the BDRM. 
3.5 Safety Analysis Set
The Safety Analysis Set (SAS) consists of all subjects who administered the IMP at least 
once.
3.6 PK Analysis Set
The PK Analysis Set (PKAS) consists of all subjects who received at least one dose of GS-248
within 30 hours before a blood sample for GS-248 bioanalysis was taken.
4 STATISTICAL ANALYSES
If not stated otherwise the following standard types of descriptive analyses will be presented:
Descriptive statistics for continuous data
Number of subjects, mean, standard deviation, minimum, lower quartile, median, upper 
quartile, maximum.
Descriptive statistics for categorical data
Percentage bases (denominators) will be identified in the table title or footnote (i.e. all 
subjects at risk, all non-missing cases, all cases).
Inferential statistics
Unless otherwise stated, all statistical tests will be performed two-sided and at a type I er-
ror probability of =0.05. 
Unless otherwise stated, all confidence intervals (CIs) will be derived two-sided and at a 
confidence probability of 1-


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For exploratory endpoints nominal p-values for comparison between treatments using a 
will be presented.
Listings
All recorded data will be listed by subject ID, treatment group and stratification group. 
4.1 Conventions
4.1.1 Baseline definition
The last non-missing measurement prior to first dose will serve as baseline for calculating 
changes from baseline. In practical terms this means that the general approach will use visit 2 
data as the defined baseline and if that is missing, the visit 1 data will be used. For some data, 
e.g demographics, there is only a screening visit and this will be defined as the baseline visit 
in this case. Unscheduled visits will not be used as baseline visits. 
4.1.2 Missing data
For the analyses of the primary endpoint and the key secondary endpoints on the FAS, missing 
data will be replaced using the placebo multiple imputation, (pMI) method. Details are de-
scribed in the primary efficacy endpoint section. All other analyses will be performed on ob-
served data only.
4.1.3 Study day definition
Study day will be calculated relative to the date of randomization i.e. 
If Assessment date < Randomisation Date then;
Study day = Assessment Date – Randomisation Date
Else if Assessment date >= Randomisation Date then;
Study day= Assessment Date – Randomisation Date +1
4.1.4 Completion of study definition
A subject is considered to have completed the study if he/she has completed all visits of the 
study including the Follow-up visit. 
4.1.5 End of Study definition
The end of the study is defined as the date of the last visit of the last subject in the study.
4.1.6 Window date
The Window date in Diary information is the actual date of the event
4.2 Demographic and other background data
Demographic, baseline and disease specific subject characteristics will be summarized in fre-
quency or sampling statistics tables for the FAS and PP population. Tables will be split by 
treatment group and will show pooled groups as well. 
The following variables will be summarized:


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Demographics
Age
Sex
Weight
Height
BMI (calculated)
Country
Centre
Race
Females only: childbearing potential (Yes/No)
Disease specific subject characteristics measured at screening/baseline only
Stratification factors i.e. Background vasodilatory treatment
Baseline Nailfold capillaroscopy (interpretation of vasculopathy of 8 fingers, density, 
width and presence of giant capillaries)
Thyroid hormones (free T3/T4, tot T4, TSH)
SSc-related antibodies
4.3 Disposition
The disposition of subjects, presenting the number of subjects, number and reasons for discon-
tinuations will be tabulated by visit, treatment and overall, for the Screened set. A CONSORT 
flow diagram on subject disposition, will be created in the CSR.
The number and percentage of subjects completing study visits and either completing or dis-
continuing the study, showing the reason for terminations will be presented by treatment for 
the FAS and PP set.
By subject listings of disposition details for discontinued subjects and subjects completing the 
study will be provided. In addition, a by-subject listing of the randomisation scheme and 
codes will be provided. 
Screen failure data will be listed.
4.4 Analysis Sets
The number/percentage of subjects in the various analysis sets will be presented by treatment, 
for the Randomized Set. Frequencies of different reasons for exclusions from the FAS and PP 
set will be presented for the Randomized set.  
Analyses on the FAS population will be done according to the ‘as randomized’ principle, i.e., 
according to the treatment group subjects were randomised to even if they may have got in-
correct treatment. 
Analyses on the SAS and PK set will be done according to the ‘as treated’ principle.
A listing displaying the analysis set information (including reasons for exclusion from each 
analysis population) on a per subject level will be created, based on the outcome of the BDRM.


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4.5 IMP exposure, compliance
The IMP extent of exposure (in days) will be derived as follows:
Duration of exposure (days)=Date of last dose-Date of first dose+1
Exposure duration is based on first and last IMP date, where the first IMP date was captured 
on Visit 2 Day 1 exposure eCRF page and last IMP intake was taken from discontinuation page 
(for early discontinuations) or Visit 4 exposure eCRF page.
Number of IMP intake days is defined as the number of days IMP was taken as recorded in the 
diary and eCRF. When diary information indicated two replies on IMP intake on a same win-
dow date (see definition of window date in section 4.1.6) the last information was used to 
determine IMP intake on that day.
IMP Compliance will be calculated as the ratio of the number of IMP intake days and the IMP 
extent of exposure (number of days IMP should have been taken).
Compliance with IMP is defined as IMP compliance 80%
Non-compliance with IMP is defined as IMP compliance <80%.
A summary of the IMP extent of exposure and cumulative exposure over time, Number of 
IMP intake days, IMP compliance, compliance/non-compliance will be presented per treat-
ment group for the FAS.
A by subject listing of IMP intake, IMP extent of exposure, Number of IMP intake days, cu-
mulative exposure and IMP compliance will be provided. 
4.6 Medical history, physical examination
Medical history will be coded with the latest available version but not older than 23.1 Medical Diction-
ary for Regulatory Activities (MedDRA) and summarized by System Organ Class, Preferred Term, 
treatment group with counts and percentages for the FAS. A subject will only be counted once in a 
System Organ Class and a System Organ Class/Preferred Term combination.
All medical history and physical examination (full and abbreviated (digital ulcer statement)) data will 
be listed.
4.7 Prior and concomitant medication
Any medication taken at time of screening and all new medications taken by the subject dur-
ing the study period are defined as ‘Concomitant’. Any changes of medications during the 
study period will also be recorded.
Prior and concomitant medications will be coded using the WHO Drug Global thesaurus in the 
version current at the time of study start. Coding will be performed by the CRO and agreed 
upon with the sponsor before data base lock. (cf. DMP). Prior and concomitant medication 
tables will show the frequencies of subjects by WHO Drug Global preferred term.


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All details of concomitant medications will also be listed including the route, dose, frequency, 
start and stop date and indication.
Prior and concomitant medications will be analysed based on two periods:
1) Prior medications: medications that the subject started to take prior to Visit 1
2) Concomitant medications: medications that the subject take anytime on or after Visit 1
up to Visit 5
Where dates are missing or partially missing medications will be assumed to be concomitant 
unless there is clear evidence (through comparison of partial dates) to suggest that the medica-
tion started and stopped prior to Visit 1 or started after Visit 5. 
The following summaries will be provided:
A summary of the number and percentage of subjects who used any prior medication 
by ATC (level 3) and PT, by treatment group and overall
A summary of prohibited concomitant medications during study period, ATC (level 3) 
and PT, by treatment group and overall
A summary of all allowed concomitant medications during study period, ATC (level 
3) and PT, by treatment group and overall
The identification of prohibited concomitant medications will be conducted as part of the med-
ical review. 
Multiple records for a subject in the same ATC level 3 category and PT will be counted only 
once in each summary.
5 EFFICACY
5.1 Primary endpoint: Mean change from baseline to week 4 in number of Raynaud’s Phenom-
enon (RP) attacks
5.1.1 Diary: Number of RP attacks
RP attacks in the daily diary 
RP attacks are captured in the diary. For each RP attack the date, start time, stop time and the 
experienced pain (scale of 0 (No pain) to 10 (worst imaginable pain)) is captured. If an RP at-
tack continues into the next day, the RP attack is counted on the date the attack started.
In addition to the daily entry of RP attacks in the diary, the diary is organized in such a way 
that patients are asked, through the previous attack details form, whether they had any RP at-
tacks on the previous day:  
Did you have any attacks yesterday (CEPERF=Yes/No) 
Did you record them all in the diary (CECONF=Yes/No) 
The replies to these questions are used for the interpretation of the RP attacks recorded in the diary in 
the following way:


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If the patient answers (CEPERF=No) or the patient answers (CEPERF=Yes and CE-
CONF=Yes), it is assumed that RP attacks on the previous day are recorded as instructed. 
If the patient confirms both questions (CEPERF=Yes and CECONF=Yes), it is assumed that RP attacks 
on the previous day are recorded as instructed.
If the patient answers CEPERF=Yes and CECONF=No, and any RP attacks are recorded on the previ-
ous day, it is assumed that RP attacks on the previous day are recorded as instructed. 
If the patient answers CEPERF=Yes and CECONF=No, and no RP attacks are recorded on the previous 
day, it is assumed the RP attacks on the previous day are confirmed missing.
Missing value imputation to come to number of RP attacks in the 7 days preceding a 
visit
For each day, starting during the baseline diary week, the number of recorded RP attacks as 
defined above and the number of days with confirmed RP attack information, are counted.
For the baseline week and for week 4 the number of daily attacks in the 7 most recent days 
before a visit (Day 1 and Day 28 (-2/+1)), will be derived by calculating the mean number of 
daily RP attacks on the days with RP attack information in the 7 most recent days and subse-
quently imputing this mean on the days with confirmed missing RP attack information in the 
7 most recent days in the following way: 
1) Summing the number of confirmed RP attacks in the 7 most recent days before a visit
(total number of confirmed RP attacks)
2) Dividing this sum by the number of days with confirmed RP attack information in the 
7 most recent days before a visit (=mean daily number of confirmed RP attacks)
3) Multiplying this mean number of daily attacks with 7.
This derivation results in the number of RP attacks in a week.
5.1.2 Derivation of the mean change from baseline to week 4 number of RP attacks
The primary endpoint for this study is the mean change from baseline to week 4 in the number 
of Raynaud’s Phenomenon attacks per week as derived in 5.1.1 i.e., number of RP attacks in 
week 4 minus the number of RP attacks during the baseline week, where a decrease change in 
the number of RP attacks at week 4 compared to baseline indicates an improvement compared 
to baseline
5.1.3 Missing value imputation of primary endpoint
Missing value imputation for the primary endpoint, i.e. the number of RP attacks in a week
prior to the week 4 visit (i.e for patients missing a week 4 diary due to early discontinuation 
or a lost diary) will be done as follows: 
Placebo multiple imputation assumes that the statistical behaviour of drug- and placebo-
treated patients after discontinuing study medication becomes that of placebo-treated patients. 
Multiple imputations (MIs) are used to replace missing change from baseline at week 4 out-
comes for drug- and placebo-treated patients who discontinued utilizing multiple draws from 
the posterior predictive distribution estimated from the placebo arm, based on the ANCOVA 


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(Analysis of Covariance) model including the  stratification factor (vasodilatory treatment i.e., 
Ca-blockers, PDE-5 inhibitors, or no background vasodilatory treatment) and treatment as 
fixed factors and baseline levels as a covariate in the model.
The final inference on treatment difference is conducted from the multiple datasets using Ru-
bin’s combining rules as implement in SAS PROC MI ANALYSE. Thus, in the effectiveness 
context, pMI assumes no pharmacological benefit of the drug after dropout. In the efficacy 
context, pMI is a specific form of a missing-not-at-random (MNAR) analysis expected to yield 
a conservative estimate of efficacy. 
This process will be performed for both the FAS and PP set.
5.1.4 Descriptive statistics
Descriptive statistics will be presented for the number of RP attacks by visit and mean change 
between visit 4 and baseline, using observed data only.
The analysis of the primary endpoint will be performed using analysis of covariance, AN-
COVA), including the stratification factor (vasodilatory treatment i.e., Ca-blockers, PDE-5 
inhibitors, or no background vasodilatory treatment) and treatment as fixed factors and base-
line levels as a covariate in the model.
5.1.5 Statistical inference on Mean change in number of RP attacks
The null hypothesis is that there is no difference between treatments.
Mean change in the number of RP attacks from baseline to week 4 will be tested using the fol-
lowing:
mean change in active treatment group
mean change in placebo group
The 
H0 : 
Ha : 
The primary objective will be met if there is a p-value <0.05 with a numerical superior effi-
cacy of the active group versus placebo with regard to the primary endpoint, i.e. the mean 
change (reduction) in RP attacks that is greater in the active group. 
Results for the outcome of the primary endpoint will be presented for the least square means 
estimates and accompanying 95% CIs. 
Analysis will be done on the FAS and PP population. The primary analysis population is the 
FAS. 
5.1.6 Robustness
Residuals will be used to assess the adequacy of the ANCOVA model and to detect outliers 
and influential points.


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As a exploratory analysis, analysis will be done on the observed cases only, i.e., with no im-
putation
5.2 Key Secondary endpoints
If the primary efficacy endpoint achieves superiority, p<0.05, formal statistical testing of the secondary 
efficacy endpoints will be performed using a closed testing procedure:
The overall type I family-wise error rate for testing the primary and the key secondary efficacy end-
points will be controlled at the 0.05 significance level using the following 2-family serial gatekeeping 
multiple comparisons procedure (MCP).  Following this MCP, progression to the next family will only 
occur if the null hypothesis with-in the current family is rejected at a family-specific overall significance 
level.  If the null hypothesis within a family is not rejected, the statistical tests corresponding to all 
subsequent families will be considered not statistically significant.  All hypothesis tests will be 2-sided. 
1.
The first family will include the primary endpoint: The p-value for the null hypotheses must be 
less than 0.05 to be considered to have met the primary efficacy objective. If the primary efficacy null 
hypotheses is not rejected (i.e., p-value >0.05), all subsequent statistical tests, i.e. on key secondary and 
will not be considered statistically significant. 
2. The second family will include the key secondary endpoints (see below) and they will be tested using 
an over-all type I error rate of 0.05 by means of a hierarchical procedure in order to control for multi-
plicity within this family. The hierarchical order to test the key secondary variables will be the follow-
ing:
Due to the closed testing procedure, no correction for multiplicity is necessary. If superiority cannot be 
shown, the secondary endpoints will be presented using descriptive statistics, per treatment, and nomi-
nal p-values.
The secondary endpoints will be analysed using the following hierarchical test order:
1) Pain
2) Raynaud’s Condition Score
3) Duration of RP attacks
5.2.1 Mean change from baseline to week 4 in pain experienced during RP attacks
For each RP attack the pain experienced during the RP attack is scored rating from 0 (No 
pain) to 10 (Worst imaginable pain). 
For the baseline week and for week 4 the individual mean pain scores of the RP attacks in the 
7 most recent days before a Visit (Visit 2 and Visit 4), will be derived by calculating the sum 
of individual pain scores of each RP attack in the 7 most recent days before the Visit divided 
by the number of RP attacks in the same period.
Change in mean daily pain will be calculated as the mean of the individual mean pain score at
Visit 4 minus the individual mean pain score at Visit 2.
If there are no attacks in a week, the pain score has no eligible values and in the calculations, 
it will be set to missing.


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The analysis of the mean daily pain experienced during RP attacks endpoint will be similar to 
the analysis of the primary endpoint
5.2.2 Mean change from baseline to week 4 in the Raynaud’s Condition Score (RCS)
Each day, at bedtime the RCS, rating how much difficulty the subject had with their Ray-
naud’s that day on a scale from 0 (No difficulty) to 10 (Extreme difficulty). Blinded diary data 
review showed that patients could enter more than 1 RCS score on a day. Daily RCS scores 
are identified in the diary database through the window date. If more than 1 RCS score was 
entered with the same window date, the last entry (identified either by the event time or by the 
visit, was used as the daily RCS score for that date. The other entry on that date is kept in the 
raw data-sets, but not used in the derivation of the daily RCS score. 
Derivation of mean RCS score in 7 days preceding a visit
The mean RCS score in the 7 days preceding a visit is defined as the mean of the non-missing 
RCS scores of 7 most recent days prior to the visit.
Change in mean RCS score will be calculated as the mean of the individual mean RCS score
at visit 4 minus the mean of the individual mean RCS score at baseline.
The analysis of the Raynaud’s Condition Score endpoint will be similar to the analysis of the 
primary endpoint.
5.2.3 Mean change from baseline to week 4 in the cumulative and mean duration of RP 
attacks
For each RP attack the duration can be derived from the start and stop time points.
The cumulative RP attack duration is defined as follows:
1) Determine the sum of confirmed RP attacks duration on the 7 most recent days with 
confirmed RP attack information prior to a visit. 
2) Determine the mean RP attack duration by dividing the sum of confirmed RP attack
duration by the number of confirmed RP attacks. 
3) Multiply the mean RP attack duration of confirmed RP attacks with the number of RP 
attacks (including imputations) as derived in 5.1.1 to come to the cumulative RP at-
tack duration. 
Blinded Diary review showed that for RP attack duration, some patients entered a stop 
date/time of an RP attack that was before the start date/time of the RP attack. For these entries 
the following rules will be applied: 
•
For the overlapping events – the latest entered event of the overlapping ones (using 
SEQ no. in the database) will be used. The other entry will not be used in any attack reporting 
(RPA, Pain, duration i.e. not be counted at all). The information will be kept in the raw data-
sets.
•
If stop time was before start time – duration will be set to missing, but attacks will as 
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•
If recall period > 1 day this will be a minor protocol deviation, recalled data will not 
be excluded from the analysis. 
Blinded review of the derived cumulative and mean RP attack duration as derived of the 7 
most recent days prior to a visit showed that the derived values have a skewed distribution. 
For that reason, the evaluation of cumulative RP attack duration and mean RP attack duration 
will be done on natural log scale. 
For each patient change in log-transformed cumulated RP attack duration and log-transformed 
mean RP attack duration will be derived as follows:
Change =LN(cumulative RP attack duration prior to week 4 visit) – LN(cumulative 
RP attack duration prior to baseline visit)
Change=LN(mean RP attack duration prior to week 4 visit) - LN(mean RP attack du-
ration prior to baseline visit)
The analysis of the mean change in LN(cumulative duration of RP attacks) and mean change 
in LN (mean RP attack duration) will be similar to the analysis of the primary endpoint.
Descriptive statistics will be provided for the cumulative RP durations and mean RP attack 
durations on both the absolute and the log-transformed scales. After summarizing the log-
transformed values, the back-transformed values of the descriptive statistics of the log-trans-
formed values and of the descriptives of the changes on log-scale will be created for these pa-
rameters at baseline visit and week 4 visit.
5.3 Exploratory objectives and endpoints
5.3.1 Patient Global Impression of Change at week 4.
Patient Global Impression of Change at week 4 will be presented for the number and percent-
age of subjects providing the categorized week 4 responses for each treatment group. 
The statistical analysis will consist of a Cochran-Mantel-Haenszel analysis comparing treat-
ment groups adjusting for the stratification factor. 
5.3.2 Physician Global Impression of Change at week 4.
Physician Global Impression of Change at week 4 will be presented for the number and per-
centage of subjects providing the categorized week 4 responses for each treatment group. 
The statistical analysis will consist of a Cochran-Mantel-Haenszel analysis comparing treat-
ment groups adjusting for the stratification factor.
5.3.3 Mean change in ASRAP Questionnaire score from baseline to week 4
The ASRAP questionnaire score (reporting on the past 7 days) results for each patient in the
ASRAP total score, the sum of all items scores.
The analysis of the Mean ASRAP Questionnaire total score will be similar to the analysis of 
the primary efficacy endpoint using observed data.


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Descriptive statistics of the observed cases and mean change from baseline will be created for 
the ASRAP Questionnaire total score at baseline, week 2, week 4 and at follow-up. 
5.3.4 Mean change from baseline to week 4 in peripheral blood flow prior to cold chal-
lenge and IMP administration 
The following parameters for peripheral blood flow prior to cold challenge are defined:
Mean temperature of all eight fingers prior to cold challenge (MTEMPALL)
Mean Distal Dorsal Difference (DDD) of all eight fingers prior to cold challenge
(MDDDF)
Descriptive statistics of the observed cases and change from baseline will be created for these
parameters at baseline (first assessment at visit 2, t<0) and week 4 (t=-5 min).
The analysis of the peripheral blood flow will be similar to the analysis of the primary effi-
cacy endpoint using observed data.
5.3.5 Mean change in peripheral blood flow from pre-IMP to post-IMP administration 
at Visit 2
The following parameters for peripheral blood flow from pre-IMP to post-IMP administration 
are defined:
Mean temperature of all eight finger after IMP administration but prior to cold chal-
lenge at visit 2 (MTEMPALL)
Mean DDD of all eight fingers after IMP administration but prior to cold challenge at 
visit 2 (MDDDF)
Descriptive statistics of the observed cases and change from baseline will be created for these 
parameters at pre-IMP (Baseline, Session 1, t=80 to 120 min) and post-IMP (Session 2, t=0 to 
150 min).
The analysis of the peripheral blood flow will be similar to the analysis of the primary effi-
cacy endpoint using observed data.
5.3.6 Mean change in recovery of peripheral blood flow after cold challenge from pre-
IMP to post-IMP administration at Visit 2
The following parameters for recovery of peripheral blood flow after cold challenge from pre-
IMP to post-IMP administration are defined:
Recovery of peripheral blood flow, in terms of mean LN(AUC temp at all eight fin-
gers after cold challenge and after IMP administration) at Visit 2. (Session 2, 
LN(MAUC8))
Mean LN(maximum temperature of all eight fingers after cold challenge and after 
IMP administration) at Visit 2. (Session 2, LN(MMAX8))
After summarizing the log-transformed values, the back-transformed values of the descriptive 
statistics of the log-transformed values and of the descriptives of the changes on log-scale will 
be created for these parameters at pre-IMP (Baseline, Session 1) and post-IMP (Session 2).


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The analysis of the peripheral blood flow will be similar to the analysis of the primary effi-
cacy endpoint using observed data.
5.3.7 Mean change from baseline to week 4 in recovery of peripheral blood flow after 
cold challenge.
The following parameters for recovery of peripheral blood flow after cold challenge are de-
fined:
Recovery of peripheral blood flow, in terms of mean LN(AUC temp all eight fingers 
after cold challenge) at visit 4.
Mean LN(maximum temperature of all eight fingers after cold challenge) at Visit 4.
After summarizing the log-transformed values, the back-transformed values of the descriptive 
statistics of the log-transformed values and of the descriptives of the changes on log-scale will 
be created for these parameters at pre-IMP (Baseline, Session 1) and post-IMP (Visit 4).
The analysis of the peripheral blood flow will be similar to the analysis of the primary effi-
cacy endpoint using observed data.
5.3.8 Mean change of maximum daily pain score for RP attacks 
For each RP attack the pain experienced during the RP attack is scored rating from 0 (No 
pain) to 10 (Worst imaginable pain). 
For the baseline week and for week 4 the mean maximum daily pain score over the 7 most re-
cent days before a visit (Day 1 and Day 28 (-2/+1)), will be derived by calculating the mean 
maximum daily pain score on the days with RP attack information in the 7 most recent days. 
Mean change of maximum daily pain scores between week 4 and baseline is derived as the 
mean of individual differences of week 4 maximum daily pain minus baseline maximum daily 
pain.
5.4 Subgroup analysis
Subgroups are defined by “use of background vasodilatory treatment” stratification factors: 
Ca-blockers
PDE-5 inhibitors
No background vasodilatory treatment 
Descriptive statistics of primary and key secondary endpoints will be created for these 3 sub-
groups. 
6 PHARMACOKINETIC ENDPOINTS ANALYSIS
The pharmacokinetic endpoints analysis of GS-248 will be described later in an amended version of the
SAP.


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7 PHARMACODYNAMIC ANALYSIS
7.1.1 Percentage change in PGE2 level in whole blood ex vivo from baseline to week 4.
PGE2 levels are measured in a subgroup at pre-selected sites. The endpoint is the percentage 
change from baseline at week 4. 
No modelling will be done.
Descriptive statistics of the observed cases will be created for these parameters at baseline, 
week 4, change from baseline and percentage change from baseline at visit 4.
A by-treatment boxplot will be created for the percentage change from baseline at week 4. 
7.1.2 Percentage change in levels of PGEM, PGIM and TXM (AA-metabolites) in urine 
from baseline to week 4.
Results for AA_metabolites will be corrected for urinary creatinine concentration in the fol-
lowing way: 
Urinary creatinine is measured in mg/dL, this results in the following formula for the AA_me-
tabolite in ng/mg:
AA_metabolite concentration in ng/mg=(100*AA-metabolite analyte concentration in 
ng/ml)/(Creatinine concentration in mg/dL).
The endpoint is the percentage change from baseline at week 4 of the AA_metabolite.
Descriptive statistics  will be created for the observed cases of AA metabolites expressed in 
ng/mg) at baseline, week 4, change from baseline (in ng/mg) and for percentage change from 
baseline at week 4.
A by-treatment boxplot will be created for the percentage change from baseline at week 4. 
7.1.3 Percentage change in levels of biomarkers in blood/plasma from baseline to week 
4.
The following biomarkers for inflammation and endothelium dysfunction are predefined:
hsCRP
Endothelin-1
sE-selectin
xICAMI
TNF
IL-lb
IL-4
IL-6
IL-10
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CD40L
von Willebrand factor
The endpoint for these parameters is the percentage change from baseline at week 4. 
Descriptive statistics of will be created for the observed cases of biomarkers at baseline, week 
4, change from baseline and for percentage change from baseline at week 4.
A by-treatment boxplot will be created for the percentage change from baseline at week 4. 
7.1.4 Expression of platelet surface markers.
The FACS (Fluorescence-activated cell sorting) at pre-selected sites was cancelled by the 
sponsor. Available FACS data gathered prior to the cancellation will be listed. 
7.1.5 Change in microvascular volume from baseline to week 4 (D-OCT)
Microvascular volume (plexus depth, vessel diameter, vessel density microvascular volume) is meas-
ured in a subgroup at one pre-selected site.
No modelling will be done.
Descriptive statistics of the observed cases will be created for the microvascular volume at 
baseline, visit 4 and change from baseline at week 4.
8 SAFETY
The Safety Analysis Set (SAS) will be used for the analysis of safety data.
8.1 Adverse events
All AEs occurring during the course of the study will be coded using the latest MedDRA coding 
dictionary at the time of DBL. All AEs (serious and non-serious) reported from the first day of 
study treatment up until and including 7 days after the last dose of study treatment will be 
considered treatment emergent AEs (TEAEs). 
Where dates are missing or partially missing, AEs will be assumed to be treatment-emergent, 
unless there is clear evidence (through comparison of partial dates) to suggest that the AE 
started prior to the first dose of study treatment or more than 7 days after the last dose of study
treatment. 
Verbatim terms will be coded by Ergomed and all relevant codes will be stored in the database. 
It is assumed that for each change in intensity, relationship or seriousness of an AE a new entry 
of the AE was recorded in the data capture database; hence such cases will be analysed like 
different phases of the same AE. 
Subjects experiencing more than one AE within a given SOC category will be counted only 
once when calculating the number and percentage of subjects experiencing that SOC (e.g., a 
subject that experiences both nausea and vomiting will only be counted once in such calcula-
tions for the SOC gastrointestinal disorders). Similarly, subjects experiencing the same AE 


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multiple times throughout the course of the trial will be counted only once when calculating the 
number and percentage of subjects experiencing that PT (e.g., a subject that experiences mild 
nausea in both the first and fourth treatment cycle will only be counted once in such calculations 
for mild nausea). If a PT is reported at more than one severity level for a given subject, the 
greatest severity will be presented in the summary table. 
If the same PT is reported multiple times for a given subject, but with varying study drug rela-
tionship assignment, the worst-case attribution will be presented in the summary table. 
An AE is considered drug-related if the relationship to study drug is classified as either ‘Pos-
sible’ or ‘Probable’.
The following AE summaries will be provided:
An AE overview table will be created displaying the number of TEAEs, number/per-
centage of subjects experiencing any TEAE, deaths, any SAE, any TEAEs causing 
discontinuation, any severe TEAE and any drug-related TEAE per treatment group. 
A summary of the number of events (TEAEs) by treatment group, SOC and PT
A summary of the number and percentage of subjects reporting a TEAE by treatment 
group, SOC and PT
A summary of the number of TEAEs by treatment group, intensity and PT
A summary of the number and percentage of subjects reporting a TEAE by treatment 
group, intensity and PT
A summary of the number and percentage of subjects reporting a TEAE by treatment 
group, relationship and PT
A summary of the number of
treatment group and PT
A summary of the number and percentage of subjects reporting a non-serious adverse 
event occuring in greater than 5% of subjects by treatment group, SOC and PT
TEAE summaries will be ordered in terms of international order of SOC, and alphabetically 
for PT within SOC.
frequency.
For each subject and each AE, the worst intensity recorded will be attributed and used in the 
by-intensity summaries. Similarly, the worst relationship will be attributed and used in the by-
relationship summaries. 
All adverse events (i.e. TEAEs as well as non-treatment emergent events) will be listed in 
section 16.2 of the CSR.  However, only TEAEs will be summarized in the tables.
AE listings will be presented by treatment group and will include: subject identifier, treatment, 
age, sex, race, AE (PT and verbatim term), study day of onset, duration, intensity, seriousness, 
action taken, relationship, outcome and concomitant medication given (incluing CM number).


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8.2 Deaths, serious adverse events and other significant adverse events
TEAEs will be included in the summary tables below.
The following AE summaries will be provided on deaths, SAEs and other significant adverse 
events:
A summary of the number and percentage of subjects reporting a TEAE with outcome 
of death by treatment group, SOC and PT
A summary of key subject information for subjects reporting TEAE with outcome of 
death
A summary of the number of SAEs reported by treatment group, SOC and PT
A summary of the number and percentage of subjects reporting a SAE by treatment 
group, SOC and PT
A summary of key subject information for subjects reporting a SAE
A listing and summary of subjects reporting COVID-19 infection as recorded as an AE
Detailed listings of all fatal and other serious events will be provided (for section 14.3.2). Nar-
ratives will not be included in section 14.3.3 but will be provided by medical writing in section 
12.3.2 of the CSR. 
8.3 Vital signs
For the vital signs safety analysis, data from Visit 2 onwards will be used only. 
Vital signs parameters (systolic/diastolic blood pressure, heart rate, body weight) will be as-
sessed at each of the visits as per schedule of assessment. 
The following summaries will be provided:
A summary of the observed absolute values and change from baseline in each vital sign 
parameter by treatment group and time point.
Any clinically relevant vital signs measurement was to be recorded as an AE and will be pre-
sented with the AEs. 
By-subject listings of vital signs (including screening data) will also be provided.
8.4 ECG
ECGs are scheduled at the following visits/time-points:  
Visit/Time
ECG schedule
Visit 1/Screening 
Triple ECG
ECG result summary


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Visit 2/Day 1, prior to dosing
Triple ECG
ECG result summary
Visit 2/Day 1, 170 min post-IMP ad-
ministration
Triple ECG 
ECG result summary
Visit 3/Day 15
Triple ECG
ECG result summary
Visit 5/Follow-up (and/or early ter-
mination)
Triple ECG
ECG result summary
For the ECG safety analysis, data from Visit 2 onwards will be used only. 
The following ECG parameters are captured: 
RR interval
PR interval
QRS interval
QT interval
QTc interval
QTcF interval
Mean QTcF interval
ECG normality/abnormality evaluation
8.4.1 Descriptive statistics
The triple ECG parameter results will be averaged per assessment (visit 2 (pre-dose, baseline), 
visit 2 (170 min post dose), 3 and 5). 
For the derivation of change from baseline, the mean of the triple ECG pre-dose measurement
on visit 2/Day 1 will be used as the baseline value.
The following summaries will be provided:
Descriptive statistics of the mean absolute values and change from baseline of the mean
values for each ECG parameter by treatment group and time point for visit 2 (pre-dose, 
baseline), visit 2 (post-dose), visit 3 and visit 5. 
8.4.2 QTc prolongation
Evaluation of QTc prolongation will be based on the mean QTcF interval parameter as captured 
in the eCRF.
QTcF Frequencies will be calculated for following classified values and changes (according to 
ICH E14):
Absolute values: <450 ms as normal, >450-480 ms, >480-500 ms, >500 ms
Changes from baseline: decreases or increases <30 as normal, increases >30-60 
ms, increases >60 ms.


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8.4.3 ECG categorical data
For the evaluation of ECG categorical data the result at the visit 2, pre-dose will be used as 
the baseline value.
The 12-lead ECG categorical data, will be summarized by treatment group using a shift table 
from baseline to each subsequent assessment time point and categories of normal, abnormal 
NCS, and abnormal CS. 
8.4.4 Listings
Screening ECG data will be included in the listings only. 
By-subject listings of ECG results (original, mean of triple measurements and ECG abnormal-
ities) will be provided. 
8.5 Laboratory variables
The following routine laboratory safety data are collected through the Central Laboratory:
Clinical chemistry
Haematology
Urinalysis
Albumin
Sodium
Potassium
Calcium, total
Glucose
C-reactive protein (P-CRP)
Bilirubin, total
Bilirubin - conjugated
Uric acid
ASAT
ALAT
Cholesterol
Cystatin C
Creatinine
eGFR
Osmolality
Urea or BUN
ALP
GT
LDH
Electrophoresis
pro-BNP
Haemoglobin
Erythrocyte count 
Ery-Mean Corpuscular Volume 
Haematocrit (Erythrocyte volume fraction)
Platelet count (Thrombocyte particle concen-
tration)
Leukocyte count (LPC)
Leukocyte differential, absolute count (lym-
phocytes, monocytes, neutrophil-, eosino-
phil- and basophil- granulocytes)
pH
Glucose
Ketone
Bilirubin
Blood
Creatinine
WOCBP pregnancy test
Drug screen
For the safety laboratory analysis, data from Visit 2 onwards will be used only. 
8.5.1 Continuous laboratory data:
Continuous data laboratory safety data (original values and change from baseline) will be 
summarized using descriptive statistics per visit and treatment group.
Frequencies of high and low values with respect to the normal range will be displayed by 
visit and treatment group
Shift tables comparing each post-baseline visit with baseline with respect to normal range 
will be displayed by treatment group. 


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In addition, abnormal values outside reference ranges will be summarized in a listing per 
visit and per subject.
8.5.2 Qualitative laboratory data:
For qualitative laboratory safety data ordered frequency tables will be prepared per visit and 
treatment group.
Frequencies of shift comparing each post-baseline visit with baseline will be displayed by 
treatment group. 
8.6 Interim analyses
There is no interim analysis planned for this study.
9 QUALITY CONTROL
The SAP was prepared by the TS. Particularly the TS has checked the consistency of the de-
scribed methods and outputs with the actual version of the study protocol. In addition, a spon-
sor representative has reviewed the SAP before final approval.
Log files of all SAS® programs used in the analysis will be checked for errors, warnings and 
suspicious notes by the statistical programmer. All findings will be either eliminated or com-
mented upon. The final version of each program will be stored along with its log file in the
electronic archive.
All programs will be validated by the program author or an independent statistical programmer
depending on the requested validation level selected in the List of TLFs
form 
(FRM/BS/001.02) for a particular program. 
The agreement of the program outputs with the SAP, their consistency and plausibility will be 
checked by the TS. Moreover, the TS will review the outputs regarding completeness, reada-
bility and comprehensibility.
The described process is associated with the 'normal' level of program validation. Additional 
levels of quality control can be specified in the List of TLFs (see Appendix, 1) for individual 
outputs.
10 DERIVATIONS AND TRANSFORMATIONS
10.1Formulas for derived variables
Variable
Definition / Derivation
BMI
Weight [kg] / (height [m])**2
10.2Transformations to be applied
Not applicable


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11 REFERENCES
Not applicable.


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12 STANDARDS USED IN PREPARATION OF STATISTICAL OUTPUTS
The below conventions will be followed as agreed with the Sponsor.
12.1Programming
One SAS program should create only one output.
One output file can contain different output types (e.g. descriptive and inferential). 
Individual output files will be created in MS Word format (Rich Text Format, RTF).
Once delivered to the client, numbering of TLFs will not be altered, unless agreed with the 
client
12.2Layout
TLFs will be produced in landscape format
TLFs will have a minimum 2 cm on every side
TLFs will be produced using the Courier New font, size 8 
Section numbering of TLFs will follow ICH E3 guideline.
Numbering of TLFs will follow the convention XXX-YY, where XXX stands for a (sub-
)section number of the ICH E3 guideline and YY represents the sequence number of the 
output within the section. A dash (‘-‘) will always be used to separate section numbers 
from output sequence numbers
Titles and footnotes for figures will also be in Courier New font, size 8.
Tables and listings will be in black and white (no colour), figures may include only colour
that can be distinguished when printed on a grey-scale printer 
Text styles, such as bolding, italics, borders, shading, and superscripted and subscripted 
text, will be used sparingly in the TLFs
The ANSI character set will be used in the TLFs. Certain subscripts and superscripts (e.g., 
m2, AUCnorm) will be employed on a case-by-case basis.
Mixed case will be used for all titles, footnotes, column headers, and programmer-supplied 
formats, unless they are derived directly from the data
12.3Headers, Titles and Footnotes
All output will have the following header at the top left of each page showing the study 
ID, the date of output generation and an internal pagination, where Y stands for the total 
number of pages in the pertaining output.
Study ID
Study description
ERGOMED, YYYY-MM-DD
Page [ X / Y ]
Also, all TLFs will have the following footer, identifying the generating SAS program 
(XXX.SAS), a reference to the relevant subject listing and the date of the data snapshot:
SAS program: <XXX>.sas
Ref. list X.X.X-YY
Data status: YYYY-MM-DD
Each TLF will bear a title which is repeated on each page of the output.
The title at the top of the page will be horizontally cantered in bold font.
A blank line will separate the title from the body of the output.


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CONFIDENTIAL
The title will consist of an Output number, a descriptive title and a description of the pre-
sented analysis set (if applicable). 
The title will have the following general appearance:
Table / Figure / List XX.X.X-YY
Descriptive Title line 1
Descriptive Title line 2
(All subjects in the FAS, N=nnn)
Each new footnote should start on a new line, where possible.
Preferably, footnotes should be left justified. When extending beyond a single line, a man-
ual linefeed should be inserted to avoid meaning distortion.
An automatic footnote ‘(continued)’ will appear at the bottom of TLFs that extend over 
more than one page.
12.4General Conventions
For measured variables column headers should include the unit in their description
The order of treatment arms in the TLFs will be consistent throughout the entire 
TLF presentation
Alphanumeric values are preferably displayed left-justified;
Dates are presented left-justified
Integer numbers (e.g., counts) can be centered or right-aligned
Numbers containing fractional portions will be decimal-aligned.
Fractional numbers with absolute value less than 1 will carry a leading zero, i.e. 0.123 not 
.123.
Units of measured or derived variables will be included where appropriate
Unless otherwise warranted, the estimated mean, median and quartiles for a set of values 
will be displayed with 1 more significant digit than the original values, and standard devi-
ations with 2 more significant digits. The minimum and maximum should report the same 
significant digits as the original values. 
P-values are output in the format: “0.xxxx”, where xxxx is the value rounded to 4 decimal 
places. P-values less than 0.0001 will be presented as <0.0001.
Precision of percentages displayed will depend on the total study size. For studies with less 
than 1000 subjects, values will be presented with one decimal place. For studies with more 
than 1000 subjects, values will be presented with two decimal places. 
Tabular display of data for medical history, prior/concomitant medications and all tabular 
displays of adverse event data are generally presented by body system, treatment class, or 
SOC according to the Internationally Agreed Sorting Order of the MedDRA, unless other-
wise agreed.
The percentage of subjects is normally calculated as a proportion of the number of subjects 
assessed in the relevant treatment group (or overall) for the analysis (sub-) population pre-
sented. 
For categorical summaries (number and percentage of subjects) where a subject can be 
included in more than one category, an explanatory text will be added to clarify that mul-
tiple answers were possible.


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Statistical Analysis Plan Version 2.0
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Gesynta Pharma AB
Protocol No
GS-2001
CONFIDENTIAL
Missing values will be displayed either by a double-dash (“--”) or as “NA” (=’not availa-
ble/applicable’), whichever is appropriate.
Dates are displayed in according to ISO date/time format as YYYY-MM-DD, e.g. 2010 03 
24. Missing dates may be represented as “NA”, if not available/applicable.
Clock times are displayed as HH:MM or HH:MM:SS based on 24-hour clock


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Statistical Analysis Plan Version 2.0
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Protocol No
GS-2001
CONFIDENTIAL
APPENDICES
1.
List of Tables, Listings, Figures
A complete List of tables, listings, figures (TLFs) will be given in a separate document 
which can be updated without updating the SAP. The List will serve as a reference for 
both the Sponsor, the TS and the SP and describes the entire set of statistical output to be 
produced. Therefore, this List will be versioned and approved by both Ergomed and Spon-
sor before commencing the statistical programming
2.
List of Efficacy Endpoints
Below the Efficacy Endpoints are listed. No derivation details beyond what is in sections 5, 6 and 
7 of this SAP are applicable.
Primary endpoint: 
Mean change from baseline to week 4 in number of Raynaud’s Phenomenon (RP) 
attacks
Key Secondary endpoints
Mean change from baseline to week 4 in pain experienced during RP attacks
Mean change from baseline to week 4 in the Raynaud’s Condition Score (RCS)
Mean change from baseline to week 4 in the cumulative and mean duration of RP 
attacks
Exploratory objectives and endpoints
Patient Global Impression of Change at week 4
Physician Global Impression of Change at week 4
Mean change in ASRAP Questionnaire score from baseline to week 4
Mean change from baseline to week 4 in peripheral blood flow prior to cold chal-
lenge and IMP administration
Mean change in peripheral blood flow from pre-IMP to post-IMP administration 
at Visit 2
Mean change in recovery of peripheral blood flow after cold challenge from pre-
IMP to post-IMP administration at Visit 2
Mean change from baseline to week 4 in recovery of peripheral blood flow after 
cold challenge.
Pharmacokinetic Endpoints analysis
GS-248 levels in plasma. And PK parameters as described in section 6.1
Pharmacodynamic analysis
Percentage change in PGE2 level in whole blood ex vivo from baseline to week 4.
Percentage change in levels of PGEM, PGIM and TXM (AA-metabolites) in urine 
from baseline to week 4.
Percentage change in levels of biomarkers in blood/plasma from baseline to week 
4.
Change in microvascular volume from baseline to week 4 (D-OCT)