Conditions: Dermatomyositis
Keywords: DM
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 95
Healthy volunteers: no

Brief summary:
Prospective, Double-blind, Randomized, Placebo-Controlled Phase III Study Evaluating Efficacy and Safety of Octagam 10% in Patients With Dermatomyositis ("ProDERM study")

Detailed description:

Arms:
arm 1: Subjects randomized to placebo will receive 4 infusions of placebo every 4 weeks during the blinded First Period (16 weeks). If confirmed deterioration (deterioration at 2 consecutive visits) during the First Period, subjects will be switched to Octagam 10%. After response assessment at Week 16, all subjects with no confirmed deterioration and subjects switched to Octagam 10% due to confirmed deterioration but without further confirmed deterioration during the First Period will continue to receive 2.0 g/kg of Octagam 10% every 4 weeks during the subsequent 6-months open-label Extension Period. At Week 28, subjects who are stable on 2.0 g/kg Octagam 10% can be switched to 1.0 g/kg Octagam 10%, at the discretion of the investigator. Subjects randomized to placebo and switched to Octagam 10% due to confirmed deterioration, who deteriorate also during Octagam 10% treatment at 2 consecutive visits will drop-out after response assessment at Week 16 and will not enter the Extension Period. arm 2: Subjects randomized to Octagam will receive 4 infusions of 2.0 g/kg Octagam 10% every 4 weeks during the blinded First Period (16 weeks). If confirmed deterioration (deterioration at 2 consecutive visits) during the First Period, subjects will be switched to the alternate treatment. After response assessment at Week 16, all subjects with no confirmed deterioration during the First Period will continue receiving 2.0 g/kg of Octagam 10% every 4 weeks during the subsequent 6-months open-label Extension Period. At Week 28, subjects who are stable on 2.0 g/kg Octagam 10% can be switched to 1.0 g/kg Octagam 10%, at the discretion of the investigator. Subjects randomized to Octagam and switched to the alternate treatment due to confirmed deterioration will drop-out after response assessment at Week 16 and will not enter the Extension Period.

Interventions: intervention 1: Octagam 10% intervention 2: Placebo
Intervention descriptions: intervention 1: Patients to be treated with Octagam 10% intervention 2: Patients to be treated with a Placebo

Protocol document:
Prot_000.pdf: 
This document contains confidential and proprietary information of Octapharma Pharmazeutika Produktionsges.m.b.H. 
Do not copy or distribute without written permission. 
090-CSP-GAM10-08-V12 / DOC ID 2983
CLINICAL
 STUDY PROTOCOL 
PROSPECTIVE, DOUBLE-BLIND, RANDOMIZED, 
PLACEBO-CONTROLLED PHASE III STUDY 
EVALUATING EFFICACY AND SAFETY OF 
OCTAGAM 10% IN PATIENTS WITH 
DERMATOMYOSITIS 
(ProDERM Study) 
Investigational Product: 
Immune Globulin Intravenous, Human 10% 
(Octagam 10%) 
Indication: 
Dermatomyositis (DM) 
Study Design: 
Prospective, parallel group, double-blind, 
randomized, placebo-controlled, multicenter, 
phase III study. 
Sponsor: 
Octapharma Pharmazeutika Produktionsges.m.b.H. 
Oberlaaer Str. 235, 1100 Vienna, Austria 
Study Number: 
GAM10-08 
EudraCT and IND Number: 
EudraCT 2016-002902-37 / IND 16925 
Development Phase: 
Phase III 
Planned Clinical Start: 
Quarter 4 2016 
Planned Clinical End: 
Quarter 4 2019 
Date of Protocol: 
18-Jun-2019
Version: 
12 
Coordinating Investigator: 
Phoenix Neurological Associates 
5090 N 40th St, Suite 250 
Phoenix, AZ 85018, USA 
This document contains confidential and proprietary information of Octapharma. Copying or
distribution of this document is only permitted with the written permission of Octapharma. Any
commercial use of the information is subject to the permission of Octapharma and a license fee.


 
 
CONFIDENTIAL 
 
Page ii 
STUDY OUTLINE  
Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H., 1100 Vienna, Austria 
Name of Investigational Product: 
Octagam 10% 
Protocol Identification Code: 
GAM10-08 (ProDERM), Version 12  
Name of Active Ingredient: 
Immune Globulin Intravenous, Human 10% 
Date of Protocol: 
18-Jun-2019 
 
Title of Study: 
Prospective, Double-blind, Randomized, Placebo-Controlled Phase III Study Evaluating 
Efficacy  and  Safety  of  Octagam 10%  in  Patients  With  Dermatomyositis  (“ProDERM 
study”) 
Indication: 
Dermatomyositis (DM). 
Number of Study Centre(s): 
Approximately 55 selected study sites worldwide. 
Objectives: 
Primary Objective: 
The primary objective of this study is to provide confirmatory data on the beneficial effect 
of 2.0 g/kg of Octagam 10% given every 4 weeks compared with placebo in subjects with 
active DM based on the percentage of responders at Week 16. 
Secondary Objectives: 
The secondary objectives of this study are 
• to evaluate the beneficial effect of Octagam 10% in subjects with active DM by 
assessing different parameters and scores at Week 16 and Week 40; 
• to confirm the sustained benefit of treatment with Octagam 10% by assessing the 
primary response measures at Week 40; 
• to evaluate the safety and tolerability of Octagam 10% in subjects with DM. 
Study Design: 
Prospective,  parallel  group,  double-blind,  randomized,  placebo-controlled,  multicenter 
Phase III study with a controlled 16-week efficacy period followed by a 24-week open-
label extension period. 
Number of Subjects: 
A minimum of 94 adult subjects of both genders are to be enrolled. 
 


 
 
CONFIDENTIAL 
 
Page iii 
Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H., 1100 Vienna, Austria 
Name of Investigational Product: 
Octagam 10% 
Protocol Identification Code: 
GAM10-08 (ProDERM), Version 12  
Name of Active Ingredient: 
Immune Globulin Intravenous, Human 10% 
Date of Protocol: 
18-Jun-2019 
 
Subject Selection Criteria: 
Inclusion Criteria: 
1. Subjects with diagnosis of definite or probable DM according to the Bohan and 
Peter criteria. 
2. Subjects  under  treatment  with  corticosteroids  and/or  maximally  2 immune-
suppressants and being on stable therapy for at least 4 weeks (see Section 4.2.1) 
OR 
Subjects with previous failure of response or previous intolerance to corticosteroid 
and  at  least  1 additional  immunosuppressive  drug,  and  with 
steroid/immunosuppressive drugs washed out as per Section 4.2.1 (Table 2).  
3. Subjects  with  active  disease,  assessed  and  agreed  upon  by  an  independent 
adjudication committee. 
4.  Manual  Muscle  Testing-8  
(MMT-8) score  <142,  with  at  
least  2 other  abnormal 
Core Set Measures (CSM) (Visual Analogue Scale [VAS] of patient global activity 
≥2 cm, physician’s global disease activity ≥2 cm, extra-muscular activity ≥2 cm; at 
least  one  muscle  enzyme  >1.5 times  upper  
limit  of  normal,  Health  Assessment 
Questionnaire ≥0.25). 
5. Males or females ≥ 18 to < 80 years of age. 
6. Voluntarily given, fully informed written consent obtained from subject before any 
study-related procedures are conducted. 
7. Subject must be capable to understand and comply with the relevant aspects of the 
study protocol. 
Exclusion Criteria: 
1. Cancer-associated myositis, defined as the diagnosis of myositis within 2 years of 
the diagnosis of cancer (except basal or squamous cell skin cancer or carcinoma in 
situ  of  the  cervix  that  has  been  excised  and  cured  and  at  least 1 or 5 years, 
respectively, have passed since excision). 
2. Evidence  of  active  malignant  disease  or  malignancies  diagnosed  within  the 
previous 5 years (including hematological malignancies and solid tumors) or breast 
cancer diagnosed within the previous 10 years. 
3. Subjects  with  overlap myositis  (except  for  overlap  with  Sjögren’s  syndrome), 
connective tissue disease associated DM, inclusion body myositis, polymyositis, 
juvenile dermatomyositis or drug-induced myopathy. 
4. Subjects with immune-mediated necrotizing myopathy with absence of typical DM 
rash. 


 
 
CONFIDENTIAL 
 
Page iv 
Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H., 1100 Vienna, Austria 
Name of Investigational Product: 
Octagam 10% 
Protocol Identification Code: 
GAM10-08 (ProDERM), Version 12  
Name of Active Ingredient: 
Immune Globulin Intravenous, Human 10% 
Date of Protocol: 
18-Jun-2019 
 
5. Subjects with generalized, severe musculoskeletal conditions other than DM that 
prevent a sufficient assessment of the subject by the physician. 
6. Subjects  who  have  received  IgG  treatment  within  the  last  6 months  before 
enrolment. 
7. Subjects  who received  blood  or  plasma-derived  products  (other  than  IgG)  or 
plasma exchange within the last 3 months before enrolment. 
8. Subjects starting or planning to start a physical therapy–directed exercise regimen 
during the trial. 
9. Cardiac  insufficiency  (New  York Heart  Association  III/IV),  cardiomyopathy, 
significant cardiac dysrhythmia requiring treatment, unstable or advanced ischemic 
heart disease. 
10. Severe liver disease, with signs of ascites and hepatic encephalopathy. 
11. Severe kidney disease (as defined by estimated glomerular filtration rate (eGFR) 
< 30 mL/min/1.73 m2). 
12. Known hepatitis B, hepatitis C or HIV infection. 
13. Subjects with a history of TEE such as deep vein thrombosis, 
pulmonary embolism, 
myocardial infarction, ischemic stroke, transient ischemic attack, peripheral artery 
disease (Fontaine IV) ever. 
14. Body mass index ≥40 kg/m2. 
15. Medical  conditions  whose  symptoms  and  effects  could  alter  protein  catabolism 
and/or IgG utilization (e.g. protein-losing enteropathies, nephrotic syndrome). 
16. Known IgA deficiency with antibodies to IgA. 
17. History of hypersensitivity, anaphylaxis or severe systemic response to immuno-
globulin, blood or plasma derived products or any component of Octagam 10%. 
18. Known blood hyperviscosity, or other hypercoagulable states. 
19. Subjects  with  a history  of  drug  abuse  within  the  past  5 years  prior  to study 
enrollment. 
20. Subjects unable or unwilling to understand or comply with the study protocol. 
21. Participating in another interventional clinical study with investigational treatment 
within 3 months prior to study enrollment. 
22. Women who are breast feeding, pregnant, or planning to become pregnant, or are 
unwilling to apply an effective birth control method (such as implants, injectables, 
combined oral contraceptives, some intrauterine devices [IUDs], sexual abstinence 
or vasectomized partner) up to four weeks after the last IMP infusion. 
23. Subjects  who  are  accommodated  in  an  institution  or  care  facility  based  on  an 
official directive or court order. 


 
 
CONFIDENTIAL 
 
Page v 
Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H., 1100 Vienna, Austria 
Name of Investigational Product: 
Octagam 10% 
Protocol Identification Code: 
GAM10-08 (ProDERM), Version 12  
Name of Active Ingredient: 
Immune Globulin Intravenous, Human 10% 
Date of Protocol: 
18-Jun-2019 
 
24. Subjects who are in any way dependent on the Sponsor, Investigator or Study Site. 
25. Subjects who received forbidden medication within the washout period as defined 
in Section 4.2.2 (Table 3). 
Test Product, Dose, and Mode of Administration: 
Octagam 10% is an IGIV ready for intravenous administration. The product is delivered 
as ready-to-use solution in glass bottles. Octagam 10% should be stored and transported 
light-protected at +2°C to +8°C (36°F to 46°F) and must not be frozen. 
First  Period  (Octagam 10% vs.  placebo in  double-blind  design): 2.0 g/kg (20 mL/kg) 
Octagam 10% or 20 mL/kg placebo given over 2 to 5 days at 4-week intervals (in total 
4 infusion cycles). 
Extension Period:  2.0 g/kg (20 mL/kg) Octagam 10%  given  over  2 to  5 days  at  4-week 
intervals (in  
total  6  
infusion cycles). At Week  28,  subjects  who  are stable  on  2.0 g/kg 
Octagam 10% can be switched to 1.0 g/kg (10 mL/kg) Octagam 10%, at the discretion of 
the investigator. 
Duration of Treatment: 
The duration of the entire study for each subject will be up to 43 weeks and consists of the 
following segments: up to 3 weeks for Screening, then 16 weeks of double-blind treatment 
phase (First Period) followed by 24 weeks of open-label treatment (Extension Period). 
Reference Therapy, Dose, Mode of Administration: 
Sodium chloride 0.9% w/v solution. 
Study Outcome Parameters (Primary and Secondary Endpoints): 
Efficacy Endpoints: 
Primary 
• Proportion  of  responders  in  the 2.0 g/kg Octagam 10%  and  placebo  arms  at 
Week 16.  A  responder is defined  as  a  subject  with  an  increase  from  baseline 
(Week 0) of ≥20 points on the Total Improvement Score (TIS) and who has not met 
“Confirmed  Deterioration”  criteria  at 2 consecutive  visits  as  defined  in 
Section 4.3.1 up to (including) Week 16. 
Secondary 
• Proportion  of  TIS  responders  by  improvement  category  (minimal,  moderate, 
major) at Week 16 and Week 40. 
• Mean  change  from  baseline  (Week 0)  to  end  of  First  Period  (Week 16)  in the 
modified Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI). 


 
 
CONFIDENTIAL 
 
Page vi 
Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H., 1100 Vienna, Austria 
Name of Investigational Product: 
Octagam 10% 
Protocol Identification Code: 
GAM10-08 (ProDERM), Version 12  
Name of Active Ingredient: 
Immune Globulin Intravenous, Human 10% 
Date of Protocol: 
18-Jun-2019 
 
• Mean  change  from  end  of  First  Period  (Week 16)  to  end  of  Extension  Period 
(Week 40) in the modified CDASI. 
• Mean  change  from  Baseline  (Week  0)  to  end  of  First  Period  (Week 16)  and 
Extension Period (Week 40) in:  
o SF-36v2 Health Survey; 
o Individual 6 CSM used for TIS calculation. 
• Mean  TIS  from  Baseline  (Week  0)  
to end  of  First  Period  (Week 16)  and from 
Baseline (Week 0) to end of Extension Period (Week 40). 
• Time to minimal, moderate and major improvement in TIS. 
• Time to confirmed deterioration in the First Period and overall. 
• Proportion  of  subjects  in  each  treatment  arm  who  met confirmed  deterioration 
criteria up to (including) Week 16 
Safety Endpoints: 
Safety (throughout the entire First and Extension Period): 
• Occurrence  of  all  adverse  events with  particular  emphasis  on  thromboembolic 
events (TEEs) and hemolytic transfusion reactions (HTRs). 
• Occurrence of all adverse drug reactions (ADRs) and suspected ADRs. 
• Vital signs (blood pressure, heart rate, body temperature and respiratory rate). 
• Physical examination (at Screening and every 12 weeks from Week 4 on). 
• Laboratory parameters (hematology, clinical chemistry). 
Safety (at Baseline and end of Extension Period): 
• Tests for viral safety.  
• Pregnancy test, if applicable. 
Study Procedures: 
Subjects eligible after screening will be randomized 1:1 to receiving up to 4 infusion cycles 
of either Octagam 10% or placebo every 4 weeks during the First Period lasting 16 weeks. 
After  response  assessment  at  Week 16,  all  subjects  who  have  not  deteriorated at 
2 consecutive visits during the First Period will continue to receive 2.0 g/kg (20 mL/kg) of 
Octagam 10% during the subsequent 6-months Extension Period. At Week 28, the subject 
may be switched to 1.0 g/kg (10 mL/kg) Octagam 10%, if previously has been stable on 
the 2.0 g/kg (20 mL/kg) Octagam 10% dose. 
In case of confirmed deterioration (i.e. deterioration at 2 consecutive visits) 
during the First 
Period, subjects will be switched to the alternate treatment. After response assessment at 
Week 16 this subgroup of subjects will be unblinded.  


 
 
CONFIDENTIAL 
 
Page vii 
Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H., 1100 Vienna, Austria 
Name of Investigational Product: 
Octagam 10% 
Protocol Identification Code: 
GAM10-08 (ProDERM), Version 12  
Name of Active Ingredient: 
Immune Globulin Intravenous, Human 10% 
Date of Protocol: 
18-Jun-2019 
 
Subjects  originally randomized  to  placebo and  switched  to 2 g/kg (20 mL/kg) 
Octagam 10% after confirmed deterioration and who do not further deteriorate during their 
Octagam 10%  treatment  will  continue  and  receive 2.0 g/kg (20 mL/kg) Octagam 10% 
during  the  6-months  Extension  Period.  For  subjects  who  will  be  stable  on  2.0 g/kg 
(20 mL/kg) Octagam 10%, the investigator may decide to switch the subject to 1.0 g/kg 
(10 mL/kg) Octagam 10%, at Week 28. Subjects originally randomized to placebo and 
switched  
to  Octagam 10%  due  
to confirmed deterioration,  who  deteriorate  also  during 
Octagam 10% treatment at 2 consecutive visits will drop-out after response assessment at 
Week 16 and will not enter the Extension Period. 
Subjects originally randomized to Octagam 10% who deteriorate at 2 consecutive visits 
in the First Period and who were subsequently switched to placebo will drop-out after the 
response assessment at Week 16 and will not enter the Extension Period. 
Subjects  dropping  out  due  
to  confirmed deterioration  will  
in  any  case  be  classified  as 
non-responders in the statistical analysis.  
Any subject deteriorating in the Extension Period will drop-out, independent of the initially 
assigned treatment arm. 
The  study  assessments  and scheduled  time  points  are  summarized  in  the  flowchart 
following this Study Outline. 
Statistical Analysis Plan: 
The primary endpoint measure ‘response’ will be assessed at Week 16 based on the TIS 
score; a subject is defined as responder if 
(i) the subject has a TIS score of ≥20 points at Week 16 and 
(ii) the subject has not met “Confirmed Deterioration” criteria at 2 consecutive visits  
as defined in Section 4.3.1 up to (including) Week 16  
Otherwise the patient will be counted as a non-responder. 
The proportion of responders within both treatment groups will be compared by Cochran-
Mantel-Haenszel test, stratified by global disease activity (randomization stratum), using 
two-sided alpha level of 0.05. The primary analysis will be considered as success if the 
proportion  of  
responders  
is  significantly  higher  
in  
the  Octagam  group  compared  
to  
the 
placebo group. 
Moreover, an exact two-sided 95% confidence-interval will be constructed for the overall 
difference in the proportion of responders between Octagam and placebo group, using the 
‘exact riskdiff’ option of the SAS FREQ procedure.   
In  a  sensitivity  analysis  for  the  primary  endpoint,  a  logistic  regression  model  will  be 
applied, including  global disease activity  and further baseline variables as applicable as 
covariates. 


 
 
CONFIDENTIAL 
 
Page viii 
Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H., 1100 Vienna, Austria 
Name of Investigational Product: 
Octagam 10% 
Protocol Identification Code: 
GAM10-08 (ProDERM), Version 12  
Name of Active Ingredient: 
Immune Globulin Intravenous, Human 10% 
Date of Protocol: 
18-Jun-2019 
 
All other endpoints will be analyzed and presented in full detail by means of descriptive 
statistics and inferential analyses as appropriate, including summary and frequency tables, 
confidence intervals and graphs. 
A formal statistical analysis plan describing all details of the analyses to be performed will 
be prepared by the study statistician and approved by the Sponsor. 
The  evaluation  of the  primary efficacy  endpoint  will  be  based  on the intention-to-treat 
population, i.e. all randomized subjects. 
The analysis of safety will be based on the safety analysis set which includes all patients 
who received at least part of one infusion of Octagam 10% or placebo. 


Study Protocol   
CONFIDENTIAL 
Version 12 
GAM10-08 (ProDERM) 
FLOWCHART OF ASSESSMENTS 
18-Jun-2019 
 
Page ix 
Table 1: 
Flowchart of Assessments Performed During the Study 
ASSESSMENTS 
Screening Baseline 
First Period 
Extension Period 
Throughout 
 
Visit 1 Week 
-3 to 0  
Visit 2 
Week 0 
Visit 3 
Week 4  
Visit 4 
Week 8 
Visit 5 
Week 12 
Visit 6 
Week 16  
Visit 7 
Week 20 
Visit 8 
Week 24 
Visit 9 
Week 28 
 Visit 10 
Week 32 
Visit 11 
Week 36 
Termination 
visit Week 40 / 
Drop-out Visit 
Unscheduled 
Visit 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic and baseline 
characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Med. hist./Prior medication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Standard ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Blood for viral markers 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Blood sample for D-dimers 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X2 
 
 
 
 
 
 
 
 
 
 
 
Physical examination2 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Vital signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Body weight2 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
Safety laboratory2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum IgG2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Enzymes2 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
Biomarkers blood sample 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
Blood sample for additional 
safety lab5 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
Direct Coombs’ test5 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
CSM for TIS determination2 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
CDASI2 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
SF-36 Health Survey2 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
Wells score for DVT4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Wells score for PE4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Infusion of IMP 
1 
 
X* 
X* 
X* 
X* 
X** 
X** 
X** 
X# 
X# 
X# 
 
 
Adverse event monitoring 
 
Throughout the study 
Concomitant medication 
 
Throughout the study 
1 Infusion cycles can last between 2 to 5 days, consisting of 2 or more infusion episodes.  
2 Before IMP administration; 
3 Before, during and after each infusion episode;  
4 At screening and after each infusion cycle; 
5 Before and after infusion cycle;   
*Blinded infusion of either placebo or 2.0 g/kg Octagam 10% 
**Unblinded infusions of 2.0 g/kg Octagam 10%;  
#In case subject is stable on the 2.0 g/kg Octagam 10% dose, they can be switched to 1.0 g/kg Octagam 10%, at the discretion of the investigator


Study Protocol
CONFIDENTIAL
Version 12
18-Jun-2019
GAMI0-08 (ProDERM)
PROTOCOL SIGNATURES
This study is intended to be conducted in compliance with the protocol,
Good Clinical Practice and applicable regulatory requirements.
International Medical Director
on behalf ofthe Sponsor
Octapharm a Pharmazeutika Produktionsges.m.b.H.
Oberlaaer Strasse 235
1100 Vienna, Austria
 
Clinical Project Manager 
Signature
Octapharm a Pharmazeutika Produktionsges.m.b.H.
Oberlaaer Str. 235
1100 Vienna, Austria
e
Manager Biometrics
O ctapharm a Pharmazeuti ka Produkti ons ge s. m. b. H
Oberlaaer Str. 235
1100 Vienna, Austria
/{. 
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Date
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Page 10 of 7l
Date




Study Protocol  
CONFIDENTIAL 
Version 12 
GAM10-08 (ProDERM) 
 
18-Jun-2019 
 
Page 12 of 71 
TABLE OF CONTENTS 
STUDY OUTLINE 
........................................................................................................................ II 
PROTOCOL SIGNATURES 
................................
................................
......................................... 10 
PROTOCOL SIGNATURES 
................................
................................
......................................... 11 
TABLE OF CONTENTS 
.............................................................................................................. 12 
LIST OF ABBREVIATIONS 
....................................................................................................... 15 
1 INTRODUCTION 
................................
................................
.................................................. 16 
1.1 I
MMUNOGLOBULINS........................................................................................... 16
 
1.2 I
DIOPATHIC I
NFLAMMATORY MYOPATHIES 
....................................................... 16
 
1.3 RATIONALE FOR CONDUCTING THE STUDY 
........................................................ 17
 
1.4 DOSE RATIONALE 
................................
.............................................................. 17 
1.5 BENEFIT-R
ISK STATEMENT................................................................................ 18
 
2 STUDY OBJECTIVES 
................................
................................
.......................................... 19 
2.1 PRIMARY OBJECTIVE(
S) 
.................................................................................... 19 
2.2 SECONDARY OBJECTIVE(
S) 
............................................................................... 19 
3 INVESTIGATIONAL PLAN 
................................
................................
................................ 19 
3.1 PRIMARY AND SECONDARY ENDPOINTS 
............................................................ 19
 
3.1.1 Primary Endpoint ............................................................................................ 19 
3.1.2 Secondary Endpoints 
................................
....................................................... 20 
3.2 OVERALL STUDY DESIGN AND PLAN 
................................
................................. 20 
3.3 DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUP 
................... 23
 
3.3.1 Study Design 
................................
................................
.................................... 23 
3.3.2 Control Groups 
................................
................................
................................ 23 
3.3.3 Study Parameters 
............................................................................................ 23 
4 STUDY POPULATION 
....................................................................................................... 24 
4.1 POPULATION BASE ............................................................................................ 24
 
4.1.1 Inclusion Criteria 
............................................................................................ 24 
4.1.2 Exclusion Criteria 
........................................................................................... 24 
4.2 PRIOR AND CONCOMITANT THERAPY 
................................
................................ 26 
4.2.1 Permitted Concomitant Therapy 
..................................................................... 26 
4.2.2 Forbidden Concomitant Therapy 
.................................................................... 27 
4.3 WITHDRAWAL AND REPLACEMENT OF SUBJECTS 
.............................................. 28
 
4.3.1 Premature Subject Withdrawal 
....................................................................... 28 
4.3.2 Subject Replacement Policy 
............................................................................ 29 
4.4 ASSIGNMENT OF SUBJECTS TO TREATMENT GROUPS 
......................................... 29
 
4.5 RELEVANT PROTOCOL DEVIATIONS .................................................................. 30
 
4.6 SUBSEQUENT THERAPY 
................................
..................................................... 30 
5 INVESTIGATIONAL MEDICINAL PRODUCT(S) 
.......................................................... 30 
5.1 CHARACTERIZATION OF I
NVESTIGATIONAL PRODUCT(
S) 
................................... 30 
5.2 PACKAGING AND LABELING .............................................................................. 31 
5.3 CONDITIONS FOR STORAGE AND USE................................................................. 34
 
5.4 DOSE AND DOSING SCHEDULE 
.......................................................................... 34 
5.5 PREPARATION AND METHOD OF ADMINISTRATION 
............................................ 35
 


Study Protocol  
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Version 12 
GAM10-08 (ProDERM) 
 
18-Jun-2019 
 
Page 13 of 71 
5.6 BLINDING,
 EMERGENCY ENVELOPES,
 AND BREAKING THE STUDY BLIND 
......... 35
 
5.7 TREATMENT COMPLIANCE 
................................................................................ 36 
5.7.1 Drug Dispensing and Accountability 
...............................................................
 36 
5.7.2 Assessment of Treatment Compliance ............................................................. 37 
6 STUDY CONDUCT ............................................................................................................... 37 
6.1 OBSERVATIONS BY VISIT 
.................................................................................. 37 
6.1.1 Screening Visit (Visit 1; duration up to 21 days, i.e. Week -3 to 0) 
................. 37 
6.1.2 Visit 2 (Week 0; Baseline of First Period) 
....................................................... 38 
6.1.3 Visit 3 (Week 4; First Period) 
......................................................................... 38 
6.1.4 Visits 4 and 5 (Week 8 and 12; First Period) .................................................. 39 
6.1.5 Visit 6 (Week 16; End of First Period, Start of Extension Period) 
.................. 40 
6.1.6 Visits 7 and 8 (Week 20 and 24; Extension Period) ........................................ 40 
6.1.7 Visit 9 (Week 28) 
............................................................................................. 41 
6.1.8 Visits 10, 11 (Week 32 and 36; Extension Period) .......................................... 42 
6.1.9 Unscheduled Visit 
................................
............................................................ 42 
6.1.10 End-of-Study (Final Examination) Visit 12 (Week 40; Extension Period) or 
Drop-out Visit 
................................
................................
.................................. 42 
6.1.11 Time Windows Used in this Study, Including Tolerances 
................................ 44 
6.1.12 Clinical Terms Used in this Study 
................................................................... 44 
6.2 DURATION OF STUDY ........................................................................................ 44
 
6.2.1 Planned Duration for an Individual Subject 
.................................................... 44 
6.2.2 Planned Duration for the Study as a Whole .................................................... 44 
6.2.3 Premature Termination of the Study 
............................................................... 45 
7 ASSESSMENTS AND METHODS ...................................................................................... 47 
7.1 DEMOGRAPHIC AND BASELINE I
NFORMATION 
................................................... 47
 
7.1.1 Demographic and Baseline Characteristics 
.................................................... 47 
7.1.2 Medical History and Prior/Concomitant Medications 
.................................... 47 
7.2 EFFICACY ASSESSMENTS 
................................
................................................... 47 
7.2.1 Assessments for Primary Efficacy Endpoint(s) 
................................................ 47 
7.2.2 Assessments for Secondary Efficacy Endpoint(s) 
............................................ 48 
7.3 SAFETY ASSESSMENTS ...................................................................................... 48 
7.3.1 Assessments for Safety Endpoints 
................................
.................................... 48 
7.3.2 Adverse Events (AEs) 
...................................................................................... 48 
7.3.3 Serious Adverse Events (SAEs) 
....................................................................... 51 
7.3.4 SAE Reporting Timelines 
................................
................................................. 52 
7.3.5 Adverse Events of Special Interest (AESI) 
....................................................... 53 
7.3.6 Laboratory Tests 
................................
.............................................................. 55 
7.3.7 Viral Safety Tests 
................................
............................................................. 56 
7.3.8 Vital Signs and Physical Examination 
............................................................. 56 
7.3.9 Other Relevant Safety Information 
................................
.................................. 56 
7.4 OTHER ASSESSMENTS 
....................................................................................... 57 
7.4.1 Drug Concentration Measurements 
................................................................ 57 
7.4.2 Blood Sample for Biomarkers of Disease Activity 
........................................... 57 
7.4.3 Quality of Life Assessment 
.............................................................................. 58 
7.5 APPROPRIATENESS OF MEASUREMENTS ............................................................ 58
 
8 DATA HANDLING AND RECORD KEEPING................................................................. 59 
8.1 DOCUMENTATION OF DATA 
.............................................................................. 59 
8.1.1 Source Data and Records 
................................
................................................ 59 


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8.1.2 Electronic Case Report Forms ........................................................................ 59 
8.1.3 Changes to Case Report Form Data 
............................................................... 59 
8.2 I
NFORMATION TO I
NVESTIGATORS 
.................................................................... 60 
8.3 RESPONSIBILITIES 
................................
.............................................................. 60 
8.4 I
NVESTIGATOR’
S SITE FILE 
............................................................................... 61 
8.5 PROVISION OF ADDITIONAL I
NFORMATION 
........................................................ 61
 
8.6 COMMITTEES 
................................
................................
..................................... 61 
8.6.1 Independent Adjudication Committee 
.............................................................. 61 
8.6.2 Independent Data Monitoring Committee 
....................................................... 61 
8.6.3 Steering Committee 
......................................................................................... 62 
9 STATISTICAL METHODS AND SAMPLE SIZE ............................................................ 62 
9.1 DETERMINATION OF SAMPLE SIZE 
................................
..................................... 62 
9.2 STATISTICAL ANALYSIS 
.................................................................................... 63 
9.2.1 Populations for Analysis 
................................................................................. 63 
9.2.2 Efficacy Analysis Plan 
................................
..................................................... 64 
9.2.3 Safety Analysis Plan......................................................................................... 65 
9.2.4 Handling of Missing Data 
............................................................................... 66 
9.3 RANDOMIZATION,
 STRATIFICATION,
 AND CODE RELEASE 
................................. 66
 
9.4 I
NTERIM ANALYSIS 
........................................................................................... 66 
10 ETHICAL/REGULATORY, LEGAL AND ADMINISTRATIVE ASPECTS 
................. 67 
10.1 ETHICAL/R
EGULATORY FRAMEWORK 
...............................................................
 67 
10.2 APPROVAL OF STUDY DOCUMENTS 
................................
................................... 67 
10.3 SUBJECT I
NFORMATION AND I
NFORMED CONSENT 
............................................ 67
 
10.4 PROTOCOL AMENDMENTS ................................................................................. 67 
10.5 CONFIDENTIALITY OF SUBJECT DATA 
............................................................... 68 
11 QUALITY CONTROL AND QUALITY ASSURANCE 
.................................................... 68 
11.1 PERIODIC MONITORING 
................................
..................................................... 68 
11.2 AUDIT AND I
NSPECTION 
.................................................................................... 68 
12 REPORTING AND PUBLICATION 
................................
................................................... 68 
12.1 CLINICAL STUDY REPORT 
................................................................................. 68 
12.2 PUBLICATION POLICY 
................................
........................................................ 68 
13 LIABILITIES AND INSURANCE 
................................
....................................................... 69 
14 REFERENCES 
................................
................................
....................................................... 70 


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LIST OF ABBREVIATIONS 
ADR(s) 
Adverse Drug Reaction(s) 
AE(s) 
Adverse Event(s) 
AESI 
Adverse Event of Special 
Interest 
ALAT 
Alanine Aminotransferase 
ASAT 
Aspartate 
Aminotransferase 
BW 
Body Weight 
CDASI 
Cutaneous 
Dermatomyositis Disease 
Area and Severity Index 
CRO 
Contract Research 
Organization 
CSM 
Core Set Measures 
DEHP 
Diethylhexylphthalate 
DM 
Dermatomyositis 
DOI 
Definition of 
Improvement 
DVT 
Deep Vein Thrombosis 
eCRF 
Electronic Case Report 
Form 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EFNS 
European Federation of 
Neurological Societies 
EMA 
European Medicines 
Agency 
FAS 
Full Analysis Set 
FDA 
Food and Drug 
Administration 
GDA 
Global Disease Activity 
GCP 
Good Clinical Practice 
HAQ 
Health Assessment 
Questionnaire 
HTR 
Hemolytic Transfusion 
Reaction 
IAC 
Independent Adjudication 
Committee 
IB 
Investigator
's Brochure 
IDMC 
Independent Data 
Monitoring Committee 
IMACS 
International Myositis 
Assessment and Clinical 
Studies Group 
IEC 
Independent Ethics 
Committee 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IGIV 
Immunoglobulin 
Intravenous 
IIM(s) 
Idiopathic Inflammatory 
Myopathy(ies) 
IMP 
Investigational Medicinal 
Product 
IRB 
Institutional Review 
Board 
IRT 
Interactive Response 
Technology 
LDH 
Lactate Dehydrogenase 
MDAAT 
Myositis Disease Activity 
Assessment Tool 
MedDRA 
Medical Dictionary for 
Regulatory Activities 
MMT 
Manual Muscle Testing 
NSAID 
Non-Steroidal Anti-
Inflammatory Drug 
PE 
Pulmonary Embolism 
PM 
Polymyositis 
PP 
Per Protocol 
PVC 
Polyvinyl Chloride 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SF-36v2 
Short Form 36 Items 
Health Status Version 2 
SOP 
Standard Operating 
Procedure 
TEAE(s) 
Treatment Emergent 
Adverse Event(s) 
TEE(s) 
Thromboembolic Event(s) 
TIS 
Total Improvement Score 
TSH 
Thyroid-stimulating 
hormone 
VAS 
Visual Analogue Scale 
VTE 
Venous 
Thromboembolism 
 


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1 INTRODUCTION 
1.1 Immunoglobulins 
Since more than 5 decades immunoglobulins have been used to provide antibodies for the 
prevention  of  viral  and  bacterial  diseases  
(replacement  
therapy)  
in  
immunocompromised 
patients. Within the last 30 years intravenous immunoglobulins (IGIVs) have been proven 
to  be  useful in  a  wide  variety  of  clinical  conditions  (other  than  classical  replacement 
therapy),  
in  which  IGIVs exhibit  an  
immunomodulatory  effect.  These  
include  
idiopathic 
thrombocytopenia in children and adults at high risk of bleeding or prior to surgery to correct 
the  platelet  count,  Kawasaki  disease  and  Guillain-Barré  syndrome.  More  
recently,  single 
IGIV  brands  have  also  been  licensed  for  chronic  inflammatory  demyelinating 
poly(radiculo)neuropathy and multifocal motor neuropathy. Experimental off-label use of 
IGIV in other neurological and dermatological indications is widespread. 
Octagam 5% and Octagam 10% are liquid intravenous polyvalent IGIV preparations, which 
are prepared from human plasma and mainly contain human normal immunoglobulin G. The 
molecules are present in their native form, which is essential for their biological activity. 
Octagam 5% is  approved since February  1995  and  
is  currently  marketed  
in 82 countries 
worldwide, while Octagam 10% got its first license in May 2008 and is now approved in 
55 countries worldwide. 
1.2 Idiopathic Inflammatory Myopathies 
Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of acquired, systemic 
connective tissue diseases characterized by chronic inflammation of striated muscles leading 
to predominantly proximal muscle weakness. They are best classified on the basis of their 
varying clinical characteristics into the most common subsets of IIM: adult dermatomyositis 
(DM) and polymyositis (PM), juvenile DM, necrotizing autoimmune myositis, myositis in 
overlap with cancer or another connective tissue disease, and inclusion body myositis.[1] 
IIMs are frequently associated with constitutional symptoms and commonly involve other 
organ systems including the skin, joints, lungs, gastrointestinal tract and heart. Patients with 
IIM  have  
increasing  difficulty  with  
tasks requiring  
the  use  of  proximal  muscles,  such  as 
getting up from a chair, climbing steps, or lifting objects. In rare acute cases also respiratory 
muscles  can  be  affected.  Extra-muscular  disease  activity  may  manifest  in  systemic 
symptoms  like  fever,  arthralgia,  and  Raynaud’s  phenomenon,  cardiac  arrhythmias  or 
ventricular  dysfunction,  and  pulmonary  complications, primarily due  to  interstitial  lung 
disease (reported in 10-40% of patients).[1] 
IIMs are rare with an estimated incidence of 4-10 cases/million population per year, and a 
bimodal  
incidence  pattern  
reflecting  childhood  onset  of  
juvenile  DM  and  a  
later  peak  
in 
adulthood.[2] 
Each IIM subtype has a different prognosis and response to therapies so that the distinction 
from other diseases is very important. Although the precise pathogenesis is unknown, the 
IIMs  
likely  
result  
from  
immune-mediated  processes  
initiated  by  environmental  
factors  
in 
genetically susceptible individuals.[3] 
Although a spectrum of severity exists for DM, this entity is more likely to be associated 
with rapid and aggressive myositis. DM is seen in both, children and adults, and the early 
symptoms  include  distinct  skin  manifestations  accompanying  or  preceding  muscle 


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weakness. The classic skin manifestations include periorbital heliotrope (blue–purple) rash 
with edema; erythematous rash on the face, knees, elbows, malleoli, neck, anterior chest (in 
a V-sign), and back and shoulders (in a shawl sign); and a violaceous eruption (Gottron’s 
rash)  on  the  knuckles,  which  may  evolve  into  a  scaling  discoloration.  The  lesions  are 
photosensitive and may be aggravated by ultraviolet radiation.[1] 
The risk of cancer is increased in adults during the first 3-5 years after the onset of DM, with 
a reported frequency of 9-32%; necessitating a thorough annual workup in the first 3 years 
after  disease  onset.  The  most  common  forms  are  ovarian,  breast,  and  colon  cancer, 
melanoma, and non-Hodgkin’s lymphoma.[1] 
1.3 Rationale for Conducting the Study 
In addition to its use for the treatment of primary and secondary immunodeficiencies, IGIV 
is increasingly used for immunomodulating therapy in the treatment of patients with a variety 
of  autoimmune  and  inflammatory  neurological  disorders.  However,  there  is  only 
1 placebo-controlled  clinical  study  in 15 subjects  with  refractory  DM  published  so  far, 
employing a dose of 2.0 g/kg IGIV or placebo for 12 weeks. After a 1-month washout phase 
the  subjects crossed  over to  
the  alternate  
therapy.[4] Subjects  on  IGIV  had  a  significant 
improvement  
in  muscle  strength  and  neuromuscular  symptoms  
in  contrast  
to subjects  on 
placebo. A total of 12 subjects received IGIV of which 9 subjects had a major improvement 
to nearly normal function. 
The rationale for conducting this study (ProDERM: “Progress in DERMatomyositis”) is to 
investigate efficacy, safety and tolerability of Octagam 10% in DM patients and to confirm 
the  efficacy  results,  which  were  observed  in the small  randomized  placebo-controlled 
cross-over trial [4] and also seen in retrospective studies or case reports, in a much larger 
setting.  Furthermore,  ProDERM  will  systematically  investigate  the  long-term  beneficial 
effect of IGIV in a 6-month open-label extension period. Long-term safety and tolerability 
of high-dose Octagam 10% (2.0 g/kg) administered for up to 40 weeks will be investigated, 
since  many  patients  need  
lifelong  
treatment.  Eventually,  Octagam 10%  should  offer  DM 
patients an additional effective and safe maintenance treatment option that is well tolerated. 
1.4 Dose Rationale 
In 1989, Imbach and colleagues published a randomized placebo-controlled trial in which 
IGIV at a dose of 2.0 g/kg has been used for the first time in an immunomodulatory setting 
in immune thrombocytopenia.[5] Later retrospective and case studies relied mostly to this 
dosage scheme and the effect of IGIV has never been systematically examined in another 
randomized placebo-controlled trial since. 
Subjects with mild to moderate DM may respond to lower doses of IGIV. Therefore, and 
following  a  recommendation  of  the  FDA,  subjects  may  receive  the  lower  1.0 g/kg 
Octagam 10% dose from Week 28 on, depending on the investigator’s decision and if the 
higher dose has shown to be effective in the individual subject. An Advisory Board of DM 
experts  in  the  fields  of  neurology,  rheumatology  and  immunology  confirmed  this 
observation.  Reference  
is  also made to a group of investigators in  
Italy  who successfully 
treat their patients with weekly (subcutaneous) doses of only 0.1-0.2 g/kg, corresponding to 
a monthly (intravenous) dose of 0.8 g/kg.[31] 


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1.5 Benefit-Risk Statement 
The risks of IGIV administration are well documented. In general, the incidence of adverse 
events (AEs) associated with IGIV tends to increase with the rate of infusion, and thus the 
recommended  dosage,  infusion  rates,  and  monitoring  procedures  should  be  adhered  to. 
Subjects that are naïve to IGIV are more at risk than those that are well maintained and on 
regular therapy. 
Subjects with pre-existing risk factors for thrombotic events (such as advanced age, obesity, 
hypertension,  diabetes  mellitus  and  a  history  of  vascular  disease  or  
thrombotic  episodes, 
subjects with acquired or inherited thrombophilic disorders, subjects with prolonged periods 
of  
immobilization,  severely  hypovolemic subjects, subjects  with  diseases  which  
increase 
blood viscosity) may be at risk.  
Subjects  with  DM  may  be  at  higher  risk  of  developing  
thromboembolic  events  (TEEs). 
Carruthers  and  colleagues  [33] conducted  matched  cohort  analyses  for venous 
thromboembolism (VTE) (i.e. deep vein thromboses [DVT] or pulmonary embolism [PE]) 
among individuals with PM (PM cohort) or DM (DM cohort) as compared with individuals 
without PM or DM (comparison cohorts), using data from the Canadian British Columbia 
Health Database (PopData BC). This was the first large general population-based study to 
assess the  risk  of  VTE  in PM/DM patients. Risk  of  VTE  was substantially  higher  in 
individuals  with PM/DM  compared to the  general  population  (six  and  eight  times, 
respectively). According to Chung and colleagues [34] DM and PM patients exhibit even an 
11.1-fold increased risk of VTE compared to non-DM/PM patient cohort.  
Elderly patients with DM/PM exhibited a multiplicative increased risk of VTE development 
compared to the control panel, and the DM/PM patients with any comorbidity showed an 
additive risk of developing VTE. 
The  risk  of  VTE  may  be  even  higher  in  the  initial years  after  diagnosis according  to 
Carruthers  and  colleagues  
[33],  PM  patients  had  
the  highest  
risk  during  
the  
first  year  of 
diagnosis and progressively  attenuated over time. Similarly, DM  patients had  
the highest 
risk during the first two years after diagnosis. 
Therefore, special emphasis will be given to the occurrence of TEEs such as DVTs and PE. 
Hemolytic  
transfusion  
reactions  
(HTRs) can  develop  subsequent  
to  
IGIV  
therapy.  
IGIV-
related hemolysis is associated with passive transfer of anti-A and anti-B hemagglutinins. 
When medicinal products prepared from human blood or plasma are given to a subject, the 
transmission of infectious agents cannot be totally excluded. This applies also to hitherto 
unknown pathogens. However, specific virus inactivation procedures are implemented in the 
manufacturing process of Octagam 10% which are described in detail in the Investigator
's 
Brochure. 
For  Octagam 10%,  
the  same  
type  of  adverse  reactions  has  been  seen  as  for  other  IGIV 
products. No new or unknown safety problems are expected to emerge which are not already 
described in the Investigator
's Brochure. 
As  per  European  Federation  of  Neurological  Societies  (EFNS)  Guidelines[6],  IGIV  is 
recommended as a second-line treatment in combination with prednisone in DM (level B) 
and treatment option in PM (level C). This is in line with the consensus statement of the 
American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) ad hoc 
committee on the use of IGIV in the treatment of neuromuscular conditions: Class I evidence 
exists to support the use of IGIV to treat patients with DM.[7] Over the last years, high-dose 
IGIV  has  become  an  effective  and  safe  
therapeutic  option  
for  DM  and  
is  beneficial  as  a 
second-line therapy for DM.[8] 
The European Dermatology Forum stated in their “Guideline 


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on  the  use  of  high-dose  intravenous  immunoglobulin  in  dermatology”  that,  besides 
Pemphigus vulgaris, DM is the dermatological condition with the highest level of evidence 
for treatment with IGIV.[9] IGIV is indicated for all severe forms of DM and its use as first-
line  treatment  may  be  justified  in  patients  with  fulminant  progressive  courses,  severe 
myolysis or paralysis. As a rule, IGIV should be used as a second-line treatment if steroid 
monotherapy has failed to produce an improvement after 1 month, or if reducing the steroid 
dose below an acceptable level results in a flare-up of the disease, or if side-effects prevent 
further steroid medication. The use of IGIV therapy is considered to be an adjuvant treatment 
with continuation of immunosuppressive therapy with corticosteroids and possibly also other 
immunosuppressive agents.[9,10] The German Society for Neurology also recommended in 
their  Guideline
1 to  
treat  patients  who  do  not  respond  
to  corticosteroids,  azathioprine  or 
methotrexate with IGIV (Class I evidence). Similarly, the Guideline of the Therapeutics and 
Technology Assessment Subcommittee of the American Academy of Neurology concluded 
that  based  on  one Class II  study,  IGIV  is  possibly  effective  for  the  treatment  of 
nonresponsive DM in adults and thus may be considered for the treatment of nonresponsive 
DM in adults (Level C).[4,11] 
Because  of  the  ease  of  its  application,  IGIV  has  become the treatment  of  choice  as 
corticosteroid-saving agent or as add-on therapy in severe myositis.[12] 
In  
terms  of  efficacy,  
it  can  
reasonably  be  assumed  
that  Octagam 10%  exhibits  
the  same 
effectiveness as other IGIV brands. 
2 STUDY OBJECTIVES 
2.1 Primary Objective(s) 
The primary objective of this study is to provide confirmatory data on the beneficial effect 
of 2.0 g/kg of Octagam 10% given every 4 weeks compared with placebo in subjects with 
active DM based on the percentage of responders at Week 16. 
2.2 Secondary Objective(s) 
The secondary objectives of this study are: 
• to evaluate  
the  beneficial  effect  of Octagam 10%  
in  subjects  with  active  DM  by 
assessing different parameters and scores at Week 16 and Week 40; 
• to confirm  
the  sustained  benefit  of  
treatment  with Octagam 10%  by  assessing  
the 
primary response measures at Week 40; 
• to evaluate the safety and tolerability of Octagam 10% in subjects with DM. 
3 INVESTIGATIONAL PLAN 
3.1 Primary and Secondary Endpoints 
3.1.1 Primary Endpoint 
• Proportion of responders in the 2.0 g/kg 
Octagam 10% and placebo arms at Week 16. 
A  responder is defined  as  a subject with  an  increase from  baseline  (Week 0) of 
 
1 Leitlinien für Diagnostik und Therapie in der Neurologie – Myositissyndrome; 
www.dgn.org/leitlinien/3011-ll-69-ll-myositis-syndrome 


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≥20 points on the Total Improvement Score (TIS) and who has not met “Confirmed 
Deterioration”  criteria  at 2 consecutive  visits as  defined  in  Section 4.3.1 up  to 
(including) Week 16. 
3.1.2 Secondary Endpoints 
Efficacy: 
• Proportion of TIS responders by improvement category (minimal, moderate, major) 
at Week 16 and Week 40. 
• Mean change from baseline (Week 0) to end of First Period (Week 16) in modified 
Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI).[29] 
• Mean  change  from  end  of First Period  (Week 16)  to  end  of Extension  Period 
(Week 40) in modified CDASI. 
• Mean change from Baseline (Week 0) to end of First Period (Week 16) and Extension 
Period (Week 40) in:  
o SF-36v2 Health Survey; 
o Individual 6 Core Set Measures (CSM) used for TIS calculation. 
• Mean  TIS  from  Baseline  (Week  0)  to end  of  First  Period  (Week 16)  and from 
Baseline (Week 0) to end of Extension Period (Week 40). 
• Time to minimal, moderate and major improvement in TIS. 
• Time to confirmed deterioration in the First Period and overall. 
• Proportion of subjects in each treatment arm who met confirmed deterioration criteria 
up to (including) Week 16 
Safety (throughout the entire First and Extension Period): 
• Occurrence of all AEs with particular emphasis on thromboembolic events (TEEs) 
and hemolytic transfusion reactions (HTRs). 
• Occurrence of all adverse drug reactions (ADRs) and suspected ADRs. 
• Vital signs (blood pressure, heart rate, body temperature and respiratory rate). 
• Physical examination (at Screening and every 12 weeks from Week 4 on). 
• Laboratory parameters (hematology, clinical chemistry). 
Safety (at Baseline and end of Extension Period): 
• Tests for viral safety.  
• Pregnancy test, if applicable. 
3.2 Overall Study Design and Plan 
ProDERM study is planned to start in Q4 2016 and be clinically completed by Q4 2019.  
ProDERM study will be a prospective, parallel group, double-blind, randomized, placebo-
controlled, multicenter Phase III study in a minimum of 94 adult subjects of both genders 
with definite or probable DM according to the criteria of Bohan and Peter.[13,14] 
As DM is a rare disease, about 55 sites are projected to participate in countries worldwide 
with emphasis on European countries and North America. 
Subjects eligible after screening will be randomized 1:1 to receiving up to 4 infusion cycles 
of either Octagam 10% or placebo every 4 weeks during the First Period lasting 16 weeks. 
An infusion cycle comprises all infusion episodes administered over 2 (to 5) days during one 


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visit. After response assessment at Week 16 (i.e. 4 weeks after start of the previous infusion 
cycle), all subjects who have not deteriorated at 2 consecutive visits during the First Period 
will continue  to receive  2.0 g/kg (20 mL/kg) of Octagam 10%  during  the subsequent 
6-months  Extension  Period. For  subjects  who  are  stable  on  the  2.0 g/kg (20 mL/kg) 
Octagam 10% dose, the investigator may decide to switch them to the 1.0 g/kg (10 mL/kg) 
Octagam 10% dose, starting at Week 28. 
In case of confirmed deterioration (for definition see Section 4.3.1) during the First Period, 
subjects will be switched to the alternate treatment. After response assessment at Week 16 
this subgroup of subjects will be unblinded (see Section 5.6). 
Subjects  originally randomized  to  placebo who  did  not  deteriorate  and  
thus  stayed  on 
placebo  until  Week  16,  will  all  
receive  open-label  2.0 g/kg (20 mL/kg) Octagam 10%  at 
Week 16. If they continue to be stable on the Octagam 10% dose, they will have the option 
to  switch  to  1.0 g/kg (10 mL/kg) Octagam 10%  at  Week 28,  at  the  discretion  of  the 
investigator. 
Subjects originally randomized to placebo and switched to Octagam 10% due to confirmed 
deterioration  who  do  not further deteriorate  during their Octagam 10%  treatment at 
2 consecutive visits will continue and receive 2.0 g/kg (20 mL/kg) Octagam 10% during the 
6-months Extension Period.  
Subjects originally randomized  to  placebo  and switched to  Octagam 10% due  to 
deterioration, who deteriorate also during  Octagam 10%  
treatment at  2 consecutive  visits 
will drop-out after response assessment at Week 16 and will not enter the Extension Period. 
Subjects originally randomized to Octagam 10% who deteriorate at 2 consecutive visits in 
the  First  Period and who  were  subsequently switched  
to  placebo will  drop-out  after the 
response assessment at Week 16 and will not enter the Extension Period. 
Subjects dropping out due to confirmed deterioration at 2 consecutive visits will in any case 
be classified as non-responders in the statistical analysis.  
Any  subject  deteriorating at  2 consecutive  visits  in  the  Extension  Period  will  drop-out, 
independent of the initially assigned treatment arm and the Octagam 10% dose administered. 
Figure 1 depicts the study design. 
 


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Figure 1: Scheme of Study Design 
 
 
 
 


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3.3 Discussion of Study Design and Choice of Control Group 
3.3.1 Study Design 
The study design of ProDERM includes all major scientific, state-of-the-art interventions 
needed to assess the efficacy, safety and tolerability of therapeutic treatments in DM patients. 
The total observation period of the study is 40 weeks. For a proper assessment of efficacy, 
clinical  experience  has  shown  that  at  least  4 treatment  cycles  are  necessary  to  be 
documented. This resulted in a duration of 16 weeks for the first (controlled) phase of the 
study.  An  active  treatment  phase  of  6 months  (24 weeks)  is  recommended  by  the 
International Myositis Assessment and Clinical Studies Group.[32] 
In order to minimize the risk for subjects in the placebo arm, a conditional switch to active 
treatment is introduced in the (blinded) First Period: All subjects in the placebo arm who 
deteriorate at 2 consecutive visits until Week 8 or after Week 8 will be switched to 2.0 g/kg 
(20 mL/kg) of  Octagam 10%. In  case  of  further,  confirmed  deterioration  on  the 
Octagam 10% treatment, subjects will drop-out. 
In contrast, subjects in the 2.0 g/kg (20 mL/kg) Octagam 10% arm will receive placebo if 
they deteriorate at 2 consecutive visits until Week 8 or after Week 8. In case of confirmed 
deterioration after the switch to placebo, subjects will eventually drop-out. Subjects who did 
not deteriorate after the switch to placebo at 2 consecutive visits will automatically drop out 
at Week 16. This procedure was introduced to maintain the blinding of treatment. 
In  
the  Extension  Period  of  
the  study, subjects  will  receive  6 infusion cycles  of  2.0 g/kg 
(20 mL/kg) of  Octagam 10%  every  4 weeks. If  the  subject  is  stable  on  the  2.0 g/kg 
(20 mL/kg) dose, the investigator may decide on a case by case basis, if they want to treat 
the subject with the lower dose of 1.0 g/kg (10 mL/kg) Octagam 10%, starting at Week 28. 
Thereby, data on long-term efficacy and tolerability will be generated. 
The 4-week interval between infusions has been chosen to make results comparable to the 
old Dalakas study [4] and to stay in line with current clinical practice.  
Immunosuppressive  agents  and  corticosteroids  are  allowed  if  stable  dosages  are  not 
exceeded (see Section 4.2.1) in order to comply with the EFNS Guidelines saying that IGIV 
is recommended as a second-line treatment.[6] 
3.3.2 Control Groups 
Since the placebo-controlled Dalakas study in 1993 which demonstrated the beneficial effect 
of IGIV in DM, no confirmatory placebo-controlled study with IGIV has been conducted. 
Therefore, Octagam 10% will be compared with placebo in the ProDERM trial.  
3.3.3 Study Parameters 
The study parameters selected in the study are appropriate to verify the clinical efficacy of 
IGIV in DM. 
Core Set Measures of myositis disease activity have been established and validated by the 
IMACS Group for DM/PM clinical trials.[15-18] Very recently, the CSM have been further 
developed  
into  conjoint-analysis  hybrid  
response  criteria  combining 6 CSM  
to  determine 


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clinically meaningful improvement in a Total Improvement Score (TIS).[19,30] ProDERM 
will employ the TIS in its final version for the definition of improvement (DOI) used as the 
primary endpoint. The final TIS used for this protocol was submitted for publication by Prof. 
Aggarwal who was a member of an Advisory Board who helped developing this protocol.  
A big advantage of these hybrid response criteria over the previous IMACS response criteria 
is that inclusion criteria for clinical trials will not require a minimal severity in any CSM. 
All levels of improvement in each CSM contribute more or less to the response. The previous 
IMACS preliminary response criteria required a baseline deficit of at least 20% in each CSM 
in the clinical trial inclusion criteria to enable reaching the threshold of ≥20% improvement 
in CSM after treatment.[18] Therefore, it is justified to use the response criterion based on 
the TIS changes as primary endpoint. 
4 STUDY POPULATION 
4.1 Population Base 
In total, 94 adult male or female subjects with acute DM will be enrolled into the study. 
4.1.1 Inclusion Criteria 
Subjects who meet all of the following criteria are eligible for the study: 
1. Subjects with diagnosis of definite or probable DM according to the Bohan and Peter 
criteria.[13,14] 
2. Subjects under treatment  with  corticosteroids  and/or maximally 2 immune-
suppressants and being on stable therapy for at least 4 weeks (see Section 4.2.1) 
OR 
Subjects with previous failure of response or previous intolerance to corticosteroid 
and  at  least  1  additional  immunosuppressive  drug,  and  with 
steroid/immunosuppressive drugs washed out as per Section 4.2.1 (Table 2).  
3. Subjects with  active  disease, assessed  and agreed  upon  by  an independent 
adjudication committee (see Section 8.6). 
4. MMT-8  score  <142,  with  at  
least 2 other  abnormal CSM  
(Visual  Analogue  Scale 
[VAS] of patient global activity ≥2 cm, physician’s global disease activity ≥2 cm, 
extra-muscular activity ≥2 cm; at least one muscle enzyme >1.5 times upper limit of 
normal, Health Assessment Questionnaire [HAQ] ≥0.25). 
5. Males or females ≥ 18 to < 80 years of age. 
6. Voluntarily given, fully informed written consent obtained from subject before any 
study-related procedures are conducted. 
7. Subject must be capable to understand and comply with the relevant aspects of the 
study protocol. 
4.1.2 Exclusion Criteria 
Subjects who meet any of the following criteria are not eligible for the study: 
1. Cancer-associated myositis, defined as the diagnosis of myositis within 2 years  of 
the diagnosis of cancer (except basal or squamous cell skin cancer or carcinoma in 


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situ  of  the  cervix  that  has  been  excised  and  cured  and  at  least 1 or  5 years, 
respectively, have passed since excision). 
2. Evidence of active malignant disease or malignancies diagnosed within the previous 
5 years  
(including  hematological  malignancies  and  solid  
tumors)  or  breast  cancer 
diagnosed within the previous 10 years. 
3. Subjects  with  overlap  myositis  (except  for  overlap  with  Sjögren’s  syndrome), 
connective  tissue  disease  associated DM,  inclusion  body  myositis,  polymyositis, 
juvenile dermatomyositis or drug-induced myopathy. 
4. Subjects with immune-mediated necrotizing myopathy with absence of typical DM 
rash. 
5. Subjects  with  generalized,  severe  musculoskeletal  conditions  other  
than  DM  
that 
prevent a sufficient assessment of the subject by the physician. 
6. Subjects who have received IgG treatment within the last 6 months before enrolment. 
7. Subjects who received blood or plasma-derived products (other than IgG) or plasma 
exchange within the last 3 months before enrolment. 
8. Subjects starting or planning to start a physical therapy–directed exercise regimen 
during the trial. 
9. Cardiac  insufficiency  (New  York  Heart  Association  III/IV),  cardiomyopathy, 
significant cardiac dysrhythmia requiring treatment, unstable or advanced ischemic 
heart disease. 
10. Severe liver disease, with signs of ascites and hepatic encephalopathy. 
11. Severe  kidney  disease (as  defined  by  estimated  glomerular  filtration  rate  [eGFR] 
< 30 mL/min/1.73 m2). 
12. Known hepatitis B, hepatitis C or HIV infection. 
13. Subjects with a history of TEE such as deep vein thrombosis, pulmonary embolism, 
myocardial infarction, ischemic stroke, transient ischemic attack, peripheral artery 
disease (Fontaine IV) ever. 
14. Body mass index ≥40 kg/m2. 
15. Medical  conditions  whose  symptoms  and  effects  could  alter  protein  catabolism 
and/or IgG utilization (e.g. protein-losing enteropathies, nephrotic syndrome). 
16. Known IgA deficiency with antibodies to IgA. 
17. History  of  hypersensitivity,  anaphylaxis  or  severe  systemic  response  
to  
immuno-
globulin, blood or plasma derived products or any component of Octagam 10%. 
18. Known blood hyperviscosity, or other hypercoagulable states. 
19. Subjects  with  a  history  of  drug  abuse  within  the  past 5 years  prior  to study 
enrollment. 
20. Subjects unable or unwilling to understand or comply with the study protocol. 
21. Participating in another interventional clinical study with investigational treatment 
within 3 months prior to study enrollment. 
22. Women who are breast feeding, pregnant, or planning to become pregnant, or are 
unwilling to apply an effective birth control method (such as implants, injectables, 
combined oral contraceptives, some intrauterine devices [IUDs], sexual abstinence 
or vasectomized partner) up to four weeks after the last IMP infusion received. 


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23. Subjects who are accommodated in an institution or care facility based on an official 
directive or court order. 
24. Subjects who are in any way dependent on the Sponsor, Investigator or Study Site. 
25. Subjects who received forbidden medication within the washout period as defined in 
Section 4.2.2 (Table 3: Forbidden Concomitant Medications). 
4.2 Prior and Concomitant Therapy 
The following must be recorded in the electronic case report form (eCRF): 
• Details of any DM–related medications received within 12 months before screening. 
• Details  of  any  previous  DM-related treatment  failure  or  intolerance,  including 
medication,  maximum  dose  reached,  and  reason  for  discontinuation  (insufficient 
therapeutic effect or intolerable side effect). 
• Details of any other medications received within 3 months before screening. 
• Concomitant medications throughout the study. 
• Non-drug  therapies  incl.  physiotherapies within  4 months  before  screening  and 
throughout the study. 
4.2.1 Permitted Concomitant Therapy 
Previous  medications  for  the  treatment  of DM (immunosuppressants,  corticosteroids  or 
biologicals) must either be  
a) washed-out (details see Table 2) 
or 
b) continued  if subject received  medication  for  at  least 3 months  prior to  study 
enrollment and at a stable dose for at least 4 weeks prior to study enrollment (details 
see Table 2).  
Table 2 specifies which DM–treatment-related medications are permitted as concomitant 
therapy. In addition, the maximally allowed dose which has to remain stable during the First 
Period is given. If treatment for DM is to be stopped prior to study enrollment, the required 
washout periods, the period which needs to elapse from discontinuing, can be retrieved from 
the table.  
During the First Period of the study, the dose regime of concomitant therapies should not be 
changed. During the Extension Period of the study, therapies may be tapered off. 
TEE prophylaxis, if deemed necessary by the investigator, is allowed as a precautionary 
measure and should follow standard of care. Its use must be documented. 
The routine use  of premedication to  alleviate  potential  side  effects  should  be  avoided. 
However, if a subject experiences 2 consecutive infusion-related AEs that are likely to be 
prevented  by  premedication,  then antipyretics,  antihistamines,  mild  analgesics 
(acetaminophen/paracetamol or acetylsalicylic acid) or antiemetic drugs are allowed before 
the  following  
infusions  of  study  drug. The  dose  of premedication  should  be  held  stable 
during the First Period and its use must be documented. 


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NSAIDs or opioids are commonly used in DM patients and are therefore allowed. The dose 
of such medications should be held stable 2 weeks prior to study enrollment and during the 
First Period. The use of such medication must be documented. 
Topical medication, except topical steroids, is allowed. Such medication should be kept 
stable during the First Phase to avoid interference with the extra-muscular activity, one of 
the CSM of the primary endpoint. 
Physical  therapy-directed  exercise  regimen is  allowed  if  started  ≥4  weeks  prior  to 
randomization and entry 
into the double-blind treatment period at Visit 2 and kept on a stable 
schedule, frequency and extent. Any such exercise regimen must be documented. 
Table 2: Washout  Periods  or  Dose Limitations for  Prior/Concomitant DM-related 
Medications to be fulfilled prior to randomization 
Drug 
Washout Period 
(prior to randomization) 
Maximally allowed stable dose as 
concomitant therapy 
Immunosuppressive Drugs 
Methotrexate 
8 weeks 
25 mg/week 
Azathioprine 
8 weeks 
2 mg/kg 
Cyclosporine 
8 weeks 
2 mg/kg 
Tacrolimus 
8 weeks 
0.2 mg/kg 
Mycophenolate mofetil 
8 weeks 
3000 mg daily 
Leflunomide 
3 months 
20 mg daily 
Other  
Hydroxychloroquine 
8 weeks 
400 mg daily 
Corticosteroids 
8 weeks 
20 mg daily prednisone equivalent 
4.2.2 Forbidden Concomitant Therapy 
The following medications or therapies are forbidden during participation in this study: 
• Corticosteroids at  any  dose  
if  given as premedication to  alleviate  potential side 
effects following Octagam 10% treatment.  
• Corticosteroids at doses higher than 20 mg/day prednisone equivalent. 
• Other blood or plasma-derived products. Note that subjects will be withdrawn from 
the study if IgG preparations other than Octagam 10% are administered. 
• Plasma exchange procedures. 
• Live attenuated vaccines such as measles, rubella, mumps and varicella. 
• Any experimental drug. 
Table 3 lists further medications that are forbidden, but patients can be included into this 
study when the respective washout period is considered. 


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Table 3: Forbidden Concomitant Medications 
Drug 
Washout Period 
(prior to randomization) 
Monoclonal antibodies (e.g. adalimumab, 
infliximab, certolizumab, golimumab, 
abatacept, tocilizumab) 
8 weeks 
Rituximab 
12 months or  
6 months plus normal CD19 count 
Cyclophosphamide 
3 months 
Immunoglobulin G 
6 months 
Etanercept 
4 weeks 
Anakinra 
2 weeks 
Rilanocept 
8 weeks 
Topical steroids 
2 weeks 
4.3 Withdrawal and Replacement of Subjects 
4.3.1 Premature Subject Withdrawal 
Subjects have the right to withdraw from the study at any time for any reason, without the 
need to justify their decision. The Investigator also has the right to withdraw subjects from 
the  study  
in  case  of  AEs,  poor  compliance,  or  other  
reasons.  Since  an  excessive  
rate  of 
withdrawal can render the study non-interpretable, the unnecessary withdrawal of subjects 
must be avoided.  
For any discontinuation after study entry, the Investigator will obtain all the required details 
and document the reason(s) for discontinuation in the eCRF. If the reason for withdrawal of 
a subject is an AE, the main specific event or laboratory test will be recorded in the eCRF, 
and the Investigator will make thorough efforts to clearly document the outcome. 
Should a subject decide to withdraw, the Investigator will make the best efforts to complete 
and report the observations. The Investigator will document the reason(s) for withdrawal of 
each subject in the eCRF. 
Subjects who terminate the study prematurely are drop-outs. The Investigator 
has to organize 
the Drop-out visit which is identical to the Termination visit procedures. 
At  Week  16,  certain  subjects  have  
to  drop-out,  especially  
in  case  of  
(further) confirmed 
deterioration after the switch to the alternate treatment option. 
Please see Figure 1 for details. 
Other reasons for premature termination of subjects may be: 
1. Withdrawal of subject’s consent.  
2. Deterioration of DM (during Extension Period). 
3. Pregnant subjects will be immediately excluded from the study. 


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4. Investigator’s opinion that the subject may be severely harmed if he/she continues 
trial participation, namely  by the treatment and procedures according to the study 
protocol. 
5. Occurrence of a disease which interferes with the study treatment or represents an 
exclusion criterion. 
6. Administration of IGIV other than Octagam 10%. 
 
"Confirmed deterioration" is essentially defined as follows according to Oddis et al. 2013 
with a slight adaptation as agreed with the study’s Steering Committee (excluding enzymes, 
which will not immediately be available for the evaluation of deterioration):[20] 
• Physician’s  Global  Disease  Activity  VAS  worsening ≥ 2 cm  and  MMT-8 
worsening ≥20% on 2 consecutive visits, 
or 
• global  extra-muscular  activity  worsening ≥2 cm  on  the  MDAAT  VAS  on 
2 consecutive visits, 
or 
• any 3 of 5 CSM (excluding enzymes) worsening by ≥30% on 2 consecutive visits. 
For all criteria worsening will be determined by comparing to baseline (Week 0) values. 
4.3.2 Subject Replacement Policy 
Not applicable. Withdrawals will not be replaced. 
4.4 Assignment of Subjects to Treatment Groups 
The  registration  of subjects as  screened/randomized  will  be  managed  via  an  interactive 
response technology (IRT) system. 
The screening ID will be a 5-digit number with the first digit being the study number (“8”), 
the next 2 digits identifying the center (01, 02, …) and the last 2 digits the sequence number 
assigned by the IRT (01, 02, …) for each site continuously. Leading zeros will be used for 
center  and subject numbers  below  10.  The  second subject screened  at  center  4  will  be 
identified as e.g. 80402.  
The Investigator will enter the screening ID into the confidential subject identification list. 
If the subject qualifies, randomization will be done centrally through the IRT. The IRT will 
ensure balance of allocation by means of a stratified block design, thus, equally distributing 
subjects  with  different  disease  course  
(mild,  moderate  or  severe defined  as  a Physician’s 
Global Disease Activity (GDA) value of 0-3 [mild], 4-6 [moderate], 7-10 [major]). The fact 
that a subject has been randomized will be reported immediately and automatically by the 
system to the Investigator, the contract research organization (CRO) and the sponsor. The 
result of randomization, i.e. the treatment group assignment, will however only be reported 
to the hospital pharmacist or designee by a dedicated email that no other trial personnel will 
have access to. 


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The subject will be identified by the previously assigned screening ID throughout the trial. 
No additional subject or randomization number will be used. 
No randomization results will be transmitted to the sponsor to comply with the double-blind 
character of this study. The responsible monitor(s) will be informed of new subjects enrolled 
automatically by the IRT system via email.  
Under no circumstances are subjects who enroll in the study permitted to re-enroll. 
4.5 Relevant Protocol Deviations 
Deviations from the protocol should be avoided. If deviations occur, the Investigator should 
promptly  
inform  
the  Monitor  and  
the  
implication  of  
the  deviation  must  be assessed  and 
discussed. Any deviation must be documented, stating the reason and date and the action 
taken. The documentation must be kept in the Investigator’s trial file and the Sponsor’s trial 
master file. A complete list of all minor and major deviations is to be compiled and regularly 
updated by the Project Manager and provided for preparation of the clinical study report. 
Examples of relevant protocol deviations that will be addressed are: 
• Subjects who entered the study even though they did not satisfy the entry criteria. 
• Subjects who developed withdrawal criteria during the study (see Section 4.3.1). 
• Subjects who received the wrong treatment or incorrect dose (also see Section 5.4). 
• Subjects who received an excluded concomitant treatment. 
• Subjects who had no CSM at Week 16. 
In  case  of  any  major  protocol  deviation,  
the  
Investigator  and Sponsor will  decide  on  
the 
further participation of the subject in this study after having discussed all relevant aspects.  
4.6 Subsequent Therapy 
All subjects who leave the study – be it prematurely or per protocol – will continue with the 
DM–related treatment they had before study participation, or with another standard of care 
as per the discretion of the investigator. 
5 INVESTIGATIONAL MEDICINAL PRODUCT(S) 
5.1 Characterization of Investigational Product(s) 
Octagam is a 10%  
IGIV ready for intravenous administration. Octagam 10% is produced 
from a pool of at least 1000 donations of human fresh frozen plasma per batch. The large 
donor pool ensures that the product contains a broad range of antibodies directed against 
pathogens  and  foreign  antigens,  which  
is  far  more  diverse  
than  
that  of  plasma  from  an 
individual  donor.  Donor  plasma  sampling,  the  manufacturing  of  the  product  and  the 
measures to ensure the product
's viral safety are subject to strict regulations laid down by 
regulatory authorities. Octapharma exclusively uses plasma which has been tested by nucleic 
acid testing techniques.  
During the manufacturing process of Octagam 10%, significant viral reduction is obtained 
via  a  combination  of 3 validated  manufacturing  steps:  cold-ethanol  fractionation, 
solvent/detergent  
treatment  with  
tri-n-butyl  phosphate  
(TNBP)  and  Octoxynol  
(Triton X-
100),  and  pH 4  treatment. The  efficacy  of  the  virus  inactivation  procedures  has  been 


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extensively validated according to relevant international guidelines. The composition with 
the most important ingredients and the biochemical characteristics are summarized in the 
Investigators’ Brochure. 
For placebo, sodium chloride 0.9% w/v solution for intravenous infusion will be used. 
5.2 Packaging and Labeling 
Octagam 10% is delivered as ready-to-use solution in glass bottles. 
Each Octagam 10% bottle will be labeled as follows: 
US Master Label – Octagam 10%: 
Caution: New Drug-Limited by Federal (or United States) law to investigational use 
  
 
Study: GAM10-08 
Octagam 10% 
Unit size: ______ mL 
1 mL contains: 100 mg protein of which ≥ 96% is human normal immunoglobulin. 
Infusion solution for intravenous administration. 
To be stored at +2°C (36°F) to +8°C (46°F) and protected from light. Must not be frozen. 
Must be inspected visually for particulate matter and discoloration prior to 
administration. Do not use non-homogenous solutions or those that have a deposit. 
To be warmed up to room or body temperature before use. 
Dosage: refer to Clinical Study Protocol, section 5.4 
Patient no.:  |__|__|__|__|__|   
Visit no.:  
|____|   
Infusion Day:  |____| 
Sponsor: OCTAPHARMA PPG, Oberlaaer Str. 235, 1100 Vienna, Austria, Tel:  
 
 
Batch no.: ___________________  
Expiration date: __________________ 
EU Master Label – Octagam 10%: 
FOR CLINICAL TRIAL USE ONLY 
Study: GAM10-08 
Octagam 10% 
Unit size: ______ mL 
1 mL contains: 100 mg protein of which ≥ 95% is human normal immunoglobulin. 
Infusion solution for intravenous administration. 
To be stored at +2°C to +8°C and protected from light. Must not be frozen. 
Must be inspected visually for particulate matter and discoloration prior to 
administration. Do not use non-homogenous solutions or those that have a deposit. 
To be warmed up to room or body temperature before use. 
Dosage: refer to Clinical Study Protocol, section 5.4 
Patient no.:  |__|__|__|__|__| 
Visit no.:  
|____|   
Infusion Day:  |____| 
Investigator:   _________________________________________________ 
Sponsor: OCTAPHARMA PPG, Oberlaaer Str. 235, 1100 Vienna, Austria, Tel:  
 
 
Batch no.: ______________ 
Expiration date: __________________ 
 


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Sodium chloride 0.9% w/v solution for intravenous infusion, licensed for the US and EU 
market, will be purchased centrally and provided to the local pharmacies. Each bottle will 
be labeled as follows: 
US Master Label – Sodium Chloride 0.9% w/v solution: 
Caution: New Drug-Limited by Federal (or United States) law to investigational 
use 
  
 
Study: GAM10-08 
Sodium Chloride 0.9% w/v solution  
Unit size: ______ mL 
Sterile solution for intravenous infusion 
1000 mL of solution contain  
  
Sodium chloride 9.00 g 
  Electrolyte concentrations mmol per 1000 mL (approx): 
  
Sodium  
154 mmol 
  
Chloride  
154 mmol 
Do not store above +25°C (+77°F) [depending on product purchased] 
Only to be used if solution is clear and container undamaged 
Dosage: refer to Clinical Study Protocol, section 5.4 
Sponsor: OCTAPHARMA PPG, Oberlaaer Str. 235, 1100 Vienna, Austria, Tel: +  
 
Batch no.: ______________ 
Expiration date: __________________ 
EU Master Label – Sodium Chloride 0.9% w/v solution: 
FOR CLINICAL TRIAL USE ONLY 
Study: GAM10-08 
Sodium Chloride 0.9% w/v solution 
Unit size: ______ mL 
Sterile solution for intravenous infusion 
1000 mL of solution contain  
  
Sodium chloride 9.00 g 
  Electrolyte concentrations mmol per 1000 mL (approx): 
  
Sodium  
154 mmol 
  
Chloride  
154 mmol 
Do not store above +25°C [depending on product purchased] 
Only to be used if solution is clear and container undamaged 
Dosage: refer to Clinical Study Protocol, section 5.4 
Investigator:   _________________________________________________ 
Sponsor: OCTAPHARMA PPG, Oberlaaer Str. 235, 1100 Vienna, Austria, Tel: +  
 
Batch no.: ______________ 
Expiration date: __________________ 
Final labeling will be in compliance with the national requirements of each country where 
the study will be conducted. 
After  transfer  and  pooling  into Polyvinyl  Chloride  (PVC)-free,  Diethylhexylphthalate 
(DEHP)-free and  latex–free,  infusion bags,  the  medication  (Octagam 10%  or sodium 


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chloride 0.9% w/v solution) will be blinded with an over pouch and re-labeled (both, the 
infusion bag  and  the  over  pouch).  The  following  labels  will  be  used  for  sending  the 
medication from the pharmacy to the ward: 
US Master Label – Blinded label for infusion bags and over pouch: 
Caution: New Drug-Limited by Federal (or United States) law to investigational 
use 
  
 
Study: GAM10-08 
Octagam 10% OR Sodium Chloride 0.9% w/v solution 
Unit size: ______ mL 
1 mL contains either 100 mg protein of which ≥ 96% is human normal immunoglobulin 
OR sodium chloride 0.9% w/v solution. 
Infusion solution for intravenous administration. 
Patient no.: |__|__|__|__|__|  
Visit no.:  
|____|   
Infusion Day:  |____| 
Investigator:   _________________________________________________ 
Date and time of preparation: _________________ 
If not infused immediately, to be stored at +2°C (36°F) to +8°C (46°F) until 
Expiration date and time: __________________ 
Must not be frozen. 
To be warmed up to room or body temperature before use. 
Sponsor: OCTAPHARMA PPG, Oberlaaer Str. 235, 1100 Vienna, Austria, Tel: +  
 
 
EU Master Label – Blinded label for infusion bags and over pouch: 
FOR CLINICAL TRIAL USE ONLY 
Study: GAM10-08 
Octagam 10% OR Sodium Chloride 0.9% w/v solution 
Unit size: ______ mL 
1 mL contains either 100 mg protein of which ≥ 95% is human normal immunoglobulin 
OR sodium chloride 0.9% w/v solution. 
Infusion solution for intravenous administration. 
Patient no.: |__|__|__|__|__|  
Visit no:  
|____|   
Infusion Day:  |____| 
Investigator:   _________________________________________________ 
Date and time of preparation: __________________ 
If not infused immediately, to be stored at +2°C to +8°C until  
Expiration date and time: __________________ 
Must not be frozen. 
To be warmed up to room or body temperature before use.
 
Sponsor: OCTAPHARMA PPG, Oberlaaer Str. 235, 1100 Vienna, Austria, Tel: +  
 
Final labeling will be in compliance with the national requirements of each country where 
the study is to be conducted. 


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5.3 Conditions for Storage and Use 
Octagam 10% should be stored and transported light-protected at  +2°C to +8°C (36°F to 
46°F) and must not be frozen. Octagam 10% must not be used after its expiration date. 
Sodium chloride 0.9% w/v solution should be stored and transported according to its product 
information. Conditions will be stated on the IMP label. 
Storage conditions for pooled IMP are described in Section 5.5. 
The authorized personnel at the individual pharmacies will ensure that the IMP is stored in 
appropriate conditions with restricted access and in compliance with national regulations. 
5.4 Dose and Dosing Schedule 
Octagam 10% is available in glass bottles with different volumes of human immunoglobulin. 
Glass bottles of different volume should be combined in order to reach the required amount 
of IgG. 
No product should be discarded; therefore, the amount to be administered will be rounded 
up  or  down  
to  
the  value  closest to  
the  smallest  vial  size available.  The range of  such  a 
rounded difference must not exceed ±2.5 g in total.  
If a subject is randomized to receive placebo (0.9% w/v isotonic sodium chloride solution), 
the same volume with the same infusion rate as would have been applied in case the subject 
would have been randomized to 2.0 g/kg Octagam 10% will be used. Therefore, they will 
receive  a  dose  of  20 mL/kg 0.9% w/v  
isotonic  sodium  chloride  solution given  over  2  
to 
5 days. 
Body weight is to be measured at certain visits prior to IMP administration and reported to 
the  pharmacist  or  designee  as  it  is  needed  for  the  preparation  of  the following study 
medication dosages. 
All  subjects  should  be  clinically  assessed  for  being  adequately  hydrated  prior  to IMP 
administration. TEE prophylaxis should be considered for subjects with risk factors for TEE 
or  subjects  in  the  early  phase  of  diagnosis  as  a  precautionary  measure. Please refer  to 
Section 4.2.1. 
The initial infusion rate for each infusion episode will be 0.01 mL/kg/min (60 mg/kg/h) for 
the first 30 minutes;  
if tolerated,  advanced to 0.02 mL/kg/min (120 mg/kg/h) for the next 
30 minutes; if tolerated, advanced to 0.04 mL/kg/min (240 mg/kg/h) for the remainder of the 
infusion.. The interval of 30 minutes may be prolonged as per discretion of the investigator. 
In  patients  at  
risk  
for  
thromboembolic  adverse  
reactions  and  acute  
renal  
failure  
(such  as 
advanced  age,  hypertension,  history  of  thrombotic  episodes not  excluded  by  exclusion 
criterion  number 13,  patients  with  prolonged  periods  of  immobilization,  concomitant 
nephrotoxic  medication,  diabetes  mellitus,  overweight,  hypovolemia), IMP  should  be 
administered at the minimum rate of infusion practicable. 
During the First Period (16 weeks), subjects will receive double-blinded treatment at 4-week 
intervals (Week 0, 4, 8 and 12; i.e. 4 infusion cycles) of either 2.0 g/kg BW (20 mL/kg BW) 
Octagam 10%  or 20 mL/kg  BW  0.9% w/v  
isotonic sodium  chloride  solution  as  placebo. 
Infusions should be given on two consecutive days. At the discretion of the investigators 
each infusion cycle can be prolonged up to five days. Total dose for an infusion cycle will 
be given in equally divided doses on each infusion episode. If a patient will be infused over 


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two days, each infusion episode will take up to about 5.5hours dependent on the infusion 
rate. If infusion will be given over more than 2 days, the time for each infusion episode will 
be proportionately shorter. At each infusion episode the infusion will be given continuously. 
In the Extension Period, subjects will receive 6 infusion cycles of 2.0 g/kg (20 mL/kg BW) 
Octagam 10% given over 2 to 5 consecutive days at 4-week intervals (Week 16, 20, 24, 28, 
32 and 36). Total dose for an infusion cycle will be given in equally divided doses on each 
infusion episode. If a patient will be infused over two days, each infusion episode which will 
be given continuously will take up to about 5.5 hours, dependent on the infusion rate. At 
each infusion episode the infusion will be given continuously. Optionally, the subject may 
receive  Octagam 10%  
in  a  dose  of  1.0 g/kg BW  
(10 mL/kg  BW) at  
the  discretion  of  
the 
investigator and if the subject remained stable on the higher dose. 
If AEs occur during the infusion, the rate is to be reduced to half the rate at which the event 
occurred or the infusion is to be interrupted until symptoms subside. The infusion may then 
be resumed at a rate tolerated by the subject. 
5.5 Preparation and Method of Administration 
During the First Period it is recommended that the calculated IMP vials/bottles are pooled 
in PVC-free, 
DEHP-free and latex–free infusion bags by the hospital pharmacist or designee.  
Each bottle of Octagam 10% must be examined visually by the pharmacist or designee for 
particulate matter and discoloration prior to pooling. Non-homogenous solutions or those 
that have a deposit must not be pooled. The same procedures should be performed also for 
sodium chloride 0.9% w/v solution. 
The  preparation  should  be  performed  under  aseptic  conditions preferably using  a  sterile 
bench, as described in the manual handed out to the hospital pharmacist or designee. IMP 
administration must be started within 3 to 4 hours after preparation.  
The  Octagam 10%  must be  allowed  
to  warm  
to  
room  or  body  
temperature  prior  
to IMP 
administration. The same holds true for sodium chloride 0.9% w/v solution for subjects in 
the placebo arm of the first period. 
Subjects  must  be  monitored  before  
infusion and  carefully  observed for  any  symptoms at 
least once throughout the infusion period and at least 1 hour thereafter.  
In the Extension Period, Octagam 10% vials may also be administered without pooling. 
Note that Octagam 10% must not be mixed with other medicinal products or saline. For other 
IV products a separate IV line must be used. 
The special warnings and precautions for use (see Investigator’s Brochure) of Octagam 10% 
must be respected. 
5.6 Blinding, Emergency Envelopes, and Breaking the Study Blind 
The  Investigators  will  be  provided  with  an  unblinding  procedure  to  disclose  the  actual 
treatment of a particular subject in case of medical emergency; this can be a sealed envelope 
or its electronic equivalence. 
To  maintain  blinding  
in the  
first  period,  
infusions  will  be  given  
in blinded infusion  bags 
(corresponding  
to  a  volume  of  0.4  
to 1.0 g/kg (4 to 10 mL/kg) Octagam 10%  or sodium 
chloride 0.9% w/v solution at each of the 2 to 5 consecutive infusion days). Thus, the old 


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label will be discarded together with the vial/bottle, and a new label will be fixed onto an 
opaque over pouch by the hospital pharmacist or designee. The over pouch (normally used 
for light protection) will be put over the infusion bag to maintain blinding. The new labels 
will be identical for both, Octagam 10% and sodium chloride 0.9% w/v solution, so that the 
content  of  
the  bags  
is  only  known  
to  
the  unblinded  hospital  pharmacist  or  designee.  An 
example of this label can be found in Section 5.2.  
The hospital pharmacist or designee will send the infusion bag(s) per subject (potentially 
already fixed to the opaque infusion line) to the ward.  
To further assure the double-blind character of this study, the Investigator or designee who 
applies the medication to the subject will not be involved in any other evaluations other than 
drawing blood samples or checking for vital signs, i.e. will not be involved in any subject 
ratings (e.g. CSM, CDASI).  
The subject 
will be blinded with respect to study treatment throughout the entire First Period. 
Treatment given  during  First  Period will also not  be  disclosed  
in  
the  Extension  Period. 
Because of the opaque (non-transparent) infusion line and over pouches, the subject will not 
be able to see the medication he/she is treated with.  
Blinding will only be broken under the following circumstances: 
• Occurrence of serious and presumably related AEs but only if the Investigator wants 
to know the assigned treatment for a proper clinical management of the subject. 
• At Week 16 for subjects who were switched to the alternate treatment group due to 
deterioration or  when  deterioration  is  confirmed  at  Week 16 (see Figure 1 for 
details). 
• If unblinding is required by the local regulatory authorities.  
Whenever possible, the Investigator should notify the Sponsor prior to unblinding. 
In order to maintain the blind, IgG plasma level results performed at the central laboratory 
will not be revealed to the Sponsor, the Investigator and other blinded personnel at the study 
site. 
5.7 Treatment Compliance 
5.7.1 Drug Dispensing and Accountability 
Any  IMP  provided  
to  
the  site  will  be accounted  for.  This  
includes  IMP  received  at  
the 
pharmacy, IMP dispensed to 
subjects, and IMP returned unused/partially used 
by the subject. 
Octagam 10% will be delivered to the participating pharmacists by the Sponsor or designee. 
A Drug Inventory and Dispensing Log will be kept current by the pharmacist, detailing the 
dates  and  quantities  of  IMP  received  and  dispensed  to  each subject and  the  remaining 
quantity.  
The inventory and dispensing log will be available to the unblinded monitor to verify drug 
accountability during the study.  
Unused IMP can be destroyed at the pharmacy or returned to the Sponsor for destruction. 
Destruction can be initiated only after accountability has been verified and fully reconciled 
by the unblinded monitor and after the Sponsor has granted written approval of destruction. 


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Empty  or  partially  used  bottles  should  be  destroyed  at  
the  study  site or  at  
the  pharmacy 
following local policies. 
5.7.2 Assessment of Treatment Compliance 
All subjects  will  be  
infused  at  
the  study  site  under  
the  surveillance  of  authorized  study 
personnel. Infusion details will be documented at the study site while the batch number(s) 
on the drug accountability form will be kept by the pharmacist or designee, which will be 
checked regularly by the unblinded monitor. 
6 STUDY CONDUCT  
Subjects have to be informed about the study details and have to give their written informed 
consent. A full written informed consent must be available before the start of any screening 
activities. 
The flowchart of assessments by study visit is shown in Table 1. 
Prior  to randomization, subjects  will  have  to  be  screened  for  eligibility  (inclusion  and 
exclusion criteria).  
If  feasible,  screening  should  be  completed  within 3 weeks.  However,  screening  results 
should  be  available  as  soon  as  possible.  Based  on  the  screening  results,  the subjects’ 
eligibility for the study is determined. 
Screening failures will be entered into the eCRF. 
6.1 Observations by Visit 
6.1.1 Screening Visit (Visit 1; duration up to 21 days, i.e. Week -3 to 0) 
The following assessments will be performed during the Screening Visit: 
• Obtaining voluntarily given, written (signed and dated) informed consent. 
• Demographic and baseline characteristics. 
• Medical history and prior/concomitant therapy. 
• Physical examination. 
• Vital signs (including body weight and height). 
• Standard ECG.  
• Blood samples for safety laboratory (hematology and clinical chemistry). 
• Blood sample for serum IgG. 
• Blood samples for enzymes. 
• Blood sample for viral markers. 
• Blood sample for biomarkers of disease activity. 
• Blood sample for D-dimers. 
• Pregnancy test. 
• CSM. 
• Wells probability score for deep vein thrombosis (DVT). 
• Wells probability score for pulmonary embolism (PE). 


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• Inclusion and exclusion criteria. 
6.1.2 Visit 2 (Week 0; Baseline of First Period) 
Subjects who are eligible will visit the study site and enter the controlled phase (First Period) 
after randomization. 
Visit 2 should take place within 3 weeks after the Screening Visit. 
All  eligible subjects  will  receive  their  first  infusion  of  either 2.0 g/kg (20 mL/kg) 
Octagam 10%  or  placebo  as  per  randomization.  The  following  assessments  will  be 
performed: 
Before infusion cycle: 
• Randomization and enrollment into the double-blind treatment period. 
• SF-36v2. 
• Vital signs. 
• Blood sample for safety laboratory (hematology and clinical chemistry). 
• Blood sample for additional safety lab parameters “Panel 1” (serum haptoglobin and 
plasma-free hemoglobin) 
• Direct Coombs’ test (if positive, the antibodies responsible for the positive Coombs’ 
test will be eluted to investigate their specificity (anti-A, anti-B or anti-D)). 
• Blood sample for serum IgG.  
• Blood samples for enzymes. 
• CSM. 
• CDASI. 
Before, during and after each infusion episode: 
• Administration/Infusion  of  IMP  (2.0 g/kg  [20 mL/kg] Octagam 10%  or  placebo 
given in infusion episodes over 2 to 5 consecutive days). 
• Vital signs before, at least once during and at least 1 hour after each infusion episode. 
At least 1 hour after the infusion cycle: 
• Blood  sample  for  additional  safety  
lab  parameters “Panel 2” (serum  haptoglobin, 
hemoglobin, plasma-free hemoglobin, LDH). 
• Direct Coombs’ test (if positive, the antibodies responsible for the positive Coombs’ 
test will be eluted to investigate their specificity (anti-A, anti-B or anti-D)). 
• Wells probability score  
for  DVT. If  score  
is  
likely  
for  DVT  
(≥2  points),  perform 
Doppler scan and take blood sample for D-dimers. 
• Wells probability score for PE. 
In addition, AEs will be monitored and concomitant medications will be documented. 
6.1.3 Visit 3 (Week 4; First Period) 
The following assessments will be performed: 
Before infusion cycle: 
• Physical examination. 


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• Vital signs. 
• Blood sample for safety laboratory (hematology and clinical chemistry). 
• Blood sample for serum IgG. 
• Blood samples for enzymes. 
• CSM. 
• CDASI. 
Before, during and after each infusion episode: 
• Administration/Infusion  of  IMP  (2.0 g/kg  [20 mL/kg] Octagam 10%  or  placebo 
given in infusion episodes over 2 to 5 consecutive days). 
• Vital signs before, at least once during and at least 1 hour after each infusion episode. 
At least 1 hour after the infusion cycle: 
• Wells probability score  
for  DVT.  
If  score  
is  
likely  
for  DVT  
(≥2 points),  perform 
Doppler scan and take blood sample for D-dimers. 
• Wells probability score for PE. 
In addition, AEs will be monitored and concomitant medications will be documented. 
6.1.4 Visits 4 and 5 (Week 8 and 12; First Period) 
The following assessments will be performed:  
Before infusion cycle: 
• Vital signs. 
• Blood sample for safety laboratory (hematology and clinical chemistry). 
• Blood sample for serum IgG. 
• Blood samples for enzymes. 
• CSM. 
• CDASI. 
Before, during and after each infusion episode: 
• Administration/Infusion  of  IMP  (2.0 g/kg  [20 mL/kg] Octagam 10%  or  placebo 
given in infusion episodes over 2 to 5 consecutive days, or alternate IMP for subjects 
who deteriorated at 2 consecutive visits). 
• Vital signs before, at least once during and at least 1 hour after each infusion episode. 
At least 1 hour after the infusion cycle: 
• Wells probability score  
for  DVT.  
If  score  
is  
likely  
for  DVT  
(≥2 points),  perform 
Doppler scan and take blood sample for D-dimers. 
• Wells probability score for PE. 
In addition, AEs will be monitored and concomitant medications will be documented. 


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6.1.5 Visit 6 (Week 16; End of First Period, Start of Extension Period)2 
The following assessments will be performed: 
Before infusion cycle: 
• SF-36v2. 
• Physical examination. 
• Vital signs and body weight. 
• Blood sample for safety laboratory (hematology and clinical chemistry). 
• Blood sample for additional safety lab parameters “Panel 1” (serum haptoglobin and 
plasma-free hemoglobin). 
• Direct Coombs’ test (if positive, the antibodies responsible for the positive Coombs’ 
test will be eluted to investigate their specificity (anti-A, anti-B or anti-D)). 
• Blood sample for serum IgG. 
• Blood samples for enzymes. 
• Blood sample for biomarkers of disease activity. 
• CSM. 
• CDASI. 
Before, during and after each infusion episode: 
• Administration/Infusion of  IMP  (2.0 g/kg  [20 mL/kg] Octagam 10%  given  in 
infusion episodes over 2 to 5 consecutive days). 
• Vital signs before, at least once during and at least 1 hour after each infusion episode. 
At least 1 hour after the infusion cycle: 
• Blood  sample  for  additional  safety  
lab  parameters “Panel 2” (serum  haptoglobin, 
hemoglobin, plasma-free hemoglobin, LDH). 
• Direct Coombs’ test (if positive, the antibodies responsible for the positive Coombs’ 
test will be eluted to investigate their specificity (anti-A, anti-B or anti-D)). 
• Wells probability score  
for  DVT.  
If  score  
is  
likely  
for  DVT  
(≥2 points),  perform 
Doppler scan and take blood sample for D-dimers. 
• Wells probability score for PE. 
In addition, AEs will be monitored and concomitant medications will be documented. 
6.1.6 Visits 7 and 8 (Week 20 and 24; Extension Period) 
The following assessments will be performed:  
Before infusion cycle: 
• Vital signs. 
• Blood samples for safety laboratory (hematology and clinical chemistry).  
• Blood sample for serum IgG. 
 
2 4 weeks after the last infusion 


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Before, during and after each infusion episode: 
• Administration/Infusion  of  IMP  (2.0 g/kg  [20 mL/kg] Octagam 10%  given  in 
infusion episodes over 2 to 5 consecutive days). 
• Vital signs before, at least once during and at least 1 hour after each infusion episode. 
At least 1 hour after the infusion cycle: 
• Wells probability score  
for  DVT.  
If  score  
is  
likely  
for  DVT  
(≥2 points),  perform 
Doppler scan and take blood sample for D-dimers. 
• Wells probability score for PE. 
In addition, AEs will be monitored and concomitant medications will be documented. 
6.1.7 Visit 9 (Week 28) 
The following assessments will be performed: 
Before infusion cycle: 
• Physical examination. 
• Vital signs and body weight. 
• Blood sample for safety laboratory (hematology and clinical chemistry). 
• Blood sample for additional safety lab parameters “Panel 1” (serum haptoglobin and 
plasma-free hemoglobin). 
• Direct Coombs’ test (if positive, the antibodies responsible for the positive Coombs’ 
test will be eluted to investigate their specificity (anti-A, anti-B or anti-D)). 
• Blood sample for serum IgG. 
• Blood samples for enzymes. 
• CSM. 
• CDASI. 
Before, during and after each infusion episode: 
• Administration/Infusion  of  IMP  (2.0 g/kg  [20 mL/kg] Octagam 10%  given  in 
infusion episodes over 2 to 5 consecutive days). At the discretion of the investigator 
and, if the subject is stable on 2.0 g/kg (20 mL/kg) Octagam 10%, the subject may 
receive 1.0 g/kg (10 mL/kg) Octagam 10%. 
• Vital signs before, at least once during and at least 1 hour after each infusion episode. 
At least 1 hour after the infusion cycle: 
• Blood  sample  for  additional  safety  
lab  parameters “Panel 2” (serum  haptoglobin, 
hemoglobin, plasma-free hemoglobin, LDH). 
• Direct Coombs’ test (if positive, the antibodies responsible for the positive Coombs’ 
test will be eluted to investigate their specificity (anti-A, anti-B or anti-D)). 
• Wells  probability  score  
for  DVT.  
If  score  
is  
likely  
for  DVT  
(≥2 points),  perform 
Doppler scan and take blood sample for D-dimers. 
• Wells probability score for PE. 
In addition, AEs will be monitored and concomitant medications will be documented. 


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6.1.8 Visits 10, 11 (Week 32 and 36; Extension Period) 
The following assessments will be performed: 
Before infusion cycle: 
• Vital signs. 
• Blood samples for safety laboratory (hematology and clinical chemistry). 
• Blood sample for serum IgG. 
Before, during and after each infusion episode: 
• Administration/Infusion  of  IMP  (2.0 g/kg [20 mL/kg] Octagam 10%  given  in 
infusion episodes over 2 to 5 consecutive days). At the discretion of the investigator 
and, if the subject is stable on 2.0 g/kg (20 mL/kg) Octagam 10%, the subject may 
receive 1.0 g/kg (10 mL/kg) Octagam 10%. 
• Vital signs before, at least once during and at least 1 hour after each infusion episode. 
At least 1 hour after the infusion cycle: 
• Wells  probability  score  
for  DVT.  
If  score  
is  
likely  
for  DVT  
(≥2 points),  perform 
Doppler scan and take blood sample for D-dimers. 
• Wells probability score for PE. 
In addition, AEs will be monitored and concomitant medications will be documented. 
6.1.9 Unscheduled Visit 
If an unscheduled visit becomes necessary, e.g. after disease deterioration between 2 regular 
visits, the same procedures as described in Section 6.1.3 for Visit 3 (without IMP infusion) 
should be performed. 
Wells probability scores for DVT and PE should also be performed. If the Wells score is 
likely (≥2 points) for DVT, a Doppler scan should be performed and a blood sample should 
be taken for assessment of D-dimers. 
6.1.10 End-of-Study (Final Examination) Visit 12 (Week 40; Extension Period) or 
Drop-out Visit 
The final examination is performed 4 weeks after the last IMP administration. 
The following investigations will be performed: 
• SF-36v2. 
• Physical examination. 
• Blood sample for safety laboratory (hematology and clinical chemistry). 
• Blood sample for additional safety lab parameters “Panel 1” (serum haptoglobin and 
plasma-free hemoglobin) 
• Direct Coombs’ test (if positive, the antibodies responsible for the positive Coombs’ 
test will be eluted to investigate their specificity (anti-A, anti-B or anti-D)). 
• Blood sample for serum IgG. 
• Blood samples for enzymes. 


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• Blood sample for viral markers. 
• Blood sample for biomarkers of disease activity. 
• CSM. 
• CDASI. 
• Monitoring of AEs. 
• Documentation of concomitant medication. 
• Pregnancy test. 
After the Final Examination, the clinical study is considered completed for the subject. No 
further study-related assessments will be performed, unless safety concerns (e.g., ongoing 
AEs) require follow-up.  


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6.1.11 Time Windows Used in this Study, Including Tolerances 
In this study, the following time windows and tolerances apply: 
Table 4:  
Time Windows Used in this Study 
Time Point 
Time stated 
Tolerance 
Interval between visits 
/ infusion cycles 
4 weeks 
 
± 4 days 
 
Interval between 
infusion episodes 
1 day (next day) 
15 – 30 hours 
Vital signs 
before IMP administration of 
infusion episode 
≤ 60 minutes 
 
after each IMP administration 
≥ 60 minutes 
Direct Coombs’ test 
before first IMP administration of 
infusion cycle 
≤ 4 hours 
 
after last IMP administration of 
infusion cycle 
≥ 60 minutes 
Wells probability score 
for DVT 
after IMP administration of last 
infusion episode of a cycle 
≥ 60 minutes 
Wells probability score 
for PE 
after IMP administration of last 
infusion episode of a cycle 
≥ 60 minutes 
6.1.12 Clinical Terms Used in this Study 
Table 5: 
Clinical Terms Used in this Study 
Term 
 
Clinical Start of Study Screening of First Subject 
Enrollment  
Randomization and entry into the double-blind treatment period  
Washout period 
Period which needs to elapse from discontinuing previous DM 
related medication until randomization 
Clinical End of Study  Last Visit of the Last Subject 
6.2 Duration of Study 
6.2.1 Planned Duration for an Individual Subject 
The duration of the entire study for each subject will be up to 43 weeks and consists of the 
following segments: up to 3 weeks for Screening, then 16 weeks of double-blind treatment 
phase (First Period) followed by 24 weeks of open-label treatment (Extension Period). 
6.2.2 Planned Duration for the Study as a Whole 
The  study  will  be  considered  completed  when  all subjects  have  completed  the  planned 
observation period/Final Examination Visit. 
The study as a whole should be completed within about 36 months. The estimated clinical 
start of the study is Q4 2016 with the estimated clinical end in Q4 2019. 


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6.2.3 Premature Termination of the Study 
Both the Investigator and the Sponsor reserve the right to terminate the study at any time. In 
this  event,  any  necessary procedures  will  be  arranged  on  an  
individual  study  basis  after 
review  and  consultation  by  both  parties.  In  terminating  the  study,  the  Sponsor  and  the 
Investigator will ensure that adequate consideration is given to the protection of the subjects’ 
interests. 
Regulatory  authorities and  IECs/IRBs should  be  informed in accordance  with national 
regulations. 
Early termination of the study as a whole or by centre may apply for the following reasons: 
6.2.3.1 Early Termination of the Entire Clinical Study 
At any time, the study as a whole will be terminated prematurely if: 
• New toxicological or pharmacological findings or safety reports invalidate the earlier 
positive benefit-risk-assessment. 
• If  more  than 3 TEEs (i.e.  ischemic  stroke,  transient  ischemic  attack,  cerebral 
infarction,  cerebrovascular  accident,  cerebral  thrombosis,  embolic  infarctions, 
[acute] myocardial infarction, deep vein thrombosis, pulmonary embolism, venous 
thrombosis  excluding  
thrombophlebitis or  
infusion  site  
thrombosis) are  observed 
during the first (controlled) period of the study, fulfilling the following criterion: 
 associated with Octagam 10% treatment; 
AND 
if less than half of the number of TEEs reported as associated with Octagam 10% are 
observed  during  
the  
first  
(controlled)  period  of  
the  study,  fulfilling  
the  following 
criterion: 
 associated with placebo treatment. 
. 
• For TEEs observed on or after the cut-off date of 04-Jul-2018 (since introduction of 
reduced  maximum  
infusion  rate  of  0.04 mL/kg/min) TEE  rates  (per  100  patient-
months) will be calculated as follows: 
 Ro = 100* Number of TEEs observed on or after the cut-off date in patients 
last treated with Octagam / Total person-months of patients on Octagam since 
the cut-off date 
 Rp  =  100*  Number  of  TEEs  
in  patients  
last  
treated  with  Placebo  
/  Total 
person-months of patients on Placebo. Rp is based on the whole study period, 
no cut-off is applied) 
These rates will be calculated on basis of the actual last treatment. 
The study as a whole will be terminated 
 if Ro exceeds Rp by more than 1.0 
AND 
 at least 4 TEEs have been observed in the Octagam group after the cut-off 
date of 04-Jul-2018. 
TEEs with a likely temporal and cause-effect relationship which occur in a single subject 
within a short clinical time period should be counted as a single AESI, including for the 


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calculations  performed  for  stopping  rules:  For  example  a  DVT  which  subsequently 
embolized to cause a PE or a transient ischemic attack (TIA) followed in short order by 
a cerebrovascular accident (CVA). 
Medical judgement  will  be  applied to  determine  if  these  represent  separate  discrete 
events or if they represent expressions of a single AESI based on the relatedness of the 
underlying  pathophysiology.  The  IDMC  will  confirm  if  they are  clinically  and 
pathophysiologically manifestations of a single process. 
However, all TEEs will be captured separately in the clinical data base. 
• If more  than  4  clinically significant  (definition see  Section 7.3.2.1) hemolytic 
transfusion reactions (HTRs) are observed during the first (controlled) period of the 
study, fulfilling the following criteria: 
 assessed  as  probably  or  possibly  related  to Octagam 10% treatment  by 
Investigator and/or Sponsor; 
 confirmed by the IDMC. 
AND 
if less than 3 clinically significant HTRs are observed during the first (controlled) 
period of the study, fulfilling the following criteria: 
 assessed as probably or possibly related to placebo treatment by Investigator 
and/or Sponsor; 
 confirmed by the Independent Data Monitoring Committee (IDMC). 
NOTE:  Causality  assessments  of  suspected HTRs have  to  be  made  in  a  blinded 
manner  by  all  involved  parties  (Investigator,  Sponsor,  IDMC).  After  individual 
causality assessment, the IDMC is entitled to unblind cases in order to monitor the 
stopping rule. 
• Any other reason rendering the continuation of the study impossible for the Sponsor. 
6.2.3.2 Early Termination at an Individual Study Centre 
At any time, the study can be terminated at an individual centre if: 
• The centre cannot comply with the requirements of the protocol. 
• The centre cannot comply with GCP standards. 
• The centre’s first subject is not recruited by 20 weeks after initiation of the centre. 
• The required recruitment rate is not met. 
Should the study be prematurely terminated, all study materials (IMPs, 
etc.) must be returned 
to the Sponsor. 


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7 ASSESSMENTS AND METHODS 
7.1 Demographic and Baseline Information 
The following information will be recorded during the Screening Visit: 
7.1.1 Demographic and Baseline Characteristics 
The demographic and baseline characteristics are sex, age, ethnic origin, height, weight, and 
Body Mass Index. 
7.1.2 Medical History and Prior/Concomitant Medications 
The relevant medical history will be obtained by interviewing the subject. Records of past 
diseases and treatments (e.g., hospital discharge letters) will be obtained for the study files, 
if available. 
Prior and concomitant medications as well as physical therapy-directed exercise regimens 
will be obtained by interview. 
7.2 Efficacy Assessments 
All participating centers will be trained in the DOI assessed by the TIS based on its 6 CSM. 
CSM  assessments  should  always  be  performed  by  the  same  investigator  or  designee. 
Training will be done by a third party. 
7.2.1 Assessments for Primary Efficacy Endpoint(s) 
The TIS is a score derived from the evaluation of the results from 6 CSM of myositis disease 
activity established for clinical trials in subjects with DM and PM: 
• Physician’s Global Disease Activity (part of MDAAT; 10 cm VAS assessing global 
disease  activity  from  “No  evidence  of  disease  activity”  to  “Extremely  active  or 
severe  disease  activity”;  Disease  Activity  being  defined  as  potentially  reversible 
pathology or physiology resulting from the myositis). 
• Patient’s Global Disease Activity (10cm VAS assessing the overall activity of the 
patient’s disease today from “No evidence of disease activity” to “Extremely active 
or  severe  disease  activity”,  Disease  Activity  being  active  inflammation  in  the 
patient’s  muscles,  skin,  
joints,  
intestines,  heart,  
lungs  or  other  parts  of  
the  body, 
which can improve when treated with medicines). 
• Manual  Muscle  Testing  (MMT-8;  a  set  of 8 designated  muscles  
tested bilaterally 
[potential score 0 – 150]). 
• Health  Assessment  Questionnaire  (HAQ;  a  generic  rather  
than  a  disease-specific 
instrument;  comprised  of 8 sections:  dressing,  arising,  eating,  walking,  hygiene, 
reach, grip, and activities. There are 2 or 3 questions for each section. Scoring within 
each section is from 0 [without any difficulty] to 3 [unable to do]. For each section 
the score given to that section is the worst score within the section. The 8 scores of 
the 8 sections are summed and divided by 8).[27,28] 


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• Enzymes  
(aldolase,  creatine  kinase, Alanine  Aminotransferase (ALAT), Aspartate 
Aminotransferase (ASAT), Lactate Dehydrogenase (LDH)).  
• Extra-muscular  activity  (part  of MDAAT; a  combined  tool  that  captures  the 
physician’s assessment of disease activity of various organ systems using (1) a scale 
from  0  = “Not  present  in  the  last 4 weeks”  to  4  = “New - in  the  last  4 weeks 
(compared to the previous 4 weeks)” and (2) a VAS). 
These CSM were validated by the International Myositis Assessment and Clinical Studies 
Group  (IMACS).  However,  conjoint  analysis  was  introduced  to  develop  a  definition  of 
improvement derived from the 6 CSM to calculate the TIS. The TIS is a scale from 0 to 100 
that  allows  for  the  discrimination  between  minimal,  moderate  and  major  responders 
depending on their improvement in the combined 6 CSM: ≥20 to 39 points being minimal 
improvement, ≥40 to 59 points being moderate improvement, and ≥60 points being major 
improvement.[19,30] It does not discriminate stable from worsening patients. 
7.2.2 Assessments for Secondary Efficacy Endpoint(s) 
The CDASI is a clinician-scored single page instrument that separately measures  activity 
and damage in the skin  of DM patients for use in clinical practice or clinical/therapeutic 
studies. The modified CDASI (version 2) is the one in current use. The modified CDASI has 
3 activity  measures  (erythema,  scale,  and  erosion/ulceration)  and 2 damage  measures 
(poikiloderma and calcinosis) which are assessed over 15 body areas. In addition, Gottron’s 
papules  on  
the  hands  are  evaluated  both  for  activity  and  damage.  Lastly,  
the  activity  of 
periungual changes and alopecia is assessed.[29] 
The Quality of Life questionnaire SF-36 is described in Section 7.4.3. 
7.3 Safety Assessments 
7.3.1 Assessments for Safety Endpoints 
Any of the following drug safety information shall be collected: 
• AEs  and  SAEs  
(for  definitions  and  
reporting  
requirements,  see Section 7.3.2 thru 
Section 7.3.5). 
• ADRs and suspected ADRs (for definition see Section 7.3.2.1). 
• Pregnancies, drug overdose, interaction, medication error, and post-study SAEs (see 
Section 7.3.9). 
7.3.2 Adverse Events (AEs) 
7.3.2.1 Definitions 
• Adverse event (AE): An AE is any untoward medical occurrence in a study subject 
receiving an IMP and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an IMP, whether or not related to the IMP. 


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• Adverse drug reaction (ADR): An ADR is any noxious and unintended response 
to an IMP related to any dose. The phrase ‘response to an IMP’ means that a causal 
relationship between the IMP and an AE carries at least a reasonable possibility, i.e., 
the relationship cannot be ruled out. 
• Suspected ADR: Suspected ADR is an AE that fulfills at least one of the following 
criteria: 
o AE starts during the infusion cycle or within 72 hours after the end of the 
last infusion episode of the respective infusion cycle/visit. 
o The incidence of the preferred term in the Octagam 10% arm is greater than 
in the placebo arm. 
o The investigator’s assessment is missing or indeterminate. 
• Other significant AEs: Any marked laboratory abnormalities or any AEs that lead 
to  an  intervention,  including  withdrawal  of  drug  treatment,  dose  reduction,  or 
significant additional concomitant therapy. 
• Withdrawal due to AE/ADR: 
AE/ADR leading to discontinuation of treatment with 
IMP.  Any  such  events  will  be  followed  up  by  
the Investigator  until  
the  event  
is 
resolved  or  until  the  medical  condition  of  the  subject is  stable.  All  follow-up 
information collected will be made available to the Sponsor. 
7.3.2.2 Collection of AEs 
The condition of the subject will be monitored throughout the study. At each visit, whether 
scheduled or unscheduled, AEs will be elicited using a standard non-leading question such 
as “How have you been since the last visit/during the previous study period?”  
Any AE or ADR which occurs during the study will be noted in detail on the appropriate 
pages of the eCRF. If the subject reports several signs or symptoms representing a single 
syndrome or diagnosis, the diagnosis should be recorded in the eCRF. The Investigator will 
grade the severity of all AEs or ADRs (mild, moderate, or severe), the seriousness (non-
serious or serious), and the causality as defined in Sections 7.3.2.3, 7.3.2.4 and 7.3.3. The 
Sponsor is responsible for assessing the expectedness of each ADR (expected or unexpected) 
as defined in Section 7.3.2.5. 
In the event of clinically significant abnormal laboratory findings other than those related to 
the basic disease, the tests will be confirmed and the subject followed up until the laboratory 
values  have  returned  
to  normal  and/or  an  adequate  explanation  for  
the  abnormality  has 
become available. 
Diseases, signs and symptoms, and/or laboratory abnormalities already present before the 
first administration of IMP will not be considered AEs unless an exacerbation in intensity or 
frequency (worsening) occurs. 
The Investigator will provide detailed information about any abnormalities and about the 
nature of and reasons for any action taken as well as any other observations or comments 
that may be useful for the interpretation and understanding of an AE or ADR. 
7.3.2.3 Severity of AEs 
The intensity/severity of AEs will be graded as follows: 


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• Mild: an AE, usually transient, which causes discomfort but does not interfere with 
the subject’s routine activities 
• Moderate: an AE which is sufficiently discomforting to interfere with the subject’s 
routine activities 
• Severe: an  AE  which  is  incapacitating  and  prevents  the  pursuit  of  the  subject’s 
routine activities 
The grading of an AE is up to the medical judgment of the Investigator and will be decided 
on a case-by-case basis. 
7.3.2.4 Causality of AEs 
The relationship of AEs to the administered IMP will be assessed by the Investigator: 
• Probable: reports including good reasons and sufficient documentation to assume a 
causal relationship, in the sense of plausible, conceivable, likely, but not necessarily 
highly  probable.  A  reaction  that  follows  a  reasonable  temporal  sequence  from 
administration of the IMP; or that follows a known or expected response pattern to 
the suspected medicine; or that is confirmed by stopping or reducing the dosage of 
the medicine and that could not reasonably be explained by known characteristics of 
the subject’s clinical state. 
• Possible: reports  containing  sufficient  information  to  accept  the  possibility  of  a 
causal  
relationship,  
in  
the  sense  of  not  
impossible  and  not  unlikely,  although  
the 
connection  is  uncertain  or  doubtful,  for  example  because  of  missing  data  or 
insufficient evidence. A reaction that follows a reasonable temporal sequence from 
administration of the IMP; that follows a known or expected response pattern to the 
suspected medicine; but that could readily have been produced by a number of other 
factors. 
• Unlikely: reports  not  following  a  reasonable  temporal  sequence  from  IMP 
administration. An event which may have been produced by the subject’s clinical 
state or by environmental factors or other therapies administered. 
• Not related (unrelated): events for which sufficient information exists to conclude 
that the etiology is unrelated to the IMP. 
• Unclassified: reports which for one reason or another are not  yet assessable, e.g., 
because of outstanding information (can only be a temporary assessment). 
7.3.2.5 Classification of ADRs by Expectedness 
ADRs will be classified by the Sponsor as either expected or unexpected: 
• Expected: an ADR that is listed in the current edition of the Investigator’s Brochure 
or other reference safety information. 
• Unexpected: an ADR that is not listed in the current edition of the Investigator’s 
Brochure  or  other  
reference  safety  
information,  or  
that  differs  because  of  greater 
severity or greater specificity. 
7.3.2.6 Outcome of AEs 
The outcome of all reported AEs has to be documented as follows: 
1. Recovered, resolved 


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2. Recovering, resolving 
3. Not recovered, not resolved 
4. Recovered, resolved with sequelae 
5. Fatal 
6. Unknown 
NOTE: A subject’s death per se is not an event, but an outcome. The event which resulted 
in the subject’s death must be fully documented and reported, even in case the death occurs 
within 4 weeks after  
IMP treatment end and  
regardless of whether or not it is considered 
treatment-related. 
7.3.2.7 Action(s) taken 
AEs requiring action or therapy must be treated with recognized standards of medical care 
to protect the health and well-being of the subject. Appropriate resuscitation equipment and 
medicines must be available to ensure the best possible treatment in an emergency situation. 
The action taken by the Investigator must be documented: 
a) General actions taken in the event of an AE 
– None 
– Medication (other than IMP) or other (e.g., physical) therapy started 
– Test performed 
– Other (to be specified) 
b) IMP-related actions taken in the event of an AE 
– None 
– Product withdrawn 
– Dose reduced 
– Dose increased 
The Investigator will follow up on each AE until it has resolved or until the medical condition 
of  
the subject has stabilized.  Any  
relevant  
follow-up  
information  will  be  
reported  
to  
the 
Sponsor. 
7.3.3 Serious Adverse Events (SAEs) 
A serious AE (SAE) is any untoward medical occurrence that at any dose: 
• results in death, 
• is life-threatening (see below), 
• requires hospitalization or prolongation of existing hospitalization, 
• results in persistent or significant disability/incapacity, 
• is a congenital anomaly/birth defect, 
• is another important medical event (including TEEs as defined in section 7.3.5.1). 
NOTE: The term ‘life-threatening’ refers to an event in which the subject was, in the view 
of the reporting Investigator, at immediate risk of death at the time of the event; it does not 
refer to an event which may hypothetically have caused death had it been more severe. 


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In deciding whether an AE/ADR is serious, medical judgment should be exercised. Thus, 
important AEs/ADRs that are not immediately life-threatening or do not result in death or 
hospitalization but may jeopardize the subject or may require intervention to prevent one of 
the other outcomes listed in the definitions above should also be considered serious.  
In addition, although not classified under the seriousness criteria, all suspected transmissions 
of an infectious agent should be reported as SAE. A suspected virus transmission means that 
virus antigen has been detected in the subject. A passive transmission of antibodies alone 
does not constitute a suspected virus transmission. 
7.3.4 SAE Reporting Timelines 
All  SAEs,  whether  or  not  
they  are  suspected  
to  be  related  
to  study  
treatment,  are  
to be 
reported  immediately  by  telephone,  fax,  or  email  to  the  Clinical  Project  Manager  or 
designee. 
The contact details will be communicated at the study initiation visit. 
In addition, within 24 hours after recognition of the event, an Octapharma Serious Adverse 
Event Report must be completed and submitted to: 
Ex- US & Canada: 
E-Mail: 
 
Fax: 
 
 
US & Canada: 
E-mail:  
 
Fax: 
 
 
24 hours emergency telephone number:  
Europe: 
 
USA: 
 
Waivers from the SAE Reporting Requirement 
Waivers from the SAE reporting requirement include: 
• hospitalizations  due  
to  
infusions  on  consecutive  days  (e.g. for subjects with  
long 
travel hours); 
• surgeries that are elective or were planned before study entry; 
• prolongation  of  existing hospitalizations for  economic  or  social,  but  not  medical, 
reasons.  
Such hospitalizations, surgeries, or prolongation of hospitalizations 
should not be considered 
SAEs. 


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7.3.5 Adverse Events of Special Interest (AESI) 
The following AEs are defined as AESI: 
• thromboembolic events (TEEs); 
• hemolytic transfusion reactions (HTRs). 
For  these AESI,  the general definitions  and  procedures  that  are  described elsewhere  in 
Section 7.3 apply  as  well.  TEEs must  be  
reported  as SAE as  described  
in  Section 7.3.3. 
Premature termination criteria related to AESI are defined in Section 6.2.3.1. 
7.3.5.1 Thromboembolic Events (TEEs) 
There is clinical evidence of an association between IGIV administration and TEEs such as 
ischemic  stroke,  transient  ischemic  attack,  cerebral  infarction,  cerebrovascular  accident, 
cerebral  thrombosis,  embolic  infarctions,  [acute]  myocardial  infarction,  deep  vein 
thrombosis (DVT), pulmonary embolism (PE), venous thrombosis. 
TEEs will be monitored as follows: 
• Wells  criteria  
for  assessment  of  probability  
for  possible  DVTs at  each  visit ([25] 
modified according to NICE Clinical Guideline 144, 2012): 
Present 
Score 
  Active cancer (treatment ongoing, within 6 months, or palliative) 
+1 
  Paralysis, paresis or recent plaster immobilization of the lower extremities 
+1 
  Recently bedridden for 3 days or more or major surgery within 12 weeks requiring general or 
regional anesthesia 
+1 
  Localized tenderness along the distribution of the deep venous system 
+1 
  Entire leg swollen 
+1 
  Calf swelling at least 3 cm larger than asymptomatic side 
+1 
  Pitting edema confined to the symptomatic leg 
+1 
  Collateral superficial veins (non-varicose) 
+1 
  Previously documented DVT* 
+1 
  An alternative diagnosis is at least as likely as DVT 
-2 
Clinical Probability Simplified Score  
  
  
 
DVT likely ≥2 points 
  
  
  
  
  
  
  
 
DVT unlikely ≤1 point 
*Note: This is also an exclusion criterion 
• If the Well’s DVT probability score is ≥2, then a Doppler screening for DVT will 
have to be completed (recommended: Doppler using color duplex sonography) and 
a blood sample will have to be taken for D-dimers. 


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• Wells  criteria  for  assessment  of  probability  for  possible PE at  each visit ([26]; 
modified according to NICE Clinical Guideline 144, 2012): 
Present 
Score 
  Clinical signs and symptoms of DVT (minimum of leg swelling and pain with palpation of the 
deep veins) 
3 
  An alternative diagnosis is less likely than PE 
3 
  Heart rate > 100 beats per minute 
1.5 
  Immobilization for more than 3 days or surgery in the previous 4 weeks 
1.5 
  Previous DVT/PE 
1.5 
  Hemoptysis 
1 
  Malignancy (on treatment, treated in the last 6 months, or palliative) 
1 
Clinical Probability Simplified Score  
  
  
 
PE likely >4 points 
  
  
  
  
  
  
  
 
PE unlikely ≤4 point 
*Note: This is also an exclusion criterion 
Therapeutic measures managing suspected TEEs shall be initiated according to local clinical 
practice (e.g. anticoagulation). 
7.3.5.2 Hemolytic Transfusion Reactions (HTRs) 
HTRs can develop subsequent to IGIV therapy. IGIV-related hemolysis is associated with 
passive transfer of anti-A and anti-B hemagglutinins. 
HTRs will be monitored as follows at pre-defined visits (see Flowchart of Study Events): 
• Direct Coombs’ test. If a positive result is obtained, the antibodies responsible for 
the positive test result will be eluted to investigate their specificity (anti-A, anti-B or 
anti-D). 
• Additional  safety  lab  parameters  (hemoglobin, serum  haptoglobin,  plasma-free 
hemoglobin, LDH). 
Intravascular  hemolysis  will  be  suspected  if  all  of  the  following  criteria  are  fulfilled 
(modified acc. to FDA Guidance for Industry 2008
3): 
• a positive direct Coombs’ test result; 
• a drop in hemoglobin of 2 g/dL or greater; 
• a drop in serum haptoglobin to below the lower limit of normal; 
• a rise in serum LDH from baseline. 
In case of a patient’s positive direct Coombs test the investigator has to check if the above 
mentioned criteria are fulfilled. The results of these additional tests and any clinical signs or 
symptoms  potentially  related  to  hemolysis  will  be  documented  in  the  patient’s  medical 
record. 
Therapeutic measures 
managing suspected HTRs shall be initiated 
according to local clinical 
practice. 
 
3 Guidance  for  Industry.  Safety,  Efficacy,  and  Pharmacokinetic  Studies  to  Support  Marketing  of  Immune 
Globulin Intravenous (Human) as Replacement Therapy for Primary Humoral Immunodeficiency. 2008 


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7.3.6 Laboratory Tests 
The following laboratory parameters will be investigated during the study at the time points 
specified in Section 6.1. 
7.3.6.1 Central Laboratory 
The following laboratory tests will be done at a central laboratory: 
Clinical  chemistry:  Na+  (sodium),  K+  (potassium),  glucose,  ALAT,  ASAT,  LDH,  total 
bilirubin,  BUN  (blood  urea  nitrogen)  or  urea,  creatinine,  albumin,  thyroid-stimulating 
hormone (TSH). 
Hematology: hematocrit, hemoglobin, complete blood count with differential (red blood cell 
counts, white  blood  cell  counts  (neutrophils,  eosinophils,  basophils,  lymphocytes, 
monocytes), platelets).  
Direct Coombs test: if positive, the antibodies responsible for the positive Coombs’ test will 
be eluted to investigate their specificity (anti-A, anti-B or anti-D) 
Additional safety laboratory parameters:  
Panel 1: serum haptoglobin and plasma-free hemoglobin. 
Panel 2: serum haptoglobin, hemoglobin, plasma-free hemoglobin, LDH. 
D-dimers. 
Serum IgG. 
Enzymes: aldolase, creatine kinase and, if clinical chemistry will be performed by a local 
laboratory,  ALAT,  ASAT  and  LHD. For  the  CSM  only  values  measured  in  the  central 
laboratory will be used. 
Viral markers: details see Section 7.3.7. 
Pregnancy test: in blood if not performed locally. 
Blood  sampling  will  take  place according  to the time  points  given  in  Section 6.1.  The 
methods  used  for  each  parameter  and  the  normal  ranges  of  each  determination  will  be 
provided in the Clinical Study Report. A lab manual detailing blood sampling and shipment 
procedures will be provided to each study site. 
7.3.6.2 Local Laboratory 
The following laboratory tests will be done in some countries by the local laboratories of 
each study site: 
• Hematology:  hematocrit,  hemoglobin,  complete  blood  count  with  differential  
(red 
blood  cell  counts, white blood  cell  counts  (neutrophils,  eosinophils,  basophils, 
lymphocytes, monocytes), platelets. 
• Chemistry:  Na+  (sodium),  K+  (potassium),  glucose,  ALAT,  ASAT,  LDH,  total 
bilirubin, BUN (blood urea nitrogen) or urea, creatinine, albumin. 
• Pregnancy test: either in urine or in blood. 
The methods of determination and normal ranges for each parameter will be provided in the 
clinical study report.  


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7.3.7 Viral Safety Tests 
Viral marker samples will be taken before the first IMP infusion  at Screening and at the 
Termination Visit. 
Viral marker samples will be analyzed at a central laboratory. 
Full blood sample must be taken and centrifuged, aliquoted, and the storage tubes must be 
frozen at ≤–70°C. Further details will be provided in the lab manual. 
At sites where a freezer of –70°C or below is not available, samples can be stored at or below 
–20°C. In such cases, shipment to the central laboratory should be performed shortly, but 
not later than 2 months after the day of collection. 
Samples will be analyzed by serology tests or nucleic acid testing for HIV, hepatitis B and 
hepatitis C  virus.  In  case  of  any  change  of  a subject’s  viral  status  between  baseline  and 
follow-up and a suspected seroconversion, the viral tests will be repeated by the laboratory. 
In case the result is confirmed, additional testing will be performed as necessary. 
Retention samples of all blood draws for virus safety will be kept at ≤–70°C at the central 
laboratory for possible future testing. 
7.3.8 Vital Signs and Physical Examination 
The vital signs obtained at the time points specified in Section 6.1 are blood pressure, body 
temperature, pulse rate,  and respiratory rate. Measurements will be carried out before the 
start of each infusion, at least once during  each  
infusion, and at  
least 1 hour after  end of 
infusion.  Hemodynamic  changes  may  occur  during  IGIV  
infusion  and  minor  changes  
in 
pulse and blood pressure are frequent. For this reason, only changes in vital signs considered 
clinically significant by the Investigator are to be reported as AEs. Fever will be defined as 
a body temperature >38°C, and has to be documented as an AE. 
Physical examinations will be performed at the visits specified in Section 6.1. Both height 
and  weight will  be  measured  at screening.  
In  addition, body weight  will  be  measured  at 
certain visits prior to IMP administration and reported back to the pharmacist or designee as 
it  is  needed  for  the  preparation  of  the  next  study  medication  dosage  by  the  unblinded 
pharmacist or designee 4 weeks later. 
7.3.9 Other Relevant Safety Information 
a) Post-study related safety reports 
Any SAE which occurs up to 4 weeks after the last IMP administration should be reported 
by the Investigator to the Sponsor in case the Investigator becomes aware of it. Proactive 
monitoring for post-study SAEs is not required. 
In case a post-study SAE is identified, the Investigator should complete an SAE form. 
Deaths occurring within 4 weeks after the last IMP administration should also be reported, 
regardless of whether or not they are considered treatment-related. 
b) Pregnancies 
Clinical  experience  with  immunoglobulins  suggests  that  no  harmful  effects  are  to  be 
expected on the course of pregnancy, or on the fetus and the neonate, or on fertility.  


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However, every effort will be made to avoid a pregnancy during the use of an IMP up to 
four weeks after last IMP infusion. However, contraception for male subjects and partners 
of women included in the trial are not compulsory. Pregnancies occurring during the study 
(fetal exposure to the IMP) need to be reported.  
In  case  of  pregnancy  during  the  study,  the Investigator  should  complete  the  Pregnancy 
Notification  Form  and  send  or  fax  it  to  the  Clinical  Project  Manager  or  designee  (see 
Section 7.3.4). 
Follow-up  
information  on  
the  outcome  of  both  mother  and fetus will  be  requested  by  a 
Sponsor representative. 
Overdose, interaction and medication error 
The following safety relevant information should be reported as AE or, if the reaction fulfils 
one of the criteria for seriousness, as SAE. 
c) Drug overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
specified  
in  
the  protocol  and  higher  
than  
the  known  therapeutic  dose  that  is  of  clinical 
relevance. The reaction must be clearly identified as an overdose. 
d) Drug interaction 
A drug interaction is a situation in which a substance or medicinal product affects the activity 
of  an  
IMP,  
i.e.,  
increases  or decreases  
its  effects,  or  produces  an  effect  
that  none  of  
the 
products  would  exhibit  on  its  own.  The  reaction  must  be  clearly  identified  as  a  drug 
interaction. 
e) Medication error 
A medication error involves the inadvertent administration or unintended use of a medicinal 
product  which  may  be  caused  by  the  naming,  presentation  of  pharmaceutical 
form/packaging, or instructions for use/labeling. The reaction must be clearly identified as a 
medication error. 
7.4 Other Assessments 
7.4.1 Drug Concentration Measurements 
The  trough  level  IgG  concentrations  will  be  measured  at  each  visit  prior  to  IMP 
administration in order to potentially correlate the IgG levels with the disease activity and 
responder classification. 
7.4.2 Blood Sample for Biomarkers of Disease Activity 
A biorepository blood sample will be taken in order to investigate potential biomarkers of 
disease  activity  (e.g.  myositis-specific  antibodies, cytokine,  chemokine  or  monoclonal 
antibody changes).  
It is not intended to conduct genetic testing on the biorepository blood samples in the future. 


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7.4.3 Quality of Life Assessment 
The  generic SF-36v2  Health  Survey will  be  used  for  assessing  quality  of  
life  (www.sf-
36.org/; www.qualitymetric.com). The SF-36 is a multi-purpose, short-form health survey 
with only 36 questions. It yields an 8-scale profile of functional health and well-being scores 
as  well  as  psychometrically-based  physical  and  mental  health  summary  measures  and  a 
preference-based health utility index. The SF-36 is the most widely evaluated generic patient 
assessed health outcome measure being used in more than 200 diseases and conditions. It 
has  been  validated  
in  multiple  diseases  and  
languages  and  has  been  used  successfully  
in 
more  than 600 randomized  clinical  trials  reported  in  over 240 scientific  and  medical 
journals. The SF-36 has been proven responsive in 44 disease conditions and is accepted by 
the FDA as proof of benefit for improved functioning and other patient-reported outcomes. 
Its newer version, the SF-36v2, is available in 170 language translations. 
The SF-36v2 has mental (4) and physical (4) component subscales. 
7.5 Appropriateness of Measurements 
The measurements selected in ProDERM in the First Period are appropriate to verify the 
clinical efficacy 
of IGIV in DM. The study design 
of ProDERM includes all major scientific, 
state-of-the-art  interventions  with  respect  to  assessment  of  the  efficacy,  safety  and 
tolerability of IGIV administration in DM patients. 
While Dalakas et al. 1993 stated that most of the IGIV responders did so after the second 
course of IGIV, an Advisory Board of DM experts in the fields of neurology, rheumatology 
and immunology recommended to extend the placebo-controlled First Period to 4 courses of 
either IGIV or placebo (last infusion at Week 12) and to evaluate the primary endpoint at 
Week 16 (4 weeks [±4 days] after the last infusion). In order to assess the long-term efficacy 
of IGIV maintenance therapy subjects will receive further 6 courses of Octagam 10% during 
the open-label Extension Period (unless they have to drop out, see Section 4.3.1). To keep 
the  blinding,  subjects  worsening  
in  both  
treatment  arms  will  be switched to  
the  alternate 
treatment. 
The comparability with the Dalakas trial results will be limited due to the different primary 
endpoint  selected.  Despite  significant  morbidity  and  mortality  associated  with  DM/PM, 
there  are  currently  no  therapies  approved  for  these  syndromes  by  the  US  or  European 
regulatory  authorities,  FDA  and  EMA,  based  on  adequate  randomized  controlled  trials. 
However, with the advancement in novel therapeutics that target various biological pathways 
implicated in the pathogenesis of DM/PM, there is a need for well-designed clinical trials 
using  validated  and  universally  accepted  outcome  measures.[21] Recent  clinical  trials 
completed in adult DM/PM and juvenile DM have utilized varying response criteria, again 
highlighting the need for both data- and consensus-driven criteria to be used uniformly in 
future studies.[22-24] 
CSM  of  myositis  disease  activity  for  DM/PM  clinical  trials  have  been  established  and 
validated by the IMACS Group.[15-17] 
Very recently, these IMACS CSM have been further 
developed into conjoint-analysis  hybrid  
response  criteria  combining 6 CSM to determine 
clinically  meaningful  improvement  in  the  Total  Improvement  Score  (TIS).[19,30] 
ProDERM will  employ the  TIS  in its  final  version  (submitted  for  publication  by  Prof. 
Aggarwal who was member of a highly experienced Advisory Board that helped developing 
this  protocol)  for  the  DOI  used  as  primary  endpoint.  A  big advantage  of  these  hybrid 
response  criteria  over  
the  previous  IMACS  
response  criteria  
is  
that  
inclusion  criteria  
for 


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clinical  trials  will  not  require  a  minimal  severity  in  any  CSM,  because  all  levels  of 
improvement in each CSM contribute more or less to the response (the previous IMACS 
preliminary response criteria required a baseline deficit of at least 20% in each CSM in the 
clinical  
trial  
inclusion  criteria  
to  enable  
reaching  
the  
threshold  of ≥20%  
improvement  
in 
CSM after treatment).[18] Therefore, it is justified to use the response criterion based on the 
TIS changes as primary endpoint. 
8 DATA HANDLING AND RECORD KEEPING 
8.1 Documentation of Data 
8.1.1 Source Data and Records 
Source data are defined as all information related to clinical findings, observations, or other 
activities in the study, written down in original records or certified copies of original records, 
allowing reconstruction and evaluation of the clinical study. 
The Investigator will maintain adequate source records (e.g., case histories or subject files 
for each subject enrolled). Source records should be preserved for the maximum period of 
time required by local regulations. 
For  each subject enrolled,  
the Investigator will  indicate  
in  
the  source  record(s)  
that  
the 
subject participates in this study. 
All data entered in the eCRF must be supported by source data in the subject records. 
The Investigator will  permit  study-related  monitoring,  audit(s),  IEC/IRB  review(s),  and 
regulatory inspection(s), by providing direct access to the source data/records. 
The Investigator may authorize site staff (e.g., sub-investigators, nurses) to enter study data 
into the eCRF. This must be documented in the Delegation of Authority Log signed by the 
Investigator. 
8.1.2 Electronic Case Report Forms 
For each subject enrolled, an eCRF will be completed within the Electronic Data Capture 
(EDC) system and approved by the Investigator or an authorized sub-investigator.  
Study site staff (e.g., research nurse) will be responsible for entering subject data into the 
validated  EDC  system.  All  site  personnel  will  be  
trained  on  
the  EDC  system  and  study 
specific eCRFs prior to receiving access to the live database for data entry. 
The site is also provided with the approved eCRF Completion Guidelines which will assist 
in data entry and data issues/questions. The site will be notified once the database is active 
to begin data entry. Additional site training may be provided as refreshers throughout the 
study, if needed. All persons allowed to enter or change eCRF data must be listed in the 
Delegation of Authority Log. 
8.1.3 Changes to Case Report Form Data 
Monitors will perform source data verification (SDV) as defined for the study. 


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If  any  errors  or  discrepancies  in  the  eCRFs  are  found  during  data  entry  or  review, 
discrepancies  will  be  generated  programmatically  within  
the  EDC  system,  and  ‘manual’ 
queries will be generated by either a monitor or Data Management.  
Discrepancies and queries can only be corrected by the Investigator(s) or other authorized 
site personnel. An audit trail documents all changes to the data over the entire study period. 
If the  reason  for  a  change  is  not  obvious,  a  comment  must  be  supplied  in  the  query’s 
response,  stating  the  reason  for  the  change,  prior  to  closing.  The  study  monitor  should 
provide  guidance  
to Investigator(s) and  
the Investigator(s)’  designated  
representatives  on 
making such corrections.  
Once  queries  have  been  resolved  by  the  site  staff,  the  resolutions  are  assessed  by  Data 
Management. If the query response provided confirms the data as correct, the discrepancy 
will be closed. If the response does not adequately address the question raised, a new query 
will be issued for further clarification. 
Manual checks are performed and programs are run throughout the study until the data is 
clean and the database is ready for lock. All discrepancies will be resolved prior to database 
lock.  There  will  be  a  
final  
run  of  
the  programmed  checks  
to  ensure  all  discrepancies  are 
closed  out,  SDV  will  be  confirmed  as  complete  by  
the  monitor,  and  all  eCRFs  will  be 
approved by the Investigator prior to database lock. 
8.2 Information to Investigators 
An Investigator’s Brochure (IB) will be handed out to the Investigator before the start of the 
study.  The  IB  contains  all  information  in  the  Sponsor’s  possession  necessary  for  the 
Investigator to be fully and accurately informed about the safety of the IMP under evaluation 
and the respective benefit-risk ratio. 
The  IB  will  be  updated  by  
the  Sponsor  at  regular  
intervals  and  whenever relevant  new 
information concerning the IMP becomes available. 
The Investigator will be informed about the methods for rating relevant study outcomes and 
for completing eCRFs to reduce discrepancies between participating Investigator and study 
sites. 
The Investigator will be kept informed of important data that relate to the safe use of the 
IMP as the study proceeds. 
8.3 Responsibilities 
The Principal Investigator  is  accountable  for  the  conduct  of  the  clinical  study. 
Responsibilities may be delegated to appropriately qualified persons. 
A Delegation of Authority Log will be filled in and signed by the Principal Investigator. In 
accordance  with  this  authority  log,  study  site  staff  (e.g.,  sub-investigators, nurses)  is 
authorized to perform tasks relating to the study. 
Monitoring will either be done by the Sponsor or by a subcontractor (to be appointed later). 
All  parties  
involved  
in  
the  study  are  responsible  
to  comply  with  
local  and  
international 
obligations,  regulatory  requirements  and  duties  
in  accordance  with  
local  
laws,  GCP  and 
Good Laboratory Practice guidelines, SOPs and other applicable regulations. 


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8.4 Investigator’s Site File 
At each study site, the Investigator is responsible for maintaining all records to enable the 
conduct  of  the  study  to  be  fully  documented.  Essential  documents  as  required  by  GCP 
guidelines and regulations (e.g., copies of the protocol, study approval letters, all original 
informed consent forms, site copies of all CRFs, drug dispensing and accountability logs, 
correspondence  pertaining  
to  
the  study,  etc.)  should  be  filed  accurately  and  kept  by  
the 
Investigator for the maximum period of time required by local regulations. 
The Investigator is responsible for maintaining a confidential subject identification code list, 
which  provides  the  unique  link  between  named  source  records  and eCRF  data  for  the 
Sponsor.  The Investigator must  arrange  for  
the  retention  of  
this  confidential  
list  for  
the 
maximum period of time required by local regulations. 
No  study  document  should  be  destroyed  without  prior  written  agreement  between  the 
Investigator and the Sponsor. Should the Investigator elect to assign the study documents to 
another party, or move them to another location, the Sponsor must be notified in writing. 
8.5 Provision of Additional Information 
On  request,  
the Investigator will  supply  
the  Sponsor  with  additional  data  relating  
to  
the 
study,  or  copies  of  relevant  source  records,  ensuring  
that  
the subject’s  confidentiality  
is 
maintained. This is particularly important when errors in data transcription are encountered. 
In case of particular issues or governmental queries, it is also necessary to have access to the 
complete study records, provided that the subject’s confidentiality is protected in accordance 
with applicable regulations. 
8.6 Committees 
8.6.1 Independent Adjudication Committee 
An Independent Adjudication Committee (IAC) will be established by the Sponsor. The IAC 
will be composed of 4 permanent members who shall have – as a group – experience in the 
fields of neurology, rheumatology and/or dermatology. The members of the IAC must not 
actively recruit subjects. 
The responsibility of the IAC will be to review individual case histories and to assess disease 
activity as requested by inclusion criterion no. 3. 
An  IAC  charter  will  be  developed  before  study  start  to  serve  as  the  central  reference 
document for the IAC process and its participants. The charter will define, at a minimum, 
the  purpose  of the  IAC,  member  requirements  and  qualifications,  event  definitions, 
adjudication rules and voting scheme that will document how events will be adjudicated and 
how final IAC decision will be reached. 
8.6.2 Independent Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) will be established by the Sponsor. 
The IDMC will be composed of 3 experts in the fields of immunology, rheumatology, and 
dermatology, and of 1 unblinded statistician. The members of the IDMC must not actively 
recruit subjects. 


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The IDMC will have the following responsibilities: 
• to review relevant safety data periodically; 
• to  
review TEEs in  a  
timely  fashion and  monitor  
the  stopping  rules  as  defined  
in 
Section 6.2.3.1; 
• to give advice on the continuation, modification, or termination of the study. 
A Charter  will  be prepared before  study  start  and will  define  
in  detail  
the  composition, 
responsibilities, and procedures of the IDMC. 
8.6.3 Steering Committee 
A Steering Committee will be appointed by the Sponsor. This committee will be composed 
of investigators,  other  experts in  myositis not  otherwise  involved  into  this  study  and 
representatives of the Sponsor.  
The Steering Committee will be responsible, among others, for the scientific integrity of the 
study,  maintaining  the  quality  of  study  conduct, scientific  quality  of any  protocol 
amendments and the final study report, and providing input to or co-authoring publications. 
The  Steering  Committee  will  also  be  responsible  for  any  decision  with  regard  to  the 
biorepository blood samples as defined in Section 7.4.2. 
The Steering Committee will be kept blinded until the blind is officially broken. 
9 STATISTICAL METHODS AND SAMPLE SIZE 
The statistical analysis will be delegated under an agreement of transfer of responsibilities 
to an external CRO. All Octapharma procedures and policies have to be met by this CRO. 
Discrepancies or exceptions are to be approved by the Sponsor
's Manager of Biometrics. 
9.1 Determination of Sample Size 
The  sample  size  calculation  is  based  on  the  target  parameters  for  the  evaluation  of  the 
primary endpoint, i.e. the proportions of responders in the Octagam 10% and the placebo 
group at the end of the 16-week efficacy period (First Period). 
A total  sample  size  of 84 subjects is  required  to  show  a  significant  difference  in  the 
proportion of responders between Octagam and placebo group with a power of 80%, under 
the assumption that the true proportions of responders are 0.6 in the Octagam group and 0.3 
in the placebo group. The sample size calculation is based on Pearson’s chi square test using 
a two-sided alpha level of 0.05.  
A stratified analysis using Cochran-Mantel-Haenszel test will finally be applied as primary 
analysis, to account for the stratification of the randomization (see Section 9.2.2).  
To have some additional safety margin with respect to unexpected drop-outs and with respect 
to  
the  use  of  a  stratified  analysis,  
it  
is  
therefore  planned  
to  enroll  a  
total  of 94 evaluable 
subjects into the study.  
The  abovementioned  assumptions  for  the  true  proportions  of  response  were  thoroughly 
discussed and agreed with an advisory board, consisting of several experts in this field. 


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9.2 Statistical Analysis 
A formal SAP describing all details of the analyses to be performed will be finalized by the 
study statistician and approved by the Sponsor prior to the start of the statistical analysis. 
The primary analysis will be the comparison between Octagam 10% and placebo on basis of 
the efficacy measures assessed in the 16-week efficacy period. 
To evaluate the sustained benefit of treatment with Octagam 10%, and also the safety and 
tolerability of Octagam 10% in subjects with DM, all data collected during treatment with 
Octagam 10% throughout the study period will be used. 
In addition to the confirmatory evaluation of the primary endpoint, descriptive summaries 
will be presented for each of the primary and secondary target variables. In general, these 
summaries will be presented for all patients overall and by treatment group, for each of the 
3 strata (GDA at screening mild|moderate|severe), as totals and by treatment group within 
each stratum. 
9.2.1 Populations for Analysis 
The following populations will be considered for the statistical analysis: 
The safety analysis set (SAF) consists of all subjects who received at least part of 1 infusion 
of Octagam 10% or placebo. 
The full  analysis  set (FAS)  is  defined  according  to  the  intention-to-treat  principle  and 
consists of all randomized subjects. It is expected that the FAS will coincide with the safety 
set. 
The  per-protocol  set  1 (PP1)  consists  of  all subjects  of  the  FAS  excluding  those  with 
significant protocol deviations that  occurred  before  
the  Week  16  assessments,  and which 
may have an impact on the analysis of the primary endpoint. This is the set of subjects for 
whom  
the  primary  endpoint  can  be  evaluated  as  planned;  
it  also  
includes subjects who 
deteriorated at 2 consecutive visits (see Section 4.3.1) up to (including) Week 16 and that 
are  
therefore  counted  as  non-responders, and  also subjects that were withdrawn from the 
study for any AEs or insufficient response before Week 16. Protocol deviations in the open-
label extension period are irrelevant for the definition of this population. 
The per-protocol set 2 (PP2) consists of all subjects of the FAS who received at least part of 
1 infusion of Octagam 10%, excluding those with significant protocol deviations which may 
have  an  impact  on  the  evaluation  of  the  treatment  effects  of  Octagam 10%.  This  set  of 
subjects is defined to allow the assessment of Octagam 10% throughout the study and will 
not be used for comparisons with the placebo group. 
Only significant protocol deviations with the potential to affect the study results significantly 
or to invalidate the interpretation of the data obtained will lead to exclusion of subjects from 
the PP sets; protocol deviations to be considered will include (but will not be limited to): 
• Violations of the study entry criteria. 
• Withdrawal criteria that developed during the study (see Section 4.3.1). 
• Wrong treatment or incorrect dose. 
• Prohibited concomitant medication (e.g., IGIV other than Octagam 10%). 
Analysis of the safety endpoints will be based on the safety set. 


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The primary endpoint will be evaluated on the basis of the FAS and the PP1 set. The intent-
to-treat analysis of the FAS population is considered the primary study outcome, and will be 
presented first in the statistical output. The primary analysis in the FAS will also include 
those subjects with significant protocol deviations that are unrelated to disease progression 
or lack of efficacy, but that have the potential to distort the TIS assessment. This would e.g. 
include subjects that start an intensive exercise during the first study period. 
Because the PP1 set will include all subjects who deteriorated or dropped out for clinical 
reasons as described above, the difference between the FAS and the PP1 is expected to be 
small. 
All other analyses will be based on the FAS set and/or the appropriate PP set; this will be 
specified in detail in the list of all tables, figures and listings. 
Repetition of an analysis in the PP set might be skipped in case the PP population differs 
from  
the  FAS  by  no  more  
than 5 subjects;  
this  does  however  not  apply  for  
the  primary 
endpoint evaluation. 
In general baseline tables will summarize data by randomized treatment. Tables by visit will 
summarize data by randomized treatment, but values obtained after the switch of treatment 
in  
first  period  will  be  excluded.  Adverse  events  
tables  will  summarize  data  according  
to 
actual treatment at time of AE i.e. any adverse event will be considered to be associated with 
the most recent treatment administered, Octagam or Placebo, when summarizing the data. 
Patients who are switched to the other treatment during the first study period will therefore 
be considered to be at risk for adverse events in both treatment groups. 
9.2.2 Efficacy Analysis Plan 
The  primary  endpoint  measure  
‘response’  will  be  assessed  at Week 16  based  on  
the  TIS 
score; a subject is defined as responder if 
(iii) the subject has a TIS score of ≥20 points at Week 16 and 
(iv) the subject has not met “Confirmed Deterioration” criteria at 2 consecutive visits as 
defined in Section 4.3.1 up to (including) Week 16. 
Otherwise the subject will be counted  as non-responder. Thus subjects who discontinued 
from the study prior to Week 16 will also be considered as non-responders. 
The proportion of responders within both treatment groups will be compared by Cochran-
Mantel-Haenszel  
test,  stratified  by  global  disease  activity  
(randomization stratum),  using 
two-sided  alpha  
level  of  0.05. The  primary  analysis  will  be  considered  as  success  
if  
the 
proportion  of  responders  is  significantly  higher  in  the Octagam group  compared  to  the 
placebo group. 
Moreover, an exact two-sided 95% confidence-interval will be constructed for the overall 
difference in the proportion of responders between Octagam and placebo group, using the 
‘exact riskdiff’ option of the SAS FREQ procedure.   
In a sensitivity analysis for the primary endpoint, a logistic regression model will be applied, 
including global disease activity and further baseline variables as applicable as covariates. 
All  other  efficacy  endpoints  will  be  analyzed  and  presented  in  full  detail  by  means  of 
descriptive statistics and inferential analyses as appropriate. 
For TIS response at Week 16 by improvement category, the proportion of subjects with at 
least moderate improvement and the proportion of subjects with major improvement will be 


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calculated together with subject counts and the associated 2-sided 95% confidence interval 
(CI) for  the  difference  in  the  proportion  of patients  with  improvement. Moreover,  both 
treatment groups will be compared using a Cochran-Mantel Haenszel test, analogously as 
for  the  primary  endpoint. The proportion  of  subjects  in  each  treatment  arm  who  meet 
confirmed deterioration criteria up to Week 16 will be presented in the same way. 
All mean changes to be evaluated as secondary endpoints (listed in section 3.1.2) will be 
presented  by  a  full  set  of  descriptive  parameters: number  of subjects with  non-missing 
values,  mean,  standard  deviation,  median,  minimum  and  maximum,  1st  and  3rd  quartile, 
95%  CI. Moreover,  for  all  continuous  secondary  endpoints, an  analysis  of  covariance 
(ANCOVA) will be used to analyze changes from baseline to Week 16. For patients who are 
switched to the alternate treatment before Week 16, the last value prior to switch will be 
carried forward to Week 16 and used to calculate change from baseline to Week 16. The 
model will include treatment and global  disease  activity as  a  
fixed  
factor.  Center  will  be 
included as random factor. The baseline value of the variable to be analyzed will be included 
as  a  covariate. Least  square  means  will  be  derived  and  presented together  with  95%-
confidence intervals by treatment group. Moreover, two-sided 95% confidence intervals will 
be derived for the overall difference in least square means between Octagam and placebo 
treatment. As  sensitivity  analysis,  a  modified  ANCOVA  model  will  be  used,  where  
the 
changes from baseline to Week 16 are calculated based on Week 16 values, even if a patient 
is switched to the alternate treatment before Week 16. To incorporate the switch into the 
model, the variable crossover (yes/no) which indicates if there was a switch to the alternate 
treatment  will  be  
included  as  additional  
factor  
into  
the  ANCOVA  model,  as  well  as  
the 
treatment-by-cross-over interaction term. 
In case the proportion of patients with missing values is greater than 10%, or if the modified 
ANCOVA detailed above gives a signal of divergence, the concerned data will be further 
reviewed and analyzed. 
The time to at least minimal, at least moderate and major improvement in TIS, and the time 
to confirmed deterioration in the First Period and overall, will be summarized using based 
on Kaplan-Meier  estimates  that  will  also  be  presented  graphically. For analysis  of 
improvement variables in the first period, the time to event will be censored at the time of 
switch to the alternate treatment group. A stratified log-rank test will be applied for time to 
event variables to compare both treatment groups. Cox regression models may be applied 
additionally to include randomization stratum and further baseline covariates in the analysis. 
To also include all data from the extension period in such Kaplan-Meier analyses, we will 
look  at  the  abovementioned  events  and  their  timely  relationship  to  the  first  infusion  of 
Octagam. 
To confirm the sustained benefit of treatment with Octagam 10%, response rates at Week 40 
and  changes  from  baseline  to  Week  40  will  be  presented  descriptively  (overall  and  by 
randomized treatment), including 95% confidence intervals.  
Further details on the statistical presentations will be given in the SAP. 
9.2.3 Safety Analysis Plan 
The  safety  analysis  will  comprise  descriptive  statistics,  tabulations  and  listings  of  all 
treatment emergent adverse events (TEAEs), safety laboratory results, viral markers, vital 
signs, physical examination findings, and any other relevant safety information as detailed 
in Section 7.3. 


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9.2.4 Handling of Missing Data 
In general, missing data will not be imputed, with a few exceptions. For ANCOVA analysis 
of changes from baseline to week 16, LOCF will be used in main model in case of missing 
values (e.g. due to early termination) and in case of switch to the alternate treatment group 
(as values obtained after the switch will not be included in the analysis). 
For  missing  weight  measurements  the  last  available  body  weight  will be  used  for  all 
calculations  related  to  dosing  (last  observation  carried  forward,  LOCF);  however,  in 
individual subject data listings missing data will not be replaced by imputed values. 
9.3 Randomization, Stratification, and Code Release 
All subjects qualified to participate in the study at Visit 2 will be randomized to 1 of the 
2 treatment  arms  by  an  electronic  IRT  tool and  thereby  enrolled  into  the  double-blind 
treatment period. The randomization will apply a randomization ratio of 1:1 with respect to 
2.0 g/kg of  Octagam 10%  vs.  placebo  by  means  of  a  stratified  block  design,  using  the 
seriousness of disease before enrollment (mild, moderate or severe defined as a Physician’s 
Global Disease Activity value of 0-3 [mild], 4-6 [moderate], 7-10 [major]) as strata and a 
fixed block size. This will ensure the desired overall randomization ratio and avoid random 
differences  between  
the treatment groups  with  
respect  
to  
the  seriousness  of  DM  prior  
to 
enrollment into the ProDERM study. 
The randomization scheme will only be available to the statisticians responsible for creating 
it, and the programmer implementing the scheme into the IRT system. No information on 
treatment  assignment  will  be  communicated  to  the  sponsor  or  any  CRO  personnel 
responsible for the conduct of the study or the analysis of data. 
The result of randomization, i.e. the treatment group assignment of individual subjects will 
only be reported to the hospital pharmacist or designee by a defined manner that no other 
trial personnel will have access to. 
Blinding will only be broken in circumstances described in Section 5.6.  
Only after completion of all procedures related to data cleaning, the medical review of the 
data,  the  finalization  of  the  statistical  analysis  plan,  the  agreement  on  the  final subject 
disposition,  and  the  formal  database  lock  the  blind  will  be  broken  and  the  individual 
treatment assignment will be added to the clinical database for analysis. 
9.4 Interim Analysis  
No interim analysis is planned. 


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10 ETHICAL/REGULATORY, LEGAL AND ADMINISTRATIVE 
ASPECTS 
10.1 Ethical/Regulatory Framework 
This  study  will  be  conducted  
in  accordance  with  
the  ethical  principles  
laid  down  
in  
the 
Declaration  of  Helsinki.  The  study  protocol  and  any  subsequent  amendment(s)  will  be 
submitted to an IEC/IRB and to the Regulatory Authority. The study will be conducted in 
compliance with the protocol, GCP guidelines, and applicable regulatory requirements. 
The  regulatory  application  or  submission  for  regulatory  approval  will  be  made  by  the 
Sponsor or designated third party (e.g., CRO) as required by national law and in accordance 
with FDA/Regulatory Authority regulations. 
10.2 Approval of Study Documents 
The  study  protocol,  a  sample  of  
the subject information  and  
informed  consent  
form,  any 
other materials provided to the subjects, and further requested information will be submitted 
by the Sponsor or the Investigator to the appropriate IEC/IRB and the Regulatory Authority. 
The study must be approved by the IEC/IRB and the Regulatory Authority before any IMP 
may be shipped to the study sites and any subject is exposed to a study-related procedure. 
The Sponsor, the Investigator, and any third party (e.g., CRO) 
involved in obtaining approval 
must  
inform  each  other  
in  writing  
that  all  ethical  and  
legal  requirements  have  been  met 
before the first subject is enrolled in the study. 
10.3 Subject Information and Informed Consent 
The Investigator will  obtain  freely  given  written  consent  from  each  subject  after  an 
appropriate explanation of the aims, methods, anticipated benefits,  potential hazards, and 
any other aspect of the study which is relevant to the subject’s decision to participate. The 
informed consent form must be signed, with name and date and time noted by the subject, 
before the subject is exposed to any study-related procedure, including screening tests for 
eligibility. 
The Investigator will explain that the subjects are completely free to refuse to enter the study 
or  
to  withdraw  
from  
it  at  any  
time,  without  any  consequences  
for  
their  further  care  and 
without the need to justify. The Investigator will complete the informed consent section of 
the eCRF for each subject enrolled. 
Each subject will be informed that his/her medical (source) records may be reviewed by the 
study monitor, a quality assurance auditor, 
or a health authority inspector, in accordance with 
applicable regulations, and that these persons are bound by confidentiality obligations. 
10.4 Protocol Amendments 
Any prospective change to the protocol will be agreed between the Coordinating Investigator 
and the Sponsor prior to its implementation. Any such amendments will be submitted to the 
any competent IEC/IRB and/or competent authority responsible as required by applicable 
regulations. 


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IEC/IRB approval will, at a minimum, be requested for any change to this protocol which 
could  affect  
the  safety  of  
the  subjects,  
the  objective/design  of  
the  study,  any  
increase  
in 
dosage or duration of exposure to the IMP, an increase in the number of subjects treated, the 
addition of a new test or procedure, or the dropping of a test intended to monitor safety. 
10.5 Confidentiality of Subject Data 
The Investigator will ensure that the subject’s confidentiality is preserved. On eCRFs or any 
other documents submitted to the Sponsor, the subjects will not be identified by their names, 
but by a unique subject identifier. Documents not intended for submission to the Sponsor, 
i.e.,  the  confidential  subject  identification  code  list,  original  consent  forms, and  source 
records, will be maintained by the Investigator in strict confidence. 
11 QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 Periodic Monitoring 
The monitor will contact and visit the Investigator periodically to review all study-related 
source data/records, verify the adherence to the protocol and the completeness, correctness 
and accuracy of all eCRF entries compared to source data. The Investigator will co-operate 
with the monitor to ensure that any discrepancies identified are resolved. 
For this study, the first routine monitoring visit shall take place shortly after the inclusion of 
the first subject. Thereafter, monitoring frequency will depend on study progress. 
The monitor must be given direct access to source documents (original documents, data and 
records). Direct access includes permission to examine, analyze, verify, and reproduce any 
records and reports that are important to the evaluation of the clinical study. Source data will 
be available for all data in the eCRFs, including all laboratory results. 
11.2 Audit and Inspection 
The Investigator will make all study-related source data and records available to a qualified 
quality  assurance  auditor  mandated  by  
the  Sponsor,  or  
to IEC/IRB/regulatory  
inspectors, 
after reasonable notice. The main purposes of an audit or inspection are to confirm that the 
rights and welfare of the subjects have been adequately protected, and that all data relevant 
for the assessment of safety and efficacy of the IMP have been reported to the Sponsor. 
12 REPORTING AND PUBLICATION 
12.1 Clinical Study Report 
A clinical study report (in accordance with relevant guidelines and the Sponsor’s SOPs) will 
be prepared by the Sponsor after completion of the study. The Coordinating Investigator will 
approve the final study report after review. 
12.2 Publication Policy 
The results of this study may be published or presented at scientific meetings. 
If this is envisaged by an Investigator, the Investigator agrees to inform the Sponsor and to 
submit all manuscripts or abstracts to the Sponsor prior to submission to an editorial board 


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or  scientific  review  committee.  This  will  allow  the  Sponsor  to  protect  proprietary 
information and to provide comments based on information that may not yet be available to 
the Investigator. 
In  accordance  with  standard  editorial  and  ethical  practice,  the  Sponsor  will  support 
publication of multi-centre studies only in their entirety and not as individual centre data. 
Authorship will be determined by mutual agreement. 
13 LIABILITIES AND INSURANCE 
In order to cover any potential damage or injury occurring to a subject in association with 
the IMP or participation in the study, the Sponsor will contract insurance in accordance with 
local regulations. 
The Investigator is responsible for dispensing the IMP according to this protocol and for its 
secure storage and safe handling throughout the study. 


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14 REFERENCES 
 
1. Dalakas  MC.  Inflammatory  Muscle  Diseases. 
New  England  Journal  of  
Medicine. 
2015;372(18):1734-47. 
2. Oddis CV, Conte CG, Steen VD, Medsger TA, Jr. 
Incidence of polymyositis-dermatomyositis: a 20-
year  study  of hospital  diagnosed  cases  in 
Allegheny County, PA 1963-1982. J Rheumatol. 
1990;17(10):1329-34. 
3. Rider  LG,  Miller  FW.  Deciphering  the  clinical 
presentations, pathogenesis, and treatment of the 
idiopathic  inflammatory  myopathies.  JAMA - 
Journal  of  the  American  Medical  Association. 
2011;305(2):183-90. 
4. Dalakas MC, Illa I, Dambrosia JM, Soueidan SA, 
Stein DP, Otero C, et al. A controlled trial of high-
dose  intravenous  immune  globulin  infusions  as 
treatment  for  dermatomyositis.  N  Engl  J  Med. 
1993;329(27):1993-2000. 
5. Imbach P, Morell A. Idiopathic thrombocytopenic 
purpura  (ITP):  immunomodulation  by 
intravenous  immunoglobulin  (IVIg).  Int  Rev 
Immunol. 1989;5(2):181-8. 
6. Elovaara  I,  Apostolski  S,  Van  DP,  Gilhus  NE, 
Hietaharju  A,  Honkaniemi  J,  et  al.  EFNS 
guidelines  for  the  use  of  intravenous 
immunoglobulin  in  treatment  of  neurological 
diseases:  EFNS  task  force  on  the  use  of 
intravenous  immunoglobulin  in  treatment  of 
neurological  diseases.  European  Journal  of 
Neurology. 2008;15(9):893-908. 
7. Donofrio  PD,  Berger  A,  Brannagan  TH,  III, 
Bromberg  MB,  Howard  JF,  Latov  N,  et  al. 
Consensus  statement:  The  use  of  intravenous 
immunoglobulin  in  the  treatment  of 
neuromuscular conditions report of the aanem AD 
HOC committee. Muscle & Nerve. 2009;40:890-
900. 
8. Lünemann  JD,  Nimmerjahn  F,  Dalakas  MC. 
Intravenous  
immunoglobulin  
in  neurology-mode 
of  action  and  clinical  efficacy.  Nature  reviews 
Neurology. 2015:doi:10.1038/nrneurol.2014.253. 
9. Enk A, Forum GSotED. Guidelines on the use of 
high-dose  intravenous  immunoglobulin  in 
dermatology.  Manuscript  ed:  European 
Dermatology Forum; 2015. 
10. 
Dimachkie  MM,  Barohn  RJ,  Amato  AA. 
Idiopathic  inflammatory  myopathies.  Neurol 
Clin. 2014;32(3):595-628, vii. 
11. 
Patwa  HS,  Chaudhry  V,  Katzberg  H,  Rae-Grant 
AD,  So  YT.  Evidence-based  guideline: 
Intravenous  
immunoglobulin  
in  
the  
treatment  of 
neuromuscular  disorders  Report  of  the 
Therapeutics  and  Technology  Assessment 
Subcommittee  of  the  American  Academy  of 
Neurology. Neurology. 2012;78:1009-15. 
12. 
Danieli MG, Calcabrini L, Calabrese V, Marchetti 
A,  Logullo  F,  Gabrielli  A.  Intravenous 
immunoglobulin  as  add  on  treatment  with 
mycophenolate  mofetil  in  severe  myositis. 
Autoimmun Rev. 2009;9:124-7. 
13. 
Bohan  A,  Peter  JB.  Polymyositis  and 
dermatomyositis (second of two parts). N Engl J 
Med. 1975;292(8):403-7. 
14. 
Bohan  A,  Peter  JB.  Polymyositis  and 
dermatomyositis  (first  of  two  parts).  N  Engl  J 
Med. 1975;292(7):344-7. 
15. 
Rider  LG,  Giannini  EH,  Harris-Love  M,  Joe  G, 
Isenberg D, Pilkington C, et al. Defining Clinical 
Improvement  in  Adult  and  Juvenile Myositis.  J 
Rheumatol. 2003;30(3):603-17. 
16. 
Rider LG, Giannini EH, Brunner HI, Ruperto N, 
James-Newton  L,  Reed  AM,  et  al.  International 
consensus  on  preliminary  definitions  of 
improvement  in  adult  and  juvenile  myositis. 
Arthritis Rheum. 2004;50(7):2281-90. 
17. 
Ruperto  N,  Pistorio  A,  Ravelli  A,  Rider  LG, 
Pilkington  C,  Oliveira  S,  et  al.  The  Paediatric 
Rheumatology  International  Trials  Organisation 
provisional criteria for the evaluation of response 
to therapy  
in  
juvenile dermatomyositis.  Arthritis 
Care Res (Hoboken ). 2010;62(11):1533-41. 
18. 
Rider LG, Werth VP, Huber AM,  Alexanderson 
H,  Rao  AP,  Ruperto  N,  et  al.  Measures  of  adult 
and juvenile dermatomyositis, polymyositis, and 
inclusion  body  myositis:  Physician  and 
Patient/Parent  Global  Activity,  Manual  Muscle 
Testing  
(MMT),  
Health  
Assessment 
Questionnaire  
(HAQ)/Childhood  
Health 
Assessment  Questionnaire  (C-HAQ),  Childhood 
Myositis  Assessment  Scale  (CMAS),  Myositis 
Disease  Activity  Assessment  Tool  (MDAAT), 
Disease  Activity  Score  (DAS),  Short  Form  36 
(SF-36),  Child  Health  Questionnaire  (CHQ), 
physician global damage, Myositis Damage Index 
(MDI),  Quantitative  Muscle  Testing  (QMT), 
Myositis  Functional  Index-2  (FI-2),  Myositis 
Activities  Profile  (MAP),  Inclusion  Body 
Myositis  Functional  Rating  Scale  (IBMFRS), 
Cutaneous  Dermatomyositis  Disease  Area  and 
Severity Index (CDASI), Cutaneous  Assessment 
Tool  (CAT),  Dermatomyositis  Skin  Severity 
Index  (DSSI),  Skindex,  and  Dermatology  Life 
Quality  Index  (DLQI).  Arthritis  Care  Res 
(Hoboken ). 2011;63 Suppl 11:S118-S57. 
19. 
Aggarwal  R,  Rider  LG,  Ruperto  N,  Bayat  N, 
Ermis B, Feldman BM, et al. A Consensus Hybrid 
Definition using a Conjoint Analysis is Proposed 


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as  Response  Criteria  
for  Minimal  and  Moderate 
Improvement  in  Adult  Polymyositis  and 
Dermatomyositis  Clinical  Trials.  Arthritis  and 
Rheumatology. 2014;66(S10):S404-S5. 
20. 
Oddis  CV,  Reed  AM,  Aggarwal  R,  Rider  LG, 
Ascherman DP, Levesque MC, et al. Rituximab in 
the  treatment  of  refractory  adult  and  juvenile 
dermatomyositis  and  adult  polymyositis:  a 
randomized, placebo-phase trial. Arthritis Rheum. 
2013;65(2):314-24. 
21. 
Ruperto N, Martini A. Networking in paediatrics: 
the  example  of  the  Paediatric  Rheumatology 
International  Trials  Organisation  (PRINTO). 
Arch Dis Child. 2011;96(6):596-601. 
22. 
Miller  FW,  Rider  LG,  Chung  YL,  Cooper  R, 
Danko K, Farewell V, et al. Proposed preliminary 
core set measures for disease outcome assessment 
in  adult  and  juvenile  idiopathic  inflammatory 
myopathies.  
Rheumatology  
(Oxford). 
2001;40(11):1262-73. 
23. 
Ruperto  N,  Ravelli  A,  Pistorio  A,  Ferriani  V, 
Calvo  I,  Ganser  G,  et  al.  The  provisional 
Paediatric  Rheumatology  International  Trials 
Organisation/American  
College  
of 
Rheumatology/European  
League  
Against 
Rheumatism  Disease  activity  core  set  for  the 
evaluation  of  response  to  therapy  in  juvenile 
dermatomyositis:  a  prospective  validation  study. 
Arthritis Rheum. 2008;59(1):4-13. 
24. 
Ruperto  N,  Ravelli  A,  Murray  KJ,  Lovell  DJ, 
ndersson-Gare B, Feldman BM, et al. Preliminary 
core  sets  of  measures  for  disease  activity  and 
damage  assessment  in  juvenile  systemic  lupus 
erythematosus  and  juvenile  dermatomyositis. 
Rheumatology (Oxford). 2003;42(12):1452-9. 
25. 
Wells  PS,  Anderson  DR,  Rodger  MA,  et  al. 
Evaluation  of  D-dimer  in  the  diagnosis  of  8 
suspected deep-vein thrombosis. New Engl J Med 
2003;349:1227-35. 
26. 
Wells  PS,  Anderson  DR,  Rodger  MA,  et  al. 
Excluding  pulmonary  embolism  at  the  bedside 
without  diagnostic  imaging:  management  of 
patients  with  suspected  pulmonary  embolism 
presenting to the emergency department by using 
a simple clinical model and D-dimer. Ann Intern 
Med 2001;135:98-107. 
27. 
Ramey  DR,  Fries  JF,  Singh  G. The  Health 
Assesment  Questionnaire  1995 – Status  and 
Review;  in  Spilker  B  (ed):  Quality  of  Life  and 
Pharmaeconomics  in  Clinical  Trials.  Lippicott-
Raven Publishers, 1996, pp 227-237. 
28. 
Fries JF, Spitz P, Kraines RG, et al. Measurement 
of  patient  outcome  
in  arthritis.  Arthritis  Rheum 
1980;23:137-145. 
29. 
Yassaee  F, Fiorentino  D,  Okawa  J,  Taylor  L, 
Coley C, Troxel AB, Werth VP: Modification of 
the  cutaneous  dermatomyositis  disease  area  and 
severity index, an outcome instrument. Br J Derm 
2010;162(3):669–673. 
30. 
Aggarwal  R,  Rider  LG,  Ruperto  N,  et  al.  2016 
American  College  of  Rheumatology/European 
League  Against  Rheumatism  Criteria  for 
Minimal, Moderate, and Major Clinical Response 
in  Adult Dermatomyositis  and  Polymyositis. 
Arthritis  and  Rheumatology  2017;69(5):pp898-
910 
31. 
Danieli  MG,  Moretti  R,  Gambini  S,  Paolini  L, 
Gabrielli  A.  Open-label  study  on  
treatment  with 
20  %  subcutaneous  IgG  administration  in 
polymyositis  and  dermatomyositis.  Clin 
Rheumatol. 2014;33(4):531-6. 
32. 
Oddis  CV,  Rider  LG,  Reed  AM,  Ruperto  N, 
Brunner  HI,  Koneru  B,  et  al.  International 
consensus guidelines for trials of therapies in the 
idiopathic  inflammatory  myopathies.  Arthritis 
Rheum. 2005;52(9):2607-15. 
33. Carruthers EC, Choi HK, Sayre EC, et al. Risk of 
deep venous thrombosis and pulmonary embolism 
in  individuals  with  polymyositis  and 
dermatomyositis:  a  general  population-based 
study. Ann Rheum Dis. 2016;75(1):110–116. 
34. Chung WS, Lin CL, Sung FC, Lu CC, Kao CH. 
Increased  risk  of  venous  thromboembolism  in 
patients  with  dermatomyositis/polymyositis:  a 
nationwide  cohort  study.  Thromb  Res. 
2014;134(3):622-626. 
 
 
 
 

SAP_001.pdf: 
This document contains confidential and proprietary information of Octapharma. Copying or 
distribution of this document is only permitted with the written permission of Octapharma. Any 
commercial use of the information is subject to the permission of Octapharma and a license fee.


Statistical Analysis Plan for GAM10-08
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Document History 
Version 
Date 
Author 
Description 
Final v1.0 29-Mar-2016
New Document 
Final v2.0 18-Jul-2016
Clarification of treatment group assignment, 
Primary analysis of the primary endpoint changed 
to full analysis set (ITT analysis), Definition of PP1 
set rephrased, Discussion of patients with missing 
Week 16 score, Descriptive subgroup analyses 
added, Possible dose reduction to 1.0 g/kg in the 
extension phase, Requirement of confirmed 
deterioration emphasized, Infusions expanded to 
infusion cycles, Clarified that the modified CDASI 
(version 2) will be used, AEs of special interest 
(TEEs, HTRs) incorporated, Additional tests (Wells 
scores, Doppler scan, lab parameters), Available 
data on screening failures, References to week 6 
changed to the next scheduled visit (week 8), 
Additional minor clarifications, cross-references, 
and rephrasing for clarity and consistency with the 
revised protocol 
Final v3.0 03-JUL-2017
Adapted to changes in the statistical section of 
study protocol, Update of definition of confirmed 
deterioration  
Final 4.0 
18-Jun-2019
Adapted to changes in protocol version 12, in 
particular adjustments requested by authorities: 
•
Definition of the FAS analysis set changed
to include all randomized subjects
•
Wording of response definition unified
across protocol and SAP
Abbreviations 
(e)CRF 
(Electronic) Case Report Form 
IMACS 
International Myositis Assessment and 
Clinical Studies Group 
AE 
Adverse Event 
IMP 
Investigational Medicinal Product 
ALAT 
Alanine Aminotransferase 
ITT 
Intention-To-Treat 
ASAT 
Aspartate Aminotransferase 
IVIG 
Intravenous Immunoglobulin 
BMI 
Body Mass Index 
LDH 
Lactate Dehydrogenase 
CDASI 
Cutaneous Dermatomyositis Disease Area and 
Severity Index 
MDAAT 
Myositis Disease Activity Assessment Tool 
CI 
Confidence Interval 
MedDRA 
Medical Dictionary for Regulatory Activities 
CK 
Creatine Kinase 
MMT 
Manual Muscle Testing 
CSM 
Core Set Measure 
PE 
Pulmonary Embolism 
CSR 
Clinical Study Report 
PP 
Per Protocol 
DM 
Dermatomyositis 
PT 
Preferred Term 
DVT 
Deep Vein Thrombosis 
QoL 
Quality of Life 


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FAS 
Full Analysis Set 
 
SAE 
Serious Adverse Event 
FDA 
Food and Drug Administration 
 
SAF 
Safety Set 
GCP 
Good Clinical Practice 
 
SAP 
Statistical Analysis Plan 
GDA 
Global Disease Activity 
 
SF-36v2 
Short Form 36 Items Health Status Version 2 
HAQ 
Health Assessment Questionnaire 
 
SOC 
System Organ Class 
HTR 
Hemolytic Transfusion Reaction 
 
TEAE 
Treatment Emergent Adverse Event 
ICH 
International Conference on Harmonisation 
 
TEE 
Thromboembolic Event 
IgG 
Immunoglobulin G 
 
TIS 
Total Improvement Score 
IGIV 
Immunoglobulin Intravenous 
 
VAS 
Visual Analog Scale 


Statistical Analysis Plan for GAM10-08  
 
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Table of Contents 
1. 
Preface ............................................................................................................................................. 6 
2. 
Purpose ............................................................................................................................................ 7 
3. 
Study Objectives and Endpoints ...................................................................................................... 8 
3.1. 
Study Objectives ...................................................................................................................... 8 
3.1.1. 
Primary Objective ............................................................................................................ 8 
3.1.2. 
Secondary Objectives ...................................................................................................... 8 
3.2. 
Study Endpoints (Target Variables) ......................................................................................... 8 
3.2.1. 
Primary Target Variables ................................................................................................. 8 
3.2.2. 
Secondary Target Variables ............................................................................................. 9 
4. 
Study Methods .............................................................................................................................. 11 
4.1. 
Overall Study Design and Plan ............................................................................................... 11 
4.2. 
Selection of Study Population ............................................................................................... 12 
4.3. 
Randomization, Stratification and Blinding ........................................................................... 12 
5. 
Sequence of Planned Analyses ...................................................................................................... 13 
5.1. 
Final Analyses and Reporting ................................................................................................ 13 
6. 
Sample Size Determination ........................................................................................................... 14 
6.1. 
Subject Replacement Policy .................................................................................................. 14 
6.2. 
Premature Termination of the Study .................................................................................... 14 
7. 
Analysis Populations ...................................................................................................................... 15 
8. 
General Issues for Statistical Analysis ........................................................................................... 17 
8.1. 
Analysis Software .................................................................................................................. 17 
8.2. 
Withdrawals .......................................................................................................................... 17 
8.3. 
Handling of Missing Data....................................................................................................... 17 
8.4. 
Derived and Computed Variables ......................................................................................... 18 
9. 
Study Subjects and Demographics ................................................................................................ 19 
9.1. 
Disposition of Subjects and Withdrawals .............................................................................. 19 
9.2. 
Protocol Deviations ............................................................................................................... 19 
9.3. 
Demographics and Other Baseline Characteristics ............................................................... 19 
9.4. 
Measurement of Treatment Compliance .............................................................................. 20 
10. Efficacy Analysis............................................................................................................................. 21 
10.1. Primary Endpoint ................................................................................................................... 21 
10.2. Secondary efficacy endpoints ............................................................................................... 21 
11. Safety and Tolerability Analyses .................................................................................................... 23 
11.1. Adverse Events ...................................................................................................................... 23 
11.2. Clinical Laboratory Evaluations ............................................................................................. 24 
11.3. Viral Markers ......................................................................................................................... 24 
11.4. Vital Signs .............................................................................................................................. 24 
11.5. Further Safety Evaluations .................................................................................................... 24 
11.5.1. 
Physical Examination ..................................................................................................... 24 
11.5.2. 
Wells Scores ................................................................................................................... 24 
12. Reporting Conventions .................................................................................................................. 25 
12.1. General Reporting Conventions ............................................................................................ 25 


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12.2. Population Summary Conventions ........................................................................................ 25 
13. Tables, Listings and Figures ........................................................................................................... 27 
 
 
 


Statistical Analysis Plan for GAM10-08  
 
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1. Preface 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for Octapharma 
Protocol GAM10-08: Prospective, double-blind, randomized, phase III study evaluating efficacy and 
safety of Octagam 10% in patients with dermatomyositis. 
This phase III study is conducted to provide confirmatory data on the beneficial effect of 
Octagam 10% every four weeks compared to placebo in patients with active dermatomyositis (DM). 
It is designed as prospective, parallel group, double-blind, randomized, multicenter study with a 16-
week efficacy period, followed by a 24-week open-label extension period. 
The primary endpoint measures for each subject will be assessed at the end of the blinded efficacy 
period, before the subject may enter the open-label extension period. 
The open-label extension period will allow to evaluate the sustained benefit as well as the safety and 
tolerability of Octagam 10% over an extended period of time. 
The structure and content of this SAP provides sufficient detail to meet the requirements identified 
by the FDA and International Conference on Harmonization (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical Trials1.  
The following documents were reviewed in preparation of this SAP: 
• 
Clinical Study Protocol GAM10-08, Version 12, dated 18-JUN-2019 
The reader of this SAP is encouraged to also read the clinical protocol for details on the planned 
conduct of this study. Operational aspects related to collection and timing of planned clinical 
assessments are not repeated in this SAP unless relevant for the specification of the planned 
analyses. 
                                                          
1 International Conference on Harmonization. (1998). Guidance on Statistical Principles. ICH Topic E9 (Statistical 
Principles for Clinical Trials) (p. 37). London: International Conference on Harmonization. 


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2. Purpose 
This SAP outlines all statistical analyses to be performed on data collected in study GAM10-08, and 
the resulting output that will be compiled to support the completion of the Clinical Study Report 
(CSR). 
The planned analyses identified in this SAP will be included in regulatory submissions and/or future 
manuscripts. Exploratory analyses not necessarily identified in this SAP may be performed to support 
the clinical development program. Any post-hoc or unplanned analyses performed that are not 
identified in this SAP will be clearly identified in the respective CSR. 
The statistical output provided to the medical writer of the CSR will closely follow the ICH guideline 
for industry on topic E3 (Structure and Content of Clinical Study Reports2) to facilitate the 
subsequent compilation of the CSR. 
This statistical output will consist of tables, figures and listings, including 
• 
Tables, figures and listings used or referenced in, or appended to the CSR as detailed in the 
remainder of this SAP (section 14 of the CSR) 
o Demographic data summary figures and tables 
o Efficacy data summary figures and tables 
o Safety data summary figures and tables 
• 
Listings provided as appendices to the CSR 
o Patient data listings (section 16.2 of the CSR) 
o Individual patient data listings (section 16.4 of the CSR) will be covered by inclusion 
of SAS datasets into the electronic submission to the authorities 
A detailed list of all tables, figures and listings will be supplied in a separate document later when all 
feedback from authorities will be available. 
                                                          
2 International Conference on Harmonization. (1996). Structure and Content of Clinical Study Reports. Structure 
and Content of Clinical Study Reports (Guideline for Industry) (S. 37). London: International Conference on 
Harmonization. 


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3. Study Objectives and Endpoints 
3.1. 
Study Objectives  
3.1.1. 
Primary Objective 
The primary objective of the study is to provide confirmatory data on the beneficial effect of 2.0 g/kg 
Octagam 10% given every four weeks compared with placebo in patients with active 
dermatomyositis (DM) based on the percentage of responders at Week 16. 
3.1.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• 
to evaluate the beneficial effect of Octagam 10% in patients with active DM by assessing 
different parameters and scores at Week 16 and Week 40; 
• 
to confirm the sustained benefit of treatment with Octagam 10% by assessing the primary 
response measures also at Week 40; 
• 
to evaluate the safety and tolerability of Octagam 10% in patients with DM.  
3.2. 
Study Endpoints (Target Variables) 
This section defines the target variables collected or derived for the evaluation of the endpoints; 
please refer to sections 8 to 12 for analysis details. 
3.2.1. 
Primary Target Variables 
The evaluation of the primary endpoint will be based on the newly developed Total Improvement 
Score (TIS), a scale from 0 to 100, with 20-39 points being minimal improvement, 40-59 points being 
moderate improvement, and ≥60 points being major improvement (Aggarwal et al., 2017, please refer 
to the protocol for details). 
In the context of this study, subjects need to have at least minimal improvement at Week 16 (i.e. 
TIS ≥ 20) to qualify as responders. 
The primary endpoint is defined as the proportion of responders in the 2.0 g/kg Octagam 10% and 
placebo arms at Week 16, a responder being defined as a subject with an increase from baseline 
(Week 0) of ≥ 20 points on the Total Improvement Score (TIS) and who has not met “Confirmed 
Deterioration” criteria at 2 consecutive visits as defined in Section 8.4 up to (including) Week 16. 
The TIS is based on the assessment of six core set measures (CSMs): 
1. Physician Global Activity: Global Disease Activity (GDA), assessed by the investigator on a 
Visual Analog Scale (VAS) 
2. Patient Global Activity: GDA, assessed by the patient on a VAS 
3. Manual muscle testing: MMT-8 Muscle Grading and Testing 
4. Health Assessment Questionnaire (HAQ): Standard HAQ used by the International Myositis 
Assessment and Clinical Studies Group (IMACS) 
5. Enzymes: Aldolase, CK, ALAT, ASAT, LDH 
6. Extra muscular activity: Evaluated as part of Myositis Disease Activity Assessment Tool 
[MDAAT] 
Please refer to the protocol for further details and references on these CSMs. The CSMs will be 
assessed at Screening, at each visit of the first period, at Visit 9 (Week 28), and at the Termination Visit. 


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The TIS is calculated as a sum of sub-scores as detailed below. The level of improvement will always 
be based on the comparison of the current CSMs compared to the baseline (Week 0) values. 
 
Core set measure 
Level of improvement 
Level score 
Physician Global Activity 
Worsening to 5% improvement 
0 
>5% to 15% improvement 
7,5 
>15% to 25% improvement 
15 
>25% to 40% improvement 
17,5 
>40% improvement 
20 
Patient Global Activity 
Worsening to 5% improvement 
0 
>5% to 15% improvement 
2,5 
>15% to 25% improvement 
5 
>25% to 40% improvement 
7,5 
>40% improvement 
10 
Manual muscle testing (MMT) 
Worsening to 2% improvement 
0 
>2% to 10% improvement 
10 
>10% to 20% improvement 
20 
>20% to 30% improvement 
27,5 
>30% improvement 
32,5 
Health Assessment Questionnaire (HAQ) 
Worsening to 5% improvement 
0 
>5% to 15% improvement 
5 
>15% to 25% improvement 
7,5 
>25% to 40% improvement 
7,5 
>40% improvement 
10 
Enzyme (most abnormal)* 
Worsening to 5% improvement 
0 
>5% to 15% improvement 
2,5 
>15% to 25% improvement 
5 
>25% to 40% improvement 
7,5 
>40% improvement 
7,5 
Extra muscular activity 
Worsening to 5% improvement 
0 
>5% to 15% improvement 
7,5 
>15% to 25% improvement 
12,5 
>25% to 40% improvement 
15 
>40% improvement 
20 
  
Improvement category 
Total 
Improvement 
Score 
Adult thresholds 
Minimal 
20 
Moderate 
40 
Major 
60 
 *The most abnormal muscle enzyme is the enzyme at baseline (Week 0) with the highest 
ratio compared to its upper limit of normal.  
3.2.2. 
Secondary Target Variables 
For Efficacy and Quality of Life (QoL), secondary endpoints will be: 
• 
Proportion of TIS responders by improvement category (minimal, moderate, major) at 
Week 16 and Week 40. 
• 
Mean change from baseline (Week 0) to end of First Period (Week 16) in modified Cutaneous 
Dermatomyositis Disease Area and Severity Index (CDASI) 
• 
Mean change from end of First Period (Week 16) to end of Extension Period (Week 40) in 
modified CDASI. 
• 
Mean change from Baseline (Week 0) to end of First Period (Week 16) and Extension Period 
(Week 40) in:  


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o SF-36v2 Health Survey; 
o Individual 6 Core Set Measures (CSM) used for TIS calculation. 
• 
Mean TIS from Baseline (Week 0) to end of First Period (Week 16) and from Baseline (Week 0) 
to end of Extension Period (Week 40). 
• 
Time to minimal, moderate and major improvement in TIS. 
• 
Time to confirmed deterioration (defined on basis of the CSM assessments, see section 8.4 
for details) in the First Period and overall. 
• 
Proportion of subjects in each treatment arm who met “confirmed deterioration” criteria up 
to (including) Week 16 
For Safety, target variables will be: 
• 
Occurrence of adverse events (AEs) with an emphasis on thromboembolic events (TEEs) and 
hemolytic transfusion reactions (HTRs) 
• 
Wells probability scores for deep vein thrombosis (DVT) and pulmonary embolism (PE), and 
Doppler scan (if indicated) 
• 
Occurrence of all adverse drug reactions (ADRs) and suspected ADRs 
• 
Vital signs (blood pressure, heart rate, body temperature and respiratory rate) 
• 
Physical examination (at Screening and every 12 weeks from Week 4 on) 
• 
Laboratory parameters (hematology, clinical chemistry, IgG, enzymes, viral markers, Coombs’ 
test [plus specific antibodies if positive], D-dimers)  
• 
Pregnancy test 


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4. Study Methods 
4.1. 
Overall Study Design and Plan 
Study GAM10-08 is designed as a prospective, parallel group, double-blind, randomized, multicenter 
phase III study with a 16-week efficacy period followed by a 24-week open-label extension period. 
As DM is a rare disease, about 55 sites are projected to participate in countries worldwide with 
emphasis on (Eastern) European countries and North America. For the same reason, it is not expected 
that single centers will enroll more than about 5 subjects. 
The duration of the entire study for each subject will be up to 43 weeks and consists of the following 
segments: 
• 
approximately 3 weeks for Screening 
• 
16 weeks of double-blind treatment 
• 
24 weeks of open-label treatment with Octagam 
Eligible subjects after screening will be randomized 1:1 to receive up to four infusion cycles of either 
2.0 g/kg Octagam 10% or placebo every 4 weeks during the 16-week First Period. An infusion cycle will 
consist of 2 to 5 days over which the study drug will be administered. 
Subjects, who deteriorate3 in this phase, will be crossed-over to the alternate treatment from week 8 
on. 
After response assessment at Week 16, the following subject groups will continue in the 6-months 
open-label Extension Period and receive 2.0 g/kg Octagam 10% given over 2 days (if tolerated by the 
patient) at 4 week intervals: 
• 
Subjects randomized to Octagam without confirmed deterioration during the First study 
period including Week 16. 
• 
Subjects randomized to placebo without confirmed deterioration prior to Week 16. 
• 
Subjects randomized to placebo who switched to Octagam and show no further deterioration 
at Week 16 
The rest of the subjects will not continue the study, but Week 16 will be considered as their termination 
visit: 
 
                                                          
3 For a definition of confirmed deterioration, please refer to section 8.4. 
*
Confirmed 
Deterioration?
Confirmed 
Deterioration?
Randomization
Yes
Yes
No
Octagam 10%
No
Placebo
Octagam 10%
Placebo
open-label
Octagam 10% 
treatment
2.0 g/kg, or, if 
appropriate 1.0 g/kg 
from Week 28 on 
Octagam 10%
Placebo
Improvement=YES
Improvement=NO(stable)
FurtherDeterioration
Improvement=YES
Improvement=NO (stable)
Deterioration at W. 16
Improvement=YES
Improvement=NO(stable)
Further Deterioration
Improvement=YES
Improvement=NO (stable)
Deterioration at W. 16
= Dropout
Week0
≥Week 8
Week  16
Screening
FIRSTPERIOD  (16 weeks)
EXTENSION PERIOD  (24 weeks)
SCREENING PHASE
*
*
Subjects who were switchedto alternate treatment due to 
deterioration and subjects  with a confirmed deterioration
on Week 16 have to be unblinded at Week 16.
*


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At Week 28, subjects who are stable on 2.0 g/kg Octagam 10% can be switched to 1.0 g/kg Octagam 
10%, at the discretion of the investigator. 
Please refer to the study protocol for a detailed flowchart of planned study events and assessments. 
4.2. 
Selection of Study Population 
The study population consists of adult patients of both sexes with a diagnosis of definite or probable 
dermatomyositis according to the Bohan and Peter criteria (1975); please refer to the protocol for a 
complete list of inclusion/exclusion criteria. 
4.3. 
Randomization, Stratification and Blinding 
All subjects qualified to participate in the study at Visit 2 will be randomized to one of the two 
treatment arms – Octagam 10% or Placebo – in a ratio of 1:1. The randomization scheme will be 
stratified according to the seriousness of disease before enrollment: Mild | Moderate | Severe. 
The Physician’s Global Disease Activity assessment will determine the correct stratum for each subject 
as follows: GDA value of 0-3 [mild], 4-6 [moderate], 7-10 [major] 
Within the strata, the same fixed block size will be used for a balanced randomization. 
This design will ensure the desired overall randomization ratio and avoid random differences between 
the treatment groups with respect to the seriousness of DM prior to enrollment. 
The randomization scheme will only be available to the statisticians responsible for creating it, and the 
programmer implementing the scheme into the IRT system. No information on treatment assignment 
will be communicated to the sponsor or any CRO personnel responsible for the conduct of the study 
or the analysis of data, with the following exceptions: 
• 
The result of randomization, i.e. the treatment group assignment of individual subjects will be 
reported to the hospital pharmacist or designee by a dedicated email that no other trial 
personnel will have access to. 
• 
Subjects with confirmed deterioration who were crossed-over during the First Period and 
subjects with confirmed deterioration at Week 16 will be unblinded at Week 16 as their further 
continuation in the Extension Period depends on their initial assignment as described in 
section 4.1 above. In the analysis of the primary endpoint these subjects will be considered as 
non-responders in the group they were randomized to. 
• 
In case of medical emergencies as described in the protocol (section 5.6)  
Only after completion of all procedures related to data cleaning, the medical review of the data, the 
finalization of the statistical analysis plan, the agreement on the final subject disposition, and the 
formal database lock the blind will be broken and the individual treatment assignment will be added 
to the clinical database for analysis 


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5. Sequence of Planned Analyses 
5.1. 
Final Analyses and Reporting 
As stated in section 4.1, this study consists of a double-blinded period, followed by an open-label 
extension period. The blind will however be maintained throughout the complete study to the extent 
possible; only for subjects who were switched during the first study period and show no further 
deterioration at Week 16 and for those subjects with confirmed deterioration at Week 16, the 
decision whether a subject is allowed to continue into the open-label period will imply whether the 
subject was initially treated with Octagam (Subject has to drop out) or Placebo (Subject continues). 
Otherwise the blind will not be broken before all subjects have completed the entire study and the 
final database has been locked and released for analysis according to the applicable standard 
operating procedures. 
This process includes a data review, the identification and classification of any protocol deviations as 
detailed in section 7, and thus the subject disposition with respect to the analysis populations. All 
final, planned analyses identified in the protocol and in this SAP will be performed only after the last 
subject has completed the study, the subject disposition has been agreed and documented, and the 
final SAP has been approved. 
Key statistics and study results will be made available to the study team following database lock and 
prior to completion of the final CSR by means of tables, figures and listings. 
Any, post-hoc, exploratory analyses completed to support planned study analyses, which were not 
identified in the final SAP, will be documented and reported in the CSR or its appendices. Any results 
from such unplanned analyses will also be clearly identified in the text of the CSR. 
No interim analysis is planned. 


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6. Sample Size Determination 
The sample size calculation is based on the target parameters for the evaluation of the primary 
endpoint, i.e. the proportions of responders in the Octagam 10% and the placebo group at the end of 
the 16 week efficacy period (First Period). 
A total sample size of 84 subjects is required to show a significant difference in the proportion of 
responders between Octagam and placebo group with a power of 80%, under the assumption that the 
true proportions of responders are 0.6 in the Octagam group and 0.3 in the placebo group. The sample 
size calculation is based on Pearson’s chi square test using a two-sided alpha level of 0.05.  
A stratified analysis using Cochran-Mantel-Haenszel test will finally be applied as primary analysis, to 
account for the stratification of the randomization.  
To have some additional safety margin with respect to unexpected drop-outs and with respect to the 
use of a stratified analysis, it is therefore planned to enroll a total of 94 evaluable subjects into the 
study.  
The abovementioned assumptions for the true proportions of response were thoroughly discussed and 
agreed with an advisory board, consisting of several experts in this field. 
6.1. 
Subject Replacement Policy 
Not applicable. Withdrawals will not be replaced. 
6.2. 
Premature Termination of the Study 
Both, the responsible Investigators and the Sponsor, reserve the right to terminate the study as a 
whole or centre-wise at any time. Should this be necessary, the procedures will be arranged on an 
individual study basis after review and consultation by both parties. In terminating the study, the 
Sponsor and the Investigator will ensure that adequate consideration is given to the protection of the 
subjects' interests. Premature termination will be notified in accordance with applicable regulatory 
requirements. Please refer to the protocol (section 6.2.3) for further details on premature termination, 
in particular for the exact stopping criteria triggering the early termination of the entire study for safety 
reasons (6.2.3.1). 
In case the study is terminated prematurely, the SAP will be revised to address all issues arising from 
such special circumstances, and to confirm or redefine the scope of the analysis. 


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7. Analysis Populations 
The following populations will be considered for the statistical analysis: 
The safety analysis set (SAF) consists of all subjects who received at least part of one infusion of 
Octagam or placebo. 
The full analysis set (FAS) is defined according to the intention-to-treat principle and consists of all 
randomized subjects. It is expected that the FAS will coincide with the safety set. 
The per-protocol set 1 (PP1) consists of all subjects of the FAS excluding those with significant protocol 
deviations that occurred before the Week 16 assessments, and which may have an impact on the 
analysis of the primary endpoint. This is the set of subjects for whom the primary endpoint can be 
evaluated as planned; it also includes subjects who deteriorated at 2 consecutive visits up to (including) 
Week 16 and that are therefore counted as non-responders, and also subjects that were withdrawn 
from the study for any AEs or insufficient response before Week 16. Protocol deviations in the open-
label extension period are irrelevant for the definition of this population. 
The per-protocol set 2 (PP2) consists of all subjects of the FAS who received at least part of one infusion 
of Octagam, excluding those with significant protocol deviations which may have an impact on the 
evaluation of the treatment effects of Octagam. This set of subjects is defined to allow the assessment 
of Octagam throughout the study and will not be used for comparisons with the Placebo group. 
Only significant protocol deviations with the potential to affect the study results significantly, or to 
invalidate the interpretation of the data obtained, will lead to exclusion of subjects from the PP sets; 
protocol deviations to be considered will include (but will not be limited to): 
• 
Violations of the study entry criteria 
• 
Withdrawal criteria that developed during the study 
• 
Wrong treatment or incorrect dose 
• 
Prohibited concomitant medication (e.g. IGIV other than Octagam) 
Analysis of the safety endpoints will be based on the safety set. 
The primary endpoint will be evaluated on basis of the FAS and the PP1 set. The intent-to-treat analysis 
of the FAS population is considered the primary study outcome, and will be presented first in the 
statistical output. The primary analysis in the FAS will also include those subjects with significant 
protocol deviations that are unrelated to disease progression or lack of efficacy, but that have the 
potential to distort the TIS assessment. This would e.g. include subjects that start an intensive exercise 
during the first study period. 
Because the PP1 set will include all subjects that deteriorated or dropped out for clinical reasons as 
described above, the difference between the FAS and the PP1 is expected to be small. 
All other analyses will be based on the FAS set and/or the appropriate PP set; this will be specified in 
detail in the list of all tables, figures and listings. 
Repetition of an analysis in the PP set might be skipped in case the PP population differs from the FAS 
by no more than 5 subjects; this does however not apply for the primary endpoint evaluation. 
In general baseline tables will summarize data by randomized treatment. Tables by visit will summarize 
data by randomized treatment, but values obtained after the switch of treatment in first period will be 
excluded. Adverse events tables will summarize data according to actual treatment at time of AE, i.e. 
any adverse event will be considered to be associated with the most recent treatment administered, 
Octagam or Placebo, when summarizing the data. Patients who are switched to the other treatment 
during the first study period will therefore be considered to be at risk for adverse events in both 
treatment groups. 


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The membership of each subject in the respective analysis populations will be determined before the 
statistical analysis in a data review meeting by a panel consisting of a medical expert from the sponsor, 
the clinical project manager, the data manager and the study statistician. 
All protocol deviations documented during the conduct of the study or identified at the data review 
process prior to DB lock will be reviewed and classified as minor or major and with respect to their 
significance for the planned analyses. Only significant protocol deviations with the potential to affect 
the study results or to invalidate the interpretation of the data obtained will lead to exclusion of 
subjects from the PP sets. This classification of protocol deviations is the joint responsibility of the 
clinical study manager, the study statistician, and Octapharma’s responsible medical expert, and will 
be performed and documented before the database is locked and the statistical analyses are 
performed. 


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8. General Issues for Statistical Analysis 
The main analysis will be the comparison between Octagam 10% and placebo on basis of the efficacy 
measures assessed in the 16 week efficacy period. 
To evaluate the sustained benefit of treatment with Octagam 10%, and also the safety and tolerability 
of Octagam 10% in subjects with DM, all data collected during treatment with Octagam 10% 
throughout the study period will be used. 
In addition to the confirmatory evaluation of the primary endpoint, descriptive summaries will be 
presented for each of the primary and secondary target variables. In general, these summaries will be 
presented for all patients overall and by treatment group, for each of the 3 strata (GDA at screening 
mild|moderate|severe), as totals and by treatment group within each stratum. 
Descriptive subgroup analyses will be performed with respect to age, sex, race, and region (U.S. vs. 
Non-U.S.). 
Depending on the number of infusions with reduced dose of 1.0 g/kg in the extension period, 
measures and events associated with this dose regimen will be contrasted with the regular 2.0 g/kg 
dose scheme. 
Continuous, quantitative variable summaries will in general include the number of subjects with non-
missing values (N), mean, standard deviation, median, minimum and maximum, 1st and 3rd quartile. 
Categorical, qualitative variable summaries will include the frequency and percentage of subjects 
who are in the particular category. In general the denominator for the percentage calculation will be 
based upon the total number of subjects in the analysis population unless otherwise specified. 
8.1. 
Analysis Software 
Statistical analyses will be performed using SAS Software version 9.3 or higher. 
8.2. 
Withdrawals 
Subjects who withdraw from the study prematurely will be considered in all data presentations for 
which they contribute data. 
8.3. 
Handling of Missing Data 
In general, missing data will not be imputed, with a few exceptions. For ANCOVA analysis of changes 
from baseline to week 16, LOCF will be used in main model in case of missing values (e.g. due to early 
termination) and in case of switch to the alternate treatment group (as values obtained after the 
switch will not be included in the analysis). 
For missing weight measurements the last available body weight will be used for all calculations 
related to dosing; in individual patient data listings missing data will however not be replaced by 
imputed values. 
No analyses of the patterns of missing data will be done. 
For adverse events the following will be applied: 
An Adverse Event (AE) is defined as treatment-emergent, if first onset or worsening is after start of 
the first infusion of Octagam 10% or placebo. 


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If the start date and time of an AE are partially or completely missing, the AE will be assumed to be 
treatment-emergent if it cannot be definitely shown that the AE did not occur or worsen during the 
treatment emergent period (worst case approach). Missing dates and times will not be replaced. 
For medications the following will be applied: A medication will be assumed to be concomitant if it 
cannot be definitely shown that the medication was not administered during the treatment period as 
defined in section 8.4 below. Missing dates will not be replaced. 
8.4. 
Derived and Computed Variables 
The following derived and computed variables have been initially identified as important for the 
analysis of the primary and secondary target variables. It is expected that additional variables will be 
required. The SAP will not be amended for additional variables that are not related to the primary 
target or key secondary target variables. Any additional derived or computed variables will be 
identified and documented in the SAS programs that create the analysis files. If the SAP is not 
amended, further derivations related to primary and secondary target variables will be described in 
the CSR. 
• 
Age will be derived according to the usual definition that a person is n years old until she or 
he has completed her or his (n+1)th year of life, using the date of informed consent as the 
reference date. This is also the definition that will be applied for evaluation of the age related 
inclusion criteria. 
[Unit: years] 
• 
Body Mass Index: BMI = (Body weight) / Height2 
[Unit: kg/m2] 
• 
The treatment period is defined as the period between the day of first treatment with study 
drug (Octagam or placebo) to the end of the observation period. This will usually be the 
termination visit. 
• 
Confirmed Deterioration is defined as follows:  
o Physician’s Global Disease Activity VAS worsening ≥ 2cm and 
MMT-8 worsening ≥ 20% on 2 consecutive visits, 
or 
o global extra-muscular activity worsening ≥ 2cm on the MDAAT VAS on 2 consecutive 
visits, 
or 
o any 3 of 5 CSM (excluding enzymes) worsening by ≥ 30% on 2 consecutive visits. 
For all criteria worsening will be determined by comparing to baseline values (Week 0). 


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9. Study Subjects and Demographics 
9.1. 
Disposition of Subjects and Withdrawals 
All subjects screened for the study will be accounted for. For screening failures only the reasons for 
not being enrolled in the study will be listed and summarized. 
For all subjects enrolled in the study, descriptive summaries of population data will be provided 
overall and by treatment group; these will include 
• 
The frequency and percent of subjects in each study period and analysis population by 
country and overall 
• 
Number of subjects enrolled, number of subjects treated, number of completers 
• 
Study withdrawals by reason of withdrawal 
9.2. 
Protocol Deviations 
Protocol deviations will be checked on complete data for all subjects prior to defining the analysis 
populations. The final decision regarding inclusion/exclusion of subjects from the analysis sets will be 
taken based on data listings and reports during data review meetings before database lock, data 
release and final analysis, applying the definitions in section 7. 
Patients that have baseline scores but no score at 16 Weeks will in general be considered as non-
responders in their respective (randomized) treatment group. If a Week 16 score is available, but not 
within the planned time window of 4 weeks ±4 days after the preceding infusion, the decision of 
whether a particular score can be used for analysis will be made at the data review meeting. 
Major and significant protocol deviations will be summarized by type of deviation. Individual subjects 
with these protocol deviations will be listed. 
A dedicated listing will cover the use of forbidden concomitant medication as detailed in the 
protocol, section 4.2.2. 
9.3. 
Demographics and Other Baseline Characteristics 
Descriptive summaries of the demographic and other baseline characteristics will be completed for 
the populations specified below, overall and by treatment group and stratum as applicable; these 
include: 
• 
Demographics (Age, Gender, Race/Ethnicity, Height, Weight, BMI (calculated))  
(SAF, FAS, PP1, PP2) 
• 
Medical History (SAF) 
Medical history will be coded with the Medical Dictionary for Regulatory Activities (MedDRA, 
according to the version specified in the Data Management Plan). Incidences of findings in 
medical history will be summarized by MedDRA system organ class (SOC) and preferred term 
(PT)  
• 
Prior and Concomitant Medications (SAF) 
Medications will be coded using the WHO Drug Dictionary (according to the version specified 
in the Data Management Plan). Incidences of prior and concomitant medications will be 
summarized by ATC level 2 and ATC level 4 


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• 
Baseline Physical Examination, including vital signs (SAF) 
• 
Baseline ECG 
9.4. 
Measurement of Treatment Compliance 
The following parameters will be listed and summarized per subject and/or per infusion cycle: 
• 
Body weight 
• 
Actual dose (total and per kg body weight, based on the latest available weight 
measurement) 
• 
Total dose administered 
• 
Total number of infusions administered 
• 
Total volume of solution administered 
• 
Number of infusions 
• 
Infusion times 
• 
Use of premedication 
• 
Overall amount of product administered (only included in data listings) 
Deviations from the planned treatment schedule will be summarized by counting the number of 
infusion cycles that deviate from the scheduled intervals by more than the allowed intervals, and by 
listing all cases with more than two days deviation individually. 


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10. 
Efficacy Analysis 
10.1. 
Primary Endpoint 
The primary endpoint measure ‘response’ will be assessed at Week 16 on bases of the TIS score 
detailed in section 3.2.1: a subject is defined as responder if 
(i) the subject has a TIS score of ≥20 points at Week 16 and 
(ii) the subject has not met “Confirmed Deterioration” criteria at 2 consecutive visits as defined in 
Section 8.4 up to (including) Week 16 
Otherwise the subject will be counted as a non-responder in the treatment group he was randomized 
to Thus subjects who discontinued from the study prior to Week 16 will also be considered as non-
responders. 
The proportion of responders within both treatment groups will be compared by Cochran-Mantel-
Haenszel test, stratified by global disease activity (randomization stratum), using two-sided alpha 
level of 0.05.The primary analysis will be considered as success if the proportion of responders is 
significantly higher in the Octagam group compared to the placebo group. 
Moreover, an exact two-sided 95% confidence-interval will be constructed for the overall difference 
in the proportion of responders between Octagam and placebo group, using the ‘exact riskdiff’ 
option of the SAS FREQ procedure.   
In a sensitivity analysis for the primary endpoint, a logistic regression model will be applied, including 
global disease activity and further baseline variables as applicable as covariates. 
10.2. 
Secondary efficacy endpoints 
All secondary efficacy endpoints will be analyzed and presented in full detail by means of descriptive 
statistics and inferential analyses as appropriate. 
For TIS response at Week 16 by improvement category, the proportion of subjects with at least 
moderate improvement and the proportion of subjects with major improvement will be calculated 
together with subject counts and the associated 2-sided 95% confidence interval (CI) for the 
difference in the proportion of patients with improvement. Moreover, both treatment groups will be 
compared using a Cochran-Mantel Haenszel test, analogously as for the primary endpoint. The 
proportion of subjects in each treatment arm who meet confirmed deterioration criteria up to 
(including) Week 16 will be presented in the same way.  
All mean changes to be evaluated as secondary endpoints (listed in section 3.2.2) will be presented 
by a full set of descriptive parameters: number of subjects with non-missing values, mean, standard 
deviation, median, minimum and maximum, 1st and 3rd quartile, 95% CI. Moreover, for all 
continuous secondary endpoints, an analysis of covariance (ANCOVA) will be used to analyze changes 
from baseline to Week 16. For patients who are switched to the alternate treatment before Week 
16, the last value prior to switch will be carried forward to Week 16 and used to calculate change 
from baseline to Week 16. The model will include treatment and global disease activity as a fixed 
factor. Center will be included as random factor. The baseline value of the variable to be analyzed 
will be included as a covariate. Least square means will be derived and presented together with 95%-
confidence intervals by treatment group. Moreover, two-sided 95% confidence intervals will be 
derived for the overall difference in least square means between Octagam and placebo treatment. As 
sensitivity analysis, a modified ANCOVA model will be used, where the changes from baseline to 
Week 16 are calculated based on Week 16 values, even if a patient is switched to the alternate 


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treatment before Week 16. To incorporate the switch into the model, the variable crossover (yes/no) 
which indicates if there was a switch to the alternate treatment will be included as additional factor 
into the ANCOVA model, as well as the treatment-by-cross-over interaction term. 
In case the proportion of patients with missing values is greater than 10%, or if the modified ANCOVA 
detailed above gives a signal of divergence, the concerned data will be further reviewed and 
analyzed. 
The time to at least minimal, at least moderate and major improvement in TIS, and the time to 
confirmed deterioration in the First Period and overall, will be summarized using based on Kaplan-
Meier estimates that will also be presented graphically. For the analysis of improvement variables in 
the first period, the time to event will be censored at the time of switch to the alternate treatment 
group. A stratified log-rank test will be applied for time to event variables to compare both 
treatment groups. Cox regression models may be applied additionally to include randomization 
stratum and further baseline covariates in the analysis. 
To also include all data from the extension period in such Kaplan-Meier analyses, we will look at the 
abovementioned events and their timely relationship to the first infusion of Octagam. 
To confirm the sustained benefit of treatment with Octagam 10% , response rates at Week 40 and 
changes from baseline to Week 40 will be presented descriptively (overall and by randomized 
treatment), including 95% confidence intervals. 
All individual core set measures (CSMs) used for the TIS, and all other efficacy endpoints will be 
analyzed and presented in full detail by means of descriptive statistics, including summary and 
frequency tables, as well as graphs according to the general principles described in sections 8 and 12. 
The development of each CSM over time will be presented graphically. 
The detailed list of all tables, figures and graphs, and the analysis populations used for each analysis 
will be provided in a separate document later, when all feedback from authorities will be available. 


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11. 
Safety and Tolerability Analyses 
The safety analysis will comprise descriptive statistics, tabulations and listings of all treatment 
emergent adverse events (TEAEs), safety laboratory results, viral markers, vital signs, Wells’ scores, 
Doppler scan results, and physical examination findings. 
11.1. 
Adverse Events 
All reported AEs will be coded according to MedDRA. 
An AE is defined as treatment-emergent, if first onset or worsening is during the treatment period. 
Only treatment-emergent AEs (TEAEs) are accounted for in the analysis. 
For each TEAE, the time relative to the start of the infusion cycle will be calculated and the TEAE will 
be classified as infusional AE if the onset is during the infusion cycle or within 72 hours after the end 
of the last infusion episode of the respective infusion cycle/visit. 
All reported events will be listed and tabulated in full detail; in particular the following key figures will 
be presented: 
• 
Total number of TEAEs reported by severity and overall 
• 
Number of related TEAEs by severity and overall 
• 
Number of TEEs and HTRs 
• 
Number of adverse drug reactions (ADRs) and suspected ADRs 
• 
Number of infusional AEs by severity and overall 
• 
Number of infusion cycles with infusional AEs 
Narratives will be prepared describing each death, other SAEs, and other significant AEs that are judged 
to be of special interest because of clinical importance, including all TEEs and HTRs reported. 
The number and percentage of patients with TEAEs and the number of TEAEs will be summarized by 
actual treatment, unless otherwise specified, i.e. any adverse event will be considered to be 
associated with the most recent treatment administered, Octagam or Placebo, when summarizing 
the data.  
Patients who are switched to the other treatment during the first study period will therefore be 
considered to be at risk for adverse events in both treatment groups. AE tables for the first period 
will summarize data within the following four groups:  
1. Octagam – before or no switch 
2. Octagam – after switch from Placebo 
3. Placebo – before or no switch 
4. Placebo – after switch from Octagam 
Moreover, exposure adjusted incidence rates of TEEs will be presented under Octagam and Placebo 
treatment. These rates will be calculated per 100 patient months on corresponding treatment, and 
will be presented together with 95% confidence intervals, based on Poisson distribution. Rates will 
be shown under Octagam and Placebo treatment in the first period and under Octagam treatment 
over the total study period and for the extension period only. Also all rates will calculated including 
only infusions before reduction of the infusion rate, those after reduction of the infusion rate, and 
including all infusions. 


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11.2. 
Clinical Laboratory Evaluations 
All laboratory data will be converted to standard units during the Data Management process. The 
laboratory data will be listed with suitable flags indicating abnormal values (L=Lower than reference 
range, H=Higher than reference range). 
Summary statistics for the laboratory values as well as their changes from baseline at each time will 
be tabulated for all laboratory parameters. 
11.3. 
Viral Markers 
Virology markers will be assessed at the screening visit and at the (early) termination visit; these data 
will be listed as well with suitable flags indicating positive results. Furthermore shift tables will be 
presented to show any changes in the viral status during the study. 
11.4. 
Vital Signs 
To evaluate short-term tolerance, monitoring of vital signs including blood pressure, body 
temperature, pulse and respiratory rate will be performed at all infusion visits. These parameters will 
be summarized by infusion and measurement time, using the standard set of summary statistics for 
both, absolute values and changes from baseline, where the baseline value is the pre-infusion 
measurement. 
11.5. 
Further Safety Evaluations 
11.5.1. 
Physical Examination 
A general physical examination will be performed at the screening visit and all relevant abnormalities 
will be documented. The physical examination will be repeated at the termination visit (irrespective of 
whether termination is regular or premature), and any clinically relevant worsening from the status at 
screening will be documented as an AE. 
11.5.2. 
Wells Scores 
To identify all occurrences of DVT and PE, Wells’ probability scores will be assessed at all visits. If the 
DVT score is likely for DVT (≥2 points), a Doppler scan is performed, and D-dimers are evaluated. 
These parameters will be combined into a dedicated listing to facilitate the assessment of these 
TEAEs of special interest.  


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12. 
Reporting Conventions 
The following reporting conventions will be adopted for the presentation of study data. These 
conventions will enhance the review process and help to standardize presentation with common 
notations. 
12.1. 
General Reporting Conventions 
• 
All tables and data listings will be developed in landscape orientation, unless presented as 
part of the text in a CSR. 
• 
Figures will in general also be presented in landscape orientation, unless presented as part of 
the text in a CSR. Exceptions are the Trellis plots that will be presented in portrait 
orientation. 
• 
Legends will be used for all figures with more than one variable or item displayed. 
• 
Figures will be in black and white, unless color figures have been identified as useful for 
discriminating presentation in the figure. Lines in figures should be wide enough to view the 
line after being photocopied. 
• 
Specialized text styles, such as bolding, italics, borders, shading, superscripted and 
subscripted text will not be used in tables, figures and data listings unless they add significant 
value to the table, figure, or data listing. 
• 
Only standard keyboard characters should be used in tables and data listings. Special 
characters, such as non-printable control characters, printer specific, or font specific 
characters, will not be used on a table, figure, or data listing. Hexadecimal character 
representations are allowed (e.g., μ, α, β). 
• 
The ICH numbering convention is to be used for all tables, figures and data listings. 
• 
All footnotes will be left justified and placed at the bottom of a page. Footnotes must be 
present on the page where they are first referenced. Footnotes should be used sparingly and 
must add value to the table, figure, or data listing. If more than four footnote lines are 
planned then a cover page may be used to display footnotes. 
• 
Missing values for both numeric and character variables will be presented as blanks in a table 
or data listing. A zero (0) may be used if appropriate to identify when the frequency of a 
variable is not observed. 
• 
All date values will be presented as DDMMMYYYY (e.g., 29AUG2001) format. 
• 
All observed time values will be presented using a 24-hour clock HH:MM format (e.g. 15:26). 
• 
Time durations will be reported in HH:MM notation. The use of decimal notation to present 
(display) time durations should be avoided (e.g. 0.083h = 5min) unless it is necessary to show 
the computation of time differences in a table, figure, or data listing, in which case both 
notations may be used to display the time duration. 
• 
All tables, figures and data listings will have the name of the program, and a date stamp on 
the bottom of each output. 
12.2. 
Population Summary Conventions 
• 
Population(s) represented on the tables or data listings will be clearly identified in the title as 
“Population: <name of population>” where <name of population> is any of the analysis 
population names or abbreviations defined in section 7 (safety analysis set (SAF), full analysis 
set (FAS), etc.). 


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• 
Sub-population(s) or special population(s) descriptions will provide sufficient detail to ensure 
comprehension of the population (e.g., ITT Females, Per-Protocol Males >60 years of age) 
used for analysis in a table or figure. 
• 
Population sizes may be presented for each treatment or dosing category as totals in the 
column header as (N=xxx), where appropriate. 
• 
Population sizes shown with summary statistics are the samples sizes (n) of subjects with 
non-missing values. 
• 
All population summaries for continuous variables will include: N, mean, SD, median, Q1, Q3, 
minimum and maximum. 
• 
All percentages are rounded and reported to a single decimal point (xx.x %). 


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13. 
 Tables, Listings and Figures 
To be supplied in a separate document later when all feedback from authorities will be available.