Clinical trial NCT02753530
Conditions: Inclusion Body Myositis
Keywords: IBM
Sponsor: ZevraDenmark
Start date: 2017-08-16; Completion date: 2021-01-11
Enrollment: 152 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Funding Source - FDA Office of Orphan Products Development (OOPD). The purpose of this study is to evaluate the safety and efficacy of the study drug, arimoclomol in IBM patients.

Detailed description:
A Phase 2/3, randomized, double-blind, placebo-controlled, international, 20-month intervention study in patients with IBM.

Arms: arm 1: 248 mg arimoclomol base (equivalent to 400 mg arimoclomol citrate) 3 times daily arm 2: 248 mg matching placebo 3 times daily
Interventions: intervention 1: Arimoclomol intervention 2: Placebo
Intervention descriptions: intervention 1: 2 capsules (2 x 124 mg arimoclomol base; equivalent to 2 x 200 mg arimoclomol citrate) taken 3 times daily during breakfast, early afternoon, and at bedtime intervention 2: 2 matched placebo capsules taken 3 times daily during breakfast, early afternoon, and at bedtime

Protocol documents:
Prot_000.pdf: 
, M.D. (KUMC) 
Arimoclomol 
Module   5.3.5.1: Phase 2/3 Study of Arimoclomol in IBM 
Page 1 
08 JUN 2020 
Phase 2/3 Study of Arimoclomol in Inclusion Body Myositis (IBM) 
A Randomized, Double-blind, Placebo-Controlled Trial 
Protocol Identifying Number: IBM4809 
Version Number and Date:  9.0, 08 June 2020 
IND Number: 076773 
EudraCT Number: 2017-004903-33 
ClinicalTrials.gov Identifier: NCT02753530
IND Sponsor: 
Orphazyme A/S 
Ole Maaløes Vej 3 
DK-2200 Copenhagen N 
Denmark  
International Coordinating 
, MD, Professor of Neurology 
Investigator: 
University of Kansas Medical Center (KUMC) 
3901 Rainbow Boulevard, Mailstop 2012 
Kansas City, Kansas 66160, U.S.A. 
International Coordinating University of Kansas Medical Center Research 
Investigator Institution:  
Institute, Inc. 
International Coordinating 
, MD, Professor in Clinical Neurology 
Co-Investigator:  
 
International Coordinating  University College of London (UCL) Institute of 
Co-Investigator Institution: Neurology, London, United Kingdom  
Study Drug Name: 
Arimoclomol 
Development Phase: 
2/3 
Date of Protocol: 
08 Jun 2020 
Date of previous protocol: 
24 JUL 2019 
This document contains information which is the property of KemPharm Denmark 
A/S and is provided here as part of the results registration on clinicaltrials.gov. It 
is understood that this information cannot and will not be disclosed to others 
without written approval from KemPharm Denmark A/S.
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Confidentiality Statement 
The information contained within this document is confidential and has been developed by 
Orphazyme A/S, UCL (
 and 
), and KUMC (
 and 
). This material should only be used in connection with the conduct of the 
study or matters authorized by Orphazyme A/S, UCL or  KUMC. The information should not 
be disclosed to others without prior written authorization of UCL’s or KUMC’s researchers or 
Orphazyme A/S’s representative. 
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TABLE OF CONTENTS 
SIGNATURE PAGE ........................................................................................................ 3 
TABLE OF CONTENTS .................................................................................................. 4 
LIST OF ABBREVIATIONS ........................................................................................... 10 
INTERNATIONAL COORDINATING INVESTIGATORS’ AUTHORIZATION ................ 13 
SITE PRINCIPAL INVESTIGATOR’S AUTHORIZATION ............................................. 14 
1 
PROTOCOL SYNOPSIS ........................................................................................ 15 
2 
KEY ROLES ........................................................................................................... 23 
3 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE ........................................................................................................... 24 
3.1 
Background Information ................................................................................ 24 
3.1.1 Name and Description of the Investigational Product ......................... 24 
3.1.2 Summary of Findings from Nonclinical In Vitro or In Vivo Studies 
That Have Potential Clinical Significance ........................................... 25 
3.1.2.1 In Vitro Cell Model of IBM ..................................................... 25 
3.1.2.2 In Vivo Model of IBM ............................................................ 27 
3.1.3 Summary of Human Clinical Pilot Research Data .............................. 28 
3.1.4 Discussion of Important Literature and Data that are Relevant to the 
Trial and that Provide Background for the Trial .................................. 29 
3.1.4.1 Pathology ............................................................................. 31 
3.1.4.2 Protein Misfolding ................................................................. 32 
3.1.4.3 Primary Endpoint: IBMFRS .................................................. 33 
3.1.5 Importance of the Study and Any Relevant Treatment Issues or 
Controversies ..................................................................................... 33 
3.1.5.1 Rationale .............................................................................. 34 
3.1.6 Potential Risks and Benefits ............................................................... 37 
3.1.6.1 Safety and Tolerability .......................................................... 37 
3.1.6.2 Known Potential Benefits ...................................................... 38 
4 
TRIAL OBJECTIVES AND PURPOSE ................................................................... 39 
4.1 
Objectives ..................................................................................................... 39 
4.1.1 Primary Objective ............................................................................... 39 
4.1.2 Safety Objective ................................................................................. 39 
4.2 
Estimands ..................................................................................................... 39 
4.2.1 Primary Estimand ............................................................................... 39 
4.2.2 Secondary Estimand .......................................................................... 39 
5 
OVERALL STUDY DESIGN ................................................................................... 41 
5.1 
Description of the Study Design .................................................................... 41 
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5.2 
Study Endpoints ............................................................................................ 41 
5.2.1 Primary Endpoint ................................................................................ 41 
5.2.2 Secondary Endpoints ......................................................................... 41 
5.2.2.1 Six Minute Walk Test ............................................................ 42 
5.2.2.2 Modified Time Up and Go ..................................................... 42 
5.2.2.3 Muscle Strength Testing ....................................................... 42 
5.2.2.4 Health Assessment Questionnaire ....................................... 43 
5.2.2.5 Number of Falls and Near Falls ............................................ 43 
5.2.2.6 SF-36 .................................................................................... 43 
5.2.2.7 Patient Global Impression of Severity and Change .............. 43 
5.2.2.8 Clinician Global Impression of Severity and Change ............ 43 
5.2.2.9 Safety Endpoints .................................................................. 43 
5.2.2.10 
 ............................................................. 44 
5.2.2.11 Pharmacokinetics Assessments ........................................... 44 
5.2.2.12 Biobanking ............................................................................ 44 
6 
STUDY ENROLLMENT AND WITHDRAWAL ........................................................ 45 
6.1 
Trial Conduct ................................................................................................. 45 
6.2 
Inclusion Criteria ........................................................................................... 45 
6.3 
Exclusion Criteria .......................................................................................... 45 
6.4 
Strategies for Recruitment and Retention ..................................................... 46 
6.5 
Participant Withdrawal or Termination .......................................................... 47 
6.5.1 Reasons for Withdrawal or Termination ............................................. 47 
6.5.2 Handling of Participant Withdrawals or Discontinuation of Study 
Treatment ........................................................................................... 47 
6.5.2.1 Premature Termination of the Study ..................................... 48 
6.5.2.2 Premature Discontinuation of Study Participation at 
Individual Centres ......................................................................... 49 
6.5.2.3 Regular Termination of Study ............................................... 49 
7 
STUDY TREATMENT ............................................................................................. 50 
7.1 
Study Agent(s) and Control Description ........................................................ 50 
7.2 
IMP Manufacturing ........................................................................................ 50 
7.3 
Formulation, Appearance, and Packaging .................................................... 50 
7.4 
Product Storage and Stability ........................................................................ 51 
7.5 
Preparation .................................................................................................... 51 
7.6 
Dosing Route and Regimen .......................................................................... 51 
7.7 
Starting Dosage, IMP interuption, rechallenge and permanent 
discontinuation ............................................................................................. 51 
7.8 
Duration of Therapy ...................................................................................... 52 
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7.9 
Investigational Product Accountability ........................................................... 52 
8 
STUDY PROCEDURES AND SCHEDULE ............................................................ 53 
8.1 
Study Specific Procedures ............................................................................ 53 
8.1.1 Consent .............................................................................................. 53 
8.1.2 Inclusion/Exclusion/Eligibility/Screen Failure ...................................... 53 
8.1.3 Medical History Including IBM history ................................................. 53 
8.1.4 Physical Examination ......................................................................... 53 
8.1.5 IBM Functional Rating Scale .............................................................. 54 
8.1.6 Patient Global Impressions of Severity and Change .......................... 54 
8.1.7 Clinician Global Impressions of Severity and Change ........................ 54 
8.1.8 Muscle Strength Testing ..................................................................... 54 
8.1.9 Modified Timed Up and Go (mTUG) ................................................... 54 
8.1.10 6 Minute Walk Test with 2 Minute Distance Captured ........................ 55 
8.1.11 Falls Diary .......................................................................................... 55 
8.1.12 Health Assessment Questionnaire – Disability Index (HAQ- DI) ........ 55 
8.1.13 Columbia Suicide Severity Rating Scale ............................................ 55 
8.1.14 Vital Signs .......................................................................................... 55 
8.1.15 ECG 55 
8.1.16 SF-36 .................................................................................................. 55 
8.1.17 
 ............................................................................................ 55 
8.1.18 Biobanking .......................................................................................... 56 
8.1.19 POP PK .............................................................................................. 56 
8.1.20 Laboratory Procedures/Evaluations ................................................... 56 
8.1.20.1 Specimen Preparation, Handling and Shipment ................... 56 
8.2 
Study Schedule ............................................................................................. 57 
8.2.1 Screening (30 Day Window) (Visit 1) .................................................. 57 
8.2.1.1 Randomization ...................................................................... 57 
8.2.2 Baseline (Visit 2, Day 1) ..................................................................... 58 
8.2.3 Ongoing Treatment Visits (Visits 3 to 13, Months 1 to 18) .................. 58 
8.2.3.1 Months 1 and 2 ..................................................................... 58 
8.2.3.2 Months 3, 5, and 6 ................................................................ 59 
8.2.3.3 Months 4, 8, 12, and 16 ........................................................ 59 
8.2.3.4 Months 10, 14, and 18 .......................................................... 60 
8.2.4 Final In-person Study Visit and Follow-Up Phone Call ....................... 60 
8.2.5 Early Termination Visit ........................................................................ 61 
8.2.6 Unscheduled Visits ............................................................................. 61 
8.2.7 Exceptional Circumstances Preventing Patient From Attending In-
Person Visits ...................................................................................... 61 
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8.3 
Concomitant Medications, Treatments, and Procedures ............................... 63 
8.4 
Precautionary Medications, Treatments, and Procedures ............................. 63 
8.4.1 Prohibited Medications, Treatments, and Procedures ........................ 63 
8.4.2 Prophylactic Medications, Treatments, and Procedures ..................... 64 
8.4.3 Rescue Medications, Treatments, and Procedures ............................ 64 
8.4.4 Participant Access to Study Drug At Study Closure ........................... 64 
9 
ASSESSMENT OF SAFETY .................................................................................. 65 
9.1 
Adverse Events ............................................................................................. 65 
9.1.1 Adverse Event Definition .................................................................... 65 
9.1.2 Definition of a Serious Adverse Event ................................................ 65 
9.2 
Recording and Reporting of Adverse Events ................................................ 66 
9.2.1 Definition of Severity of Adverse Events ............................................. 67 
9.2.2 Definition of Relationship of AEs to a Medicinal Product and/or 
Study Procedure ................................................................................. 67 
9.2.3 SAE Reporting Procedure for Site Investigators ................................. 68 
9.2.4 Follow-up SAE Reports ...................................................................... 69 
9.3 
Reporting Serious Adverse Events to the IEC/IRB ........................................ 69 
9.4 
Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) 69 
9.5 
Adverse Event Reporting Period ................................................................... 70 
9.6 
Follow-up for specific laboratory abnormalities ............................................. 70 
9.6.1 Increased serum creatinine ................................................................ 70 
9.6.2 Increased transaminases ................................................................... 70 
9.7 
Study Halting Rules ....................................................................................... 72 
9.8 
Study Discontinuation ................................................................................... 72 
9.9 
Safety Oversight ............................................................................................ 72 
9.10 Data Monitoring Committee ........................................................................... 72 
10 CLINICAL MONITORING ....................................................................................... 73 
11 STATISTICAL CONSIDERATIONS ........................................................................ 74 
11.1 General Considerations ................................................................................ 74 
11.2 Statistical Hypotheses ................................................................................... 74 
11.3 Analysis Populations ..................................................................................... 74 
11.4 Description of Statistical Methods ................................................................. 74 
11.4.1 Baseline Descriptive Statistics ............................................................ 74 
11.4.2 Analysis of the Primary Efficacy Endpoint(s) ...................................... 74 
11.4.3 Analysis of the Secondary Endpoint(s) ............................................... 76 
11.5 Safety Analyses ............................................................................................ 76 
11.6 Adherence and Retention Analyses .............................................................. 76 
11.7 Planned Analyses ......................................................................................... 76 
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11.7.1 Safety Review .................................................................................... 76 
11.7.2 Additional Sub-Group Analyses .......................................................... 76 
11.7.3 Sensitivity Analyses ............................................................................ 76 
11.8 Sample Size Considerations ......................................................................... 77 
11.9 Measures to Minimize Bias ........................................................................... 77 
11.9.1 Breaking the Study Blind/Participant Code ......................................... 77 
11.9.2 Unblinding for Data Monitoring Committee ......................................... 77 
12 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ....... 78 
13 QUALITY ASSURANCE AND QUALITY CONTROL .............................................. 79 
13.1 Quality Control .............................................................................................. 79 
13.2 Quality Assurance ......................................................................................... 79 
13.3 Audit .............................................................................................................. 79 
14 ETHICS/PROTECTION OF HUMAN SUBJECTS .................................................. 80 
14.1 Institutional Review Board ............................................................................. 80 
14.2 Regulatory Body Approval............................................................................. 80 
14.3 Informed Consent and Screening Data ......................................................... 81 
14.3.1 Confidentiality ..................................................................................... 81 
14.3.2 Staff Information and Responsibilities ................................................ 82 
14.3.3 Essential Document Retention ........................................................... 82 
14.4 Data Handling and Record Keeping .............................................................. 83 
14.4.1 Data Collection and Management Responsibilities ............................ 83 
14.4.2 Protocol Adherence ............................................................................ 83 
14.4.3 Data Storage and Backup .................................................................. 84 
14.4.4 Study Records Retention .................................................................... 84 
14.4.5 Protocol Deviations ............................................................................. 84 
14.4.6 Publication and Data Sharing Policy................................................... 85 
15 STUDY ADMINISTRATION .................................................................................... 86 
15.1 Study Leadership .......................................................................................... 86 
16 CONFLICT OF INTEREST POLICY ....................................................................... 87 
17 CORONAVIRUS (COVID) OPERATIONAL CHANGES ......................................... 88 
18 LITERATURE REFERENCES ................................................................................ 89 
APPENDIX 1: EUROPEAN NEUROMUSCULAR CENTRE INCLUSION ..................... 94 
APPENDIX 2: IBM FUNCTIONAL RATING SCALE ...................................................... 95 
APPENDIX 3: 
 SUB-STUDY ................................................................................... 96 
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List of Tables 
Table 1: Retrospective chart review of IBM from 2000 to 2010 at KUMC ..................... 30 
Table 2: Schedule of Events ......................................................................................... 62 
List of Figures 
Figure 1. Arimoclomol amplifies cell signal to make molecular chaperones .................. 25 
Figure 2. Over-expression of β-APP and exposure to inflammatory mediators induces 
IBM like pathology in cultured myocytes which is ameliorated by treatment with 
arimoclomol ........................................................................................................ 26 
Figure 3. Treatment with arimoclomol prevents the loss in muscle force and 
appearance of IBM-like pathology in mutant VCP mice ...................................... 28 
Figure 4. Proposed pathogenic cascade of sIBM35 ....................................................... 32 
Figure 5. Schematic of the mechanism of action of HSP7040 ........................................ 33 
Figure 6. Arimoclomol-induced increase in HSP70 and HSP90 in SOD1 mice42 .......... 34 
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LIST OF ABBREVIATIONS 
Abbreviation Description 
Ab 
antibody 
AB-42 
amyloid beta-42 
AE 
adverse event 
ALS 
amyotrophic lateral sclerosis 
ALSFRS 
Amyotrophic Lateral Sclerosis Functional Rating Scale 
ALT 
alanine aminotransferase (SGPT) 
API 
active pharmaceutical ingredient 
AST 
aspartate aminotransferase (SGOT) 
β-APP 
beta amyloid precursor protein 
BiP 
binding immunoglobulin protein 
BUN 
blood urea nitrogen 
CE 
clinical evaluator 
CGIC 
Clinician Global Impression of Change 
CGIS 
Clinician Global Impression of Severity 
CHOP 
C enhancer-binding protein homologous protein 
CIOMS 
Council for International Organizations of Medical Sciences 
CRF 
case report form 
CRO 
contract research organization 
C-SSRS
Columbia Suicide Severity Rating Scale 
DILI 
Drug-induced liver injury 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
EDL 
extensor digitorum longus 
EMA 
European Medicines Agency 
ER 
endoplasmic reticulum 
FDA 
Food and Drug Administration 
FF 
finger flexor 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GGT 
gamma-glutamyl transferase 
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Abbreviation Description 
H&E 
histopathological 
HAQ-DI 
Health Assessment Questionnaire – Disability Index 
HDPE 
high density polyethylene 
HERG 
human ether-a-go-go-related gene 
HIV 
human immunodeficiency virus 
HRQoL 
Health Related Quality of Life 
HSF-1 
heat shock factor-1 
HSP 
heat shock protein 
HSR 
heat shock response 
IB 
investigator’s brochure 
IBM 
inclusion body myositis 
IBMFRS 
IBM Functional Rating Scale 
IBMPFD 
inclusion body myopathy with Pagets’ disease and frontotemporal 
dementia 
ICH 
International Conference on Harmonisation 
ID 
identification 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IMPD 
investigational medicinal product dossier 
INR 
International Normalised Ratio 
IRB 
institutional review board 
ITT 
intention-to-treat 
IUD 
intrauterine device 
IUS 
intrauterine system 
IVIg 
intravenous immunoglobulin 
KUMC 
University of Kansas Medical Center 
LDH 
lactate dehydrogenase 
MAR 
missing at random 
MCV 
mean corpuscular volume 
MMT 
Manual Muscle Testing 
MMRM 
mixed model repeated measures 
MSG 
Muscle Study Group 
mTUG 
Modified Timed Up and Go 
mVCP 
mutant valosin-containing protein 
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Abbreviation Description 
MVICT 
Maximal Voluntary Isometric Contraction Testing 
NASH 
Non-Alcoholic Steatohepatitis 
NFkB 
nuclear factor kappa-B 
NOAEL 
no-observed-adverse-effect-level 
OPD 
Orphan Products Development 
p62 
nucleoporin protein p62 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
PI 
principal investigator 
PIB 
Pittsburgh Compound B 
PK/PD 
Pharmacokinetic/Pharmacodynamic 
PO 
by mouth 
POP PK 
population pharmacokinetics 
p-Tau
tau protein 
QA 
quality assurance 
QC 
quality control 
RBC 
red blood cells 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SF-36 
36-Item Short Form Health Survey
sIBM 
sporadic inclusion body myositis 
SOD1 
superoxide dismutase 1 
SUSAR 
suspected unexpected serious adverse reaction 
SMR 
standard mortality ratio 
TA 
tibialis anterior 
TBL 
Total Bilirubin 
TDP-43 
transactive response DNA binding protein 43 
t.i.d.
three times a day 
UCL 
University College of London 
ULN 
upper limit of normal 
VCP 
valosin-containing protein 
WBC 
white blood cells 
wt-VCP 
wild-type human valosin-containing protein 
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SITE PRINCIPAL INVESTIGATOR’S AUTHORIZATION 
I have read the Phase 2/3 Study of Arimoclomol in IBM protocol dated 08 Jun 2020 
(Version 9.0), and agree to abide by all provisions set forth therein. I agree to comply with 
the International Conference on Harmonisation Guideline for Good Clinical Practice 
(ICH-GCP), national and local regulations and the Declaration of Helsinki. 
The amendments contained in this version of the Clinical Trial Protocol are intended to 
be implemented immediately by all investigators as either an Urgent Safety Measure as 
defined by the EU clinical trials directive or as permitted in other regions. This may mean 
that the implementation of the amendment is prior to approval by competent authority or 
IRB/IEC. 
SIGNATURE: 
DATE: 
......................................................................... 
.................................. 
Print name: 
......................................................................... 
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1 
PROTOCOL SYNOPSIS 
Title: 
Phase 2/3 Study of Arimoclomol in IBM 
Protocol Number 
IBM4809 
Type of Study 
Phase 2/3 
Indication 
Treatment of sporadic Inclusion Body Myositis (sIBM) 
Principal 
Investigator 
, MD 
Number of Study 
Centers 
Approximately 12 
Study Duration 
This study is co-funded by a 4-year FDA Orphan Products 
Development (OPD) grant and Orphazyme. We anticipate 
approximately 15 months of active screening and enrollment, 
and 21 months of treatment and follow-up. 
Participant Duration 
Each participant’s duration will be approximately a total of 22 
months. 
Population: 
It is intended to randomize approximately 150 patients with the 
aim of achieving 75 evaluable patients in each of the two 
groups (arimoclomol and placebo).   
Study Design 
The clinical study will be a randomized, double-blind, 
placebo-controlled study in 150 patients with sporadic IBM 
followed for a 20 month treatment period. In this study there will 
be two treatment groups of 75 patients each, i.e., 75 patients 
receiving arimoclomol 400 mg three times a day (t.i.d) and the 
remaining 75 patients receiving placebo. 
Efficacy outcomes, safety laboratory tests, and adverse events 
will be collected. The long-term goal is to find an effective 
treatment for patients with sporadic IBM. 
A data monitoring committee (DMC) will monitor safety and 
tolerability during the trial according to the DMC charter. 
Upon completion of this study, qualified patients may enter an 
open-label extension study at their last treatment visit (Month 
20). 
Objectives 
Primary Objective 
•
To evaluate the efficacy of arimoclomol at a daily
dosage of 1200 mg (400 mg t.i.d) compared to placebo
in the treatment of sporadic IBM at 20 months.
•
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Title: 
Phase 2/3 Study of Arimoclomol in IBM 
Safety Objective 
•
To evaluate the safety and tolerability of arimoclomol at
a daily dosage of 1200 mg (400 mg t.i.d.) compared to
placebo in the treatment of sporadic IBM over
20 months.
Primary and 
Secondary 
Endpoints 
Primary efficacy endpoint is the change from baseline to 
Month 20 in the IBM Functional Rating Scale (IBMFRS) total 
score. 
Secondary efficacy endpoints will include changes from 
baseline to Months 12 and 20 in the following measures of 
strength and function: 
•
IBMFRS total score (12 months)   6 minute walk test with
2 minute distance captured
•
Modified Timed Up and Go (mTUG)
•
Muscle Strength Testing
o
Manual Muscle Testing (MMT)
o
Isometric 
Contraction 
Testing 
of 
bilateral
quadriceps strength using the MicroFET
•
Health Assessment Questionnaire (HAQ-DI)
•
Grip strength using the Jamar device
•
SF-36
•
Falls and near falls
•
Patient Global Impression of Severity (PGIS) and
Patient Global Impression of Change (PGIC)
•
Clinician Global Impression of Severity (CGIS) and
Clinician Global Impression of Change (CGIC)
Safety Endpoints 
•
Adverse events (AEs);
•
Hematology;
•
Clinical chemistry;
•
Vital signs;
•
Columbia Suicide Severity Rating Scale (C-SSRS)
AEs will be recorded from the time of consent to the end of the 
study or patient withdrawal.  
Physical examination and vital signs will be recorded at 
screening, baseline (no repeat of physical examination), 1, 2, 
4, 8, 12, 16 and 20 months after the commencement of 
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Title: 
Phase 2/3 Study of Arimoclomol in IBM 
continuous dosing, and at any unscheduled visits. A short-form 
physical examination is also included at months 3, 5 and 6.  
Laboratory parameters will be recorded at screening (Visit 1), 
1, 2, 3, 4, 5, 6, 8, 12, 16 and 20 months after the 
commencement of continuous dosing, and at any unscheduled 
visits. 
The C-SSRS will be assessed at all post-baseline in-clinic visits 
including unscheduled visits. 
Unscheduled visits that are solely for the purpose of refilling 
medication do not require any of the safety assessments. 
Other Endpoints 
 
Exploratory endpoints include: 
•
Population pharmacokinetics (POP PK) and exposure
response analysis.
•
Presence of
• 
 (sub-study in selected 
sites only; in a subset of patients) 
Study Drug and 
dosage form 
Arimoclomol 200 mg capsules and matching placebo. 
Doses to be 
studied, Dosing 
route and regimen 
Two capsules of investigational medicinal product (IMP), each 
containing 200 mg (400 mg total arimoclomol or placebo) will 
be administered orally t.i.d. 
If required, the IMP can be dispersed in 10-30 mL (i.e. 1-2 
tablespoons) of liquid or in a tablespoon of soft foodstuff.  
Dispersed in water, the IMP can also be administered via a 
gastric tube (as applicable). 
IMP interuption, 
rechallenge and 
permanent 
discontinuation 
If a patient experiences an intolerable adverse event, dosing 
may be interrupted and supportive therapy administered as 
required. All dosing interruptions must be discussed with the 
contract research organization (CRO)’s medical monitor.  
An interruption of up to 4 weeks (calculated from the first day 
of interruption) is permitted following discussion with the CRO’s 
medical monitor prior to resuming IMP. The interruption of the 
dose should be as short as possible. 
Re-challenge with IMP in cases of increased transaminases 
should only be done in accordance with section 6.5.2 of the 
protocol. 
If the patient experiences the same intolerable adverse event 
after re-challenge with the full dose of IMP, the dose can be 
reduced to half, i.e., 200 mg t.i.d., following discussion with the 
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CRO’s medical monitor. The patient must continue this dose 
for the remaining part of the study. If this dose is not tolerated, 
the IMP must be discontinued permanently. This sequence of 
events can be implemented only once for intolerable AEs within 
a given organ/body system. If the patient experiences a 
different intolerable AE within a different organ/body system, 
this sequence of events can be repeated for that AE. 
Randomization 
Randomization will be stratified by center and will include 
blocking to facilitate approximate balance in the number of 
subjects assigned to each treatment group within each center.  
Selection Criteria 
Inclusion criteria 
Study subjects must meet all of the following criteria which 
must be documented in the study site source documents: 
1. Meet any of the European Neuromuscular Centre
Inclusion Body Myositis research diagnostic criteria 2011
categories for IBM.1 (see Appendix 1)
2. Demonstrate being able to arise from a chair without
support from another person or device
3. Able to ambulate at least 20 ft/6 meters with or without
assistive device. Once arisen from the chair, participant
may use any walking device, i.e. walker/frame, cane,
crutches, or braces. They cannot be supported by another
person and cannot use furniture or wall for support.
4. Age at onset of weakness > 45 years
5.
Body weight of > 40 kgs
6. Able to give informed consent
Exclusion Criteria 
Study subjects must not meet any of the following criteria which 
must be documented in the study site source documents: 
1. History of any of the following excludes subject
participation in the study: chronic infection particularly HIV
or Hepatitis B or C; cancer other than basal cell cancer
less than five years prior, or other chronic serious medical
illnesses.
2. Presence of any of the following on routine blood
screening: WBC < 3000; platelets < 100,000;
hematocrit < 30%; BUN > 30 mg/dL; creatinine > 1.5 x
upper limit of normal; symptomatic liver disease with
serum albumin < 3 g/dl
3. History of most recent creatine kinase >15x the upper limit
of normal without any other explanation besides IBM.
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4. History of non-compliance with other therapies.
5. Use of testosterone except for physiologic replacement
doses in case of androgen deficiency. Participants must
have documented proof of the androgen deficiency.
6. Coexistence of any other disease that would likely to affect
outcome measures.
7. Drug or alcohol abuse within past three months. Patient
has recent history (within 6 months before Screening) of
chronic alcohol or drug abuse which may compromise the
patient’s safety or ability to participate in study activities.
Cannabis for IBM symptoms will be allowed (where legal).
8. Participation in a recent drug study in the last 30 days
prior to the screening visit or use of biologic agents less
than 6 months prior to the screening visit.
9. Women who are lactating or pregnant, or sexually active
female subjects of child-bearing potential* intending to
become pregnant or unwilling to use a highly effective
method of contraception** during the trial through 1 month
after the last dose of trial medication. Sexually active
males with female partners of child-bearing potential*
unwilling to use a condom with or without spermicide in
addition to the birth control used by their partners during
the trial until 3 months after the last dose of trial
medication unless surgically sterile (vasectomy).
* Non child-bearing potential is defined as post-menopausal
(minimum of 12 months with no menses and follicle-
stimulating hormone in the post-menopausal range) or 
sterilisation (hysterectomy, oophorectomy, or bilateral 
tubal ligation). 
** Highly effective methods of contraception include combined 
(oestrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation (oral, 
intravaginal, or transdermal); progestogen-only hormonal 
contraception associated with inhibition of ovulation (oral, 
injectable, or implantable); intrauterine device; intrauterine 
hormone-releasing system; bilateral tubal occlusion; and 
vasectomised partner. 
According to the recommendations from the Clinical Trial 
Facilitation Group (CTFG, 2014), sexual abstinence is 
considered a highly effective birth control method only if it 
is defined as refraining from heterosexual intercourse 
during the trial until 1 month after the last dose of trial 
medication (for female subjects of child-bearing potential) 
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and for 3 months after the last dose of trial medication (for 
male subjects with female partners of child-bearing 
potential). The reliability of sexual abstinence needs to be 
evaluated by the investigator in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the 
subject. 
10. Participants taking >7.5 mg prednisolone or equivalent or
participants on intravenous immunoglobulin (IVIg) or other
immunosuppressants within the last 3 months. Topical, nasal,
and ocular corticosteroids are allowed unless they are being
widely applied or the severity of the underlying condition
makes them unsuitable in the Investigator’s opinion. Local
steroid injections are allowed.
11. Clinically significant renal or hepatic disease, as indicated
by clinical laboratory assessment (results ≥3 times the
upper limit of normal [ULN] for alanine aminotransferase
combined with bilirubin ≥2 times the ULN; symptomatic
liver disease with serum albumin < 3 g/dL; or creatinine
≥1.5 times the ULN). Laboratory tests may be repeated
once at screening. Reasons to repeat laboratory tests may
include that the medication causing laboratory abnormality
was suspended, any other suspected cause may no
longer exist, or to rule out laboratory error.
Total Sample Size 
Up to 150 patients will be randomized in the study, final target 
is 150 patients with the aim of achieving 75 evaluable patients 
in each of the two groups (Arimoclomol and Placebo).   
Number of Planned 
Visits 
Following the screening and baseline visits, Visits 3 to 7 are to 
occur every 30 days (± 7 days) and the remaining visits are to 
occur every 60 days relative to baseline (± 7 days). In-person 
follow-up visits at the trial site are to occur at Months 1, 2, 3, 4, 
5, 6, 8, 12, 16, and 20. Phone calls will be made at Months  10, 
14, 18, and 21. If a patient must stop the trial medication for 
any reason, every effort will be made to have the patient 
participate in each subsequent visit as scheduled. 
Statistical Methods 
Analysis of the Primary Endpoint 
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The primary analysis of the primary estimand will be based on 
the FAS using all observations from schedueld in-clinic visits 
regardless of treatment adherence and used of concomittant 
medication. The analysis is a Mixed Model for Repeated 
Measurements (MMRM). The independent effects included in 
the model are treatment interacting with visit, trial centre as a 
separate main effect and baseline IBMFRS interacting with 
visit. An unstructured covariance matrix for IBMFRS 
measurements within the same patient will be used, hereby 
assuming that measurements from different subjects are 
conditionally independent. Only the in-clinic assessments of 
IBMFRS will contribute data to the primary analysis, whereas 
the assessments of IBMFRS conducted by telephone will be 
included in explorative analysis only. 
To investigate the sensitivity of the primary analysis results, 
complementary and separate analyses will be performed for 
the primary estimand. The change from baseline in IBMFRS 
total score will also be assessed for the secondary estimand 
using an MMRM analysis. The MMRM will be based on all 
observed IBMFRS-data from scheduled visits during the on-
treatmemt period.  
Further details on analyses of the secondary estimand and 
sensitivity analyses will be provided in the SAP. 
Analysis of Secondary Endpoints 
The Secondary endpoints will be analysed for both the primary 
and secondary estimands using the same imputation and 
analysis set-ups as described for IBMFRS.  
All statistical tests will be conducted at the 0.05 significance 
level using 2-tailed tests, and P values will be reported. 
Corresponding 95% confidence intervals (CIs) will be 
presented for statistical tests. 
Adverse events (AEs) will be summarized by treatment group, 
maximum severity, and perceived relationship to study 
medication.  
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Continuous measures of safety (vital signs, laboratory test 
results) will be presented using descriptive statistics and the 
C-SSRS will be summarized.
Compliance data will be summarized by treatment group, 
overall and by visit. 
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3 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
3.1 Background Information 
3.1.1 Name and Description of the Investigational Product 
The University of Kansas Medical Center (KUMC) and University College of London (UCL) 
Institute of Neurology in collaboration with Orphazyme A/S are developing arimoclomol 
for sporadic inclusion body myositis (sIBM).  
Arimoclomol was originally developed for the treatment of Amyotrophic Lateral Sclerosis 
(ALS) by the small biotechnology company Biorex R&D renamed CytRx Corp. and the 
drug is now owned by Orphazyme. The investigational product, arimoclomol, was 
supplied to KUMC to conduct investigator initiated clinical trials in IBM. A Phase 2 clinical 
study in 24 IBM patients was conducted under the investigator IND 076773 (IND Sponsor: 
Dr. 
, KUMC).  
Arimoclomol 
(/+/-(2R),(Z)-N-[2-hydroxy-3-(piperidin-1-yl)propoxy]-pyridine-1-oxide-3-
carboximidoyl chloride citrate (1:1)) (BRX-345) is an analog of bimoclomol, a 
hydroxylamine derivative that acts as a co-inducer of “heat shock” or “molecular 
chaperone” gene expression. Although the precise molecular mechanism of action of 
arimoclomol is not known, the compound has been shown to co-induce molecular 
chaperone genes, meaning that it further elevates the chaperone protein levels already 
induced by physical or metabolic stresses in cell lines and in isolated cells/tissues (see 
Figure 1). It apparently accomplishes this by stabilizing the active phosphorylated trimer 
of the transcription factor, Heat Shock Factor-1 (HSF-1). Recent evidence suggests 
protein misfolding and aggregation play a key role in pathogenesis in IBM. Indeed heat 
shock protein-70 (HSP70) levels have been shown to be increased in IBM muscle 
biopsies. Arimoclomol may slow down the process of protein misfolding and aggregation 
in IBM by helping the muscle fiber to up-regulate inducible heat shock proteins. It may 
also slow progression of muscle degeneration in this progressively debilitating disease.   
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subunit p65 nuclear staining was reduced from 43% in untreated cultures to 23% in 
arimoclomol-treated cultures (p<0.05). Finally, examination of ER calcium handling and 
markers of ER stress revealed that β-APP transfection resulted in a significant reduction 
in ER [Ca2+] (an indicator of ER stress), compared to empty vector treated controls 
(190nM compared to 280nM; p<0.05), a deficit that was completely prevented by 
arimoclomol (ER [Ca2+] 290nM). This dramatic and beneficial effect of arimoclomol on ER 
stress was reflected in a reduction in the expression of the ER stress markers 
C-enhancer-binding protein homologous protein (CHOP) and binding immunoglobulin
protein (BiP) in arimoclomol-treated β-APP transfected myotubes, compared to untreated
cultures.3-5
Together these results indicate that arimoclomol ameliorates several key pathological 
features of IBM-like pathology, at least in an in vitro model of the disease (see Figure 2). 
Figure 2. Over-expression of 
β-APP and exposure to 
inflammatory mediators induces 
IBM like pathology in cultured 
myocytes which is ameliorated 
by treatment with arimoclomol  
Formation of cytoplasmic inclusion 
bodies in myocytes immunoreactive 
for (a) β-APP and ubiquitin and (b) 
TDP-43. The bar chart (c) shows 
the percentage of myocytes 
containing ubiquitinated inclusion 
bodies. (d) Expression of TDP-43 
(green) following β-APP 
transfection and arimoclomol 
treatment and (e) quantification of 
the number of cells with 
cytoplasmic mislocalization of 
TDP-43. (f) TDP-43 expression 
(green) following exposure to 
inflammatory mediators and 
arimoclomol treatment and 
(g) quantification of TDP-43
mislocalization in inflammatory
mediator exposed cultures.
(h) Western blot analysis of TDP-43 expression in myocyte cultures exposed to
inflammatory mediators in the presence and absence of arimoclomol. (i) Images show
the expression of NFkB subunit p65 (green) in β-APP transfected cultures (DAPI
labelled nuclei in blue) and (j) cultures exposed to inflammatory mediators, in the
presence and absence of arimoclomol. (k) The bar chart shows the percentage of cells
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with nuclear NFkB subunit p65 under all culture conditions investigated. Error 
bars = S.E.M; Scale bars: a, b =10μm, d, i and j =20μm 
3.1.2.2 In Vivo Model of IBM 
Professor 
 has recently completed an efficacy trial of arimoclomol in a 
mouse model which recapitulates several key features of IBM.6 Patients with an A232E 
mutation in valosin-containing protein (VCP), a protein involved in numerous cellular 
functions including protein degradation, present with a condition called inclusion body 
myopathy with Pagets’ disease and frontotemporal dementia (IBMPFD). Transgenic mice 
over-expressing the same human mutation in VCP display a muscle pathology that 
closely resembles that of IBM, including muscle weakness and histopathological signs of 
IBM such as rimmed vacuoles and TDP-43 and ubiquitin-positive pathology. Dr. 
Greensmith’s team treated mutant VCP (mVCP) mice treated with arimoclomol 
(120 mg/kg per day, orally, in drinking water) from the start of symptom onset at 4 months 
until 14 months of age, a late stage of disease. Transgenic mice over-expressing 
wild-type human VCP (wt-VCP) were used as controls, and 10 male mice per group were 
studied. Muscle strength was assessed longitudinally by performing grip-strength 
measurements fortnightly from the start of treatment (see Figure 3a). In addition, muscle 
force was also established using isometric muscle force measurements performed on 
terminally anaesthetized mice at 14 months of age (Figure 3b,c). In control wt-VCP mice, 
there was no significant reduction in grip strength relative to body weight between 4 
(6.44g +/- 0.49 SEM) and 14 months of age (5.91g +/- 0.62 SEM). In contrast, in mVCP 
mice, there was a 44.1% reduction in grip strength during the same period (from 7.19 g 
+/- 0.39g SEM to 4.02g +/- 0.3g SEM). However, in mVCP mice treated with arimoclomol, 
there was no significant reduction in grip strength over time; with only a mild reduction 
from 6.24g +/- 0.42g SEM to 5.18g +/- 0.34g SEM by 14 months. These longitudinal 
readouts of muscle strength were reflected in the maximal tetanic force measurements 
obtained from extensor digitorum longus (EDL) muscles of mice examined at 14 months 
of age. In mVCP mice, EDL muscles generated significantly less force (16.59g +/- 1.86 g 
SEM) than EDL muscles in wt-VCP controls (24.18g +/- 1.94g SEM). However, in 
arimoclomol treated mVCP mice, there was no significant difference in the force output 
of EDL muscles (22.47g+/- 1.84g SEM) compared to controls. These results show that 
treatment with arimoclomol prevents the loss in muscle force that occurs as disease 
progresses in mVCP mice.  
Histological assessment of the hindlimb muscles of mVCP mice showed remarkable 
pathological changes which correspond with characteristic IBM features seen in patient 
muscle biopsies (Figure 3d,e). Tibialis anterior (TA) muscles of mVCP mice showed clear 
signs of degenerating and atrophied fibers of irregular sizes, infiltration of inflammatory 
cells, presence of vacuoles and proteinaceous aggregates. Furthermore, an increase in 
the number of centralized nuclei was observed which is regarded as a feature of 
regenerating muscle fibers. Examination of muscle from arimoclomol treated mVCP mice 
however showed a greatly reduced level of degenerating and atrophied fibers (Figure 3f). 
Quantification of the number fibers containing centralized nuclei showed that Arimoclomol 
treated 
mVCP 
mice 
had 
significantly 
more 
fibers 
with 
centralized 
nuclei 
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(35.28% +/- 4.51% SEM) compared to untreated mVCP mice (18.67% +/- 3.43% SEM) 
or wt-VCP mice (3.09% +/- 3.39% SEM), suggesting a greater extent of regeneration in 
the muscle of arimoclomol treated mice.  
Since arimoclomol is known to be a co-inducer of the HSR, 
 also 
examined whether the beneficial effects of arimoclomol on the muscle pathology in 
mVCP mice was reflected in a change in expression of HSP70. As can be seen in  
Figure 3h, Western blot analysis of muscle from mVCP mice treated with arimoclomol 
showed a two-fold increase in the expression of HSP70 compared to that of untreated 
mVCP mice.  
The results of this in vivo efficacy study in a mouse that models key aspects of IBM 
confirm that treatment with arimoclomol prevents the decline in muscle strength and 
improves the histopathological characteristics of IBM, most likely as a result of an 
upregulation in HSPs. 
Figure 3. Treatment with arimoclomol 
prevents the loss in muscle force and 
appearance of IBM-like pathology in mutant 
VCP mice  
a) Longitudinal analysis of grip strength shows that
there is a significant decline in grip strength in
mVCP mice between 4 and 14 months of age
which 
is 
prevented 
in 
mice 
treated 
with
arimoclomol. b) Typical traces of maximum tetanic
force of EDL muscles in anaesthetized mVCP and
arimoclomol treated mVCP mice are shown. c)
The bar chart shows that treatment with
arimoclomol prevents the loss in EDL force that occurs in mVCP mice by 14 months of 
age. Histopathological (H&E) analysis of TA muscles reveals the presence of key IBM-like 
pathological characteristics in mVCP mice. Compared to wt-VCP mice (d) TA muscles 
from mVCP mice (ei-v) show atrophied and degenerating fibers, inflammatory cell 
infiltration, centralized nuclei and the presence of rimmed vacuoles. In contrast, TA 
muscles from mVCP mice treated with arimoclomol shows few if any of these pathological 
changes (f). Quantification of the number of fibers with centralized nuclei (g) shows that 
there is a significant increase in the number of fibers with centralized nuclei in 
arimoclomol-treated mVCP TA muscles which is indicative of active regeneration. h) 
Western blot analysis shows that here is a significant increase in the expression of HSP70 
in TA muscles of mVCP mice treated with arimoclomol, compared to either untreated 
mVCP or wt-VCP mice.6
3.1.3 Summary of Human Clinical Pilot Research Data 
A randomized controlled pilot study in 24 IBM subjects, 18 of whom received arimoclomol 
100 mg PO TID for four months and 8 were on placebo.6 The IBM functional rating scale 
(IBMFRS) decline at 1 year was less in the arimoclomol group compared to placebo with 
the p value approaching significance at 8 months. Results from the clinical 
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proof-of-concept trial in IBM patients showed that arimoclomol was both safe and well 
tolerated, and identified a promising positive trend of effect on disease outcome measures 
although the study was not powered for efficacy. 
3.1.4 Discussion of Important Literature and Data that are Relevant to the Trial and that 
Provide Background for the Trial 
IBM is the most common progressive and debilitating muscle disease beginning in 
persons over age 50 years, with an annual incidence estimated at 2.2 to 7.9 per 
million.8-16,20 Because biopsies of IBM muscle contain lymphocytic inflammatory cells, 
IBM was originally grouped with the inflammatory idiopathic myopathies: polymyositis and 
dermatomyositis. However, pathologic studies during the past 25 years have clearly 
defined it as a unique pathogenic entity.17,18 IBM is a progressive, debilitating disease 
causing both proximal and distal muscle weakness, characteristically most prominent in 
the quadriceps and finger flexors.19-21 Over time it can lead to severe disability, including 
falls due to quadriceps muscle weakness and foot drop, dysphagia, and eventually 
respiratory muscle weakness.11,19, 22-23 Sporadic inclusion body myositis (sIBM) is the 
most frequently occurring form of IBM; hereditary forms of IBM occur very rarely. sIBM 
seldom affects patients under 40 and is much more common over the age of 50. Men are 
affected more frequently than women.24 The natural history of IBM has been followed 
prospectively in three studies.25,26,29 Rose et al. followed 11 subjects for six months, and 
found an overall four percent decrease of strength from baseline.26  Data collection from 
136 IBM patients from the Paris and Oxford groups was completed either during a clinic 
visit (52%), or by extraction from previous medical records (48%). After a median duration 
of 14 years from onset, 75% of patients had significant walking difficulties and 37% used 
a wheelchair.29 Patients were treated with immunosuppression agents (prednisone, 
intravenous immunoglobulins, methotrexate or azathioprine) for a median duration of 41 
months were more severely disabled on last assessment. In a 12-year follow-up study, 
46/64 Dutch patients with sporadic IBM follow-up patients had died; with six patients 
(13%) having end-of-life care interventions.60 The high frequency in sIBM is about 
one-third of the rate found in amyotrophic lateral sclerosis, and it highlights the heavy 
disease burden in the final stage. While life expectancy is not shortened, the causes of 
death differed from an age-matched Dutch general population in that aspiration 
pneumonia was significantly more frequent as a cause of death in sIBM. In another study, 
patients with sIBM who were aged 41 years and older had an approximately 7-fold higher 
risk of premature mortality than the age-matched external comparison population 
(standard mortality ratio [SMR], 6.58; 95% CI, 5.6–7.7). As expected, the risk of 
premature mortality in patients with sIBM decreased with increasing age, but was still 
approximately 5-fold higher than the age-matched external comparison population in 
patients over 70 years of age (SMR, 4.82; 95% CI, 3.9–5.9).61 There is also preliminary 
evidence for increased mortality in sIBM patients who harbor 
62
We performed a retrospective chart review of 51 IBM cases from the University of 
Kansas.18,30 After a 7.5-year mean disease duration, 56% of our cases required an 
assistive device, with 20% requiring a wheelchair or motorized scooter (Table 1).18
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Table 1: Retrospective chart review of IBM from 2000 to 2010 at KUMC 
Male: female ratio 
1.7:1 
Ethnicity (n=51) 
49 Caucasian; 2 Hispanics 
Mean age at onset (yrs) 
61 (45-80) 
Symptom onset before age 50 yrs: 
12% 
Mean time to diagnosis (yrs) 
5.1 (1-15) 
Mean follow up period (yrs) 
2.5 (0.5-8) 
CK (IU/L) 
609 (59-3000) 
Nerve conductions with axon loss 
neuropathy 
32% 
Electromyography 
60% irritative myopathy  
12% non-irritative myopathy 
28% mixed neuropathic/ myopathic 
pattern  
Asymmetry 
90% 
Non-dominant side weaker 
85% 
Typical phenotype:  
Weak Finger Flexor (FF) and quadriceps 
(quads)  
39/51 (76%): 
13 - Classic phenotype (FF and quads 
weakest) 
11 - Classic FF, no preferential quads 
weakness 
 6  - Classic quads, no preferential FF 
weakness 
 9  - FF and quads weak but not weakest 
Atypical phenotype 
12/51 (24%): 
5/12: classic FF with leg weakness 
sparing quads 
4/12: limb-girdle weakness 
3/12: other atypical phenotypes (FF arm 
only,  hip flexion/ankle dorsiflexion, 
facioscapulohumeral) 
Muscle pathology 
43: inflammation and rimmed vacuoles  
8: phenotypic IBM with inflammation but 
no vacuoles 
Mobility Outcome 
75%: recurrent falls 
56%: assistive device use at mean 
7.5 years 
20%: wheelchair or scooter 
Bulbar dysfunction 
51%: dysphagia 
55%: facial weakness 
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3.1.4.1 Pathology 
There is also myonuclear degeneration early on in IBM because the majority of rimmed 
vacuoles are lined with nuclear membrane proteins. IBM myonuclei are often abnormally 
filled with neurofilaments and this may be the earliest detectable pathologic change in 
IBM.10
In IBM, myofibers contain nonnuclear sarcoplasmic TDP-43 accumulations together with 
a reduction of the normal nuclear TDP-43 content. This suggests that TDP-43 has 
redistributed from nuclei to sarcoplasm in a large percentage of IBM myofibers.31 The 
extranuclear accumulation of TDP-43 may be toxic to cells perhaps through altered 
binding to and splicing of mRNA. There are similarly cytoplasmic aggregates of 
sequestosome 1/p62 (referred to from here on as p62) which is encoded for by the 
SQSTM1 gene. This multifunction protein participates in the autophagy pathway and 
transduction pathways such as nuclear factor kappaB (NFkB) signaling and apoptosis.32 
Immunohistochemically, TDP-43 and p62 were the most sensitive markers, accumulating 
in all definite IBM and in 31% and 37%, respectively, of possible IBM cases.33 Therefore, 
IBM muscle accumulates multiple toxic protein aggregates suggesting a disorder of 
protein homeostasis. 
The degenerative theory of IBM hypothesizes that IBM is a degenerative muscle disease 
occurring in an aged cellular environment, associated with cellular accumulation and 
aggregation of several proteins, involving abnormal signal transduction and transcription, 
protein misfolding, inhibition of the cellular protein degradation pathway, and 
mitochondrial dysfunction.34 The lymphocytic infiltrate is considered likely to be secondary 
to muscle fiber degeneration.   
A model of pathogenesis in IBM has been proposed (see Figure 4).35 In this model the 
aging muscle intracellular environment, combined with environmental factors like 
oxidative stress, viruses, or other toxins, and in combination with mutations in 
predisposing genes leads to up-regulation of Аβ precursor protein. This leads to abnormal 
accumulation of Аβ 40 and 42 fragments. The Аβ 42 fragment in particular has a 
hydrophilic face and tends to aggregate into cytotoxic oligomers. Increased transcription 
of Аβ precursor protein leads to up-regulation of other proteins which co-aggregate with 
Аβ fragments. The effects of these toxic oligomers cause oxidative stress in the cell, 
phosphorylation of tau protein, an increase in misfolded proteins, and inhibition of the 
proteasome protein degradation pathway. This creates a positive feedback cascade. The 
cell increases its levels of heat shock proteins to help counteract this increase in misfolded 
proteins, in particular HSP70, but cannot keep up with increasing levels of toxic protein 
products. This upregulation of Аβ precursor protein can also lead to mitochondrial defects, 
further exacerbating the cycle. In support of this theory, cultured muscle fibers with 
overexpressing Аβ precursor proteins display similar pathology to that seen in human 
IBM muscle biopsies. Accumulation of these misfolded proteins eventually leads to the 
characteristic Аβ amyloid inclusions and paired helical fibers containing phosphorylated 
tau seen in IBM muscle biopsy specimens.34,36-38
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Figure 4. Proposed pathogenic cascade of sIBM35
3.1.4.2 Protein Misfolding 
Many systemic and neurodegenerative disorders, termed ‘protein-misfolding disorders’ 
are characterized by the accumulation of intracellular or extracellular protein 
aggregates.38 The initiating event in the disease process may be a crucial conformational 
change that occurs in the disease protein, possibly mediated by physical trauma, 
oxidative damage, or an infectious agent that leads to protein aggregates. These 
aggregates, or more likely their intermediate oligomeric precursor forms, can act to 
catalyze the process of additional aggregation, accelerating the “sequestration” of the 
normal protein and potentially trapping other important proteins that are prone to 
aggregation. In most instances these aggregated protein products are found to be 
cytotoxic, although the exact mechanism of toxicity is unclear.   
A highly conserved class of proteins called molecular chaperones has evolved to prevent 
inappropriate interactions within and between non-native polypeptides, to enhance the 
efficiency of de novo protein folding, and to promote the refolding repair of proteins that 
have become misfolded as a result of cellular stress39-42 (see Figure 5). In addition to this 
protein repair activity, chaperones can mediate targeting to the proteasome system or to 
lysosomes, resulting in selective degradation of the misfolded protein when the 
chaperones cannot repair the misfolded proteins. These activities of the molecular 
chaperones may be sufficient to prevent the normal accumulation of misfolded proteins. 
Under conditions of cellular stress, chaperone activity is increased, adjusting to the 
consequent increase in damaged proteins. However, under certain pathological 
conditions (perhaps due to prolonged exposure during chronic disease), the capacity of 
this protein quality control machinery can be exceeded, and misfolded proteins 
accumulate to dangerous levels.  
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Figure 5. Schematic of the mechanism of action of HSP7040 
3.1.4.3 Primary Endpoint: IBMFRS 
The Inclusion Body Myositis Functional Rating Scale (IBMFRS) is a quickly 
administered (10-minute) ordinal rating scale (ratings 0-40) used to determine patients' 
assessment of their capability and independence in 10 functional activities. The scale 
was developed by the Muscle Study Group (MSG) investigators and was utilized in the 
beta-interferon-IBM trials.27,28 All 10 activities are relevant in IBM. The advantages of 
the IBMFRS are that the categories are relevant to IBM, it is a sensitive and reliable 
tool for assessing activities of daily living function in patients with IBM, and it is quickly 
administered. In the beta-interferon trial, the IBMFRS correlated well with MVICT, 
MMT, SF-36, and the Amyotrophic Lateral Sclerosis Functional Rating Scale 
(ALSFRS).43  
The IBMFRS (see Appendix 2) was derived from the ALSFRS which is another 
patient-derived subjective scale currently accepted as the primary endpoint measure 
for nearly all ALS clinical trials for the last 15 years. The IBMFRS has been validated 
in its use with IBM patients as it correlated well with objective strength measures 
(Maximum Voluntary Isometric Contraction and Manual Muscle Testing) and quality of 
life as assessed by the SF-36.44 Recently, we presented an analysis of prospective 
IBMFRS data collected over several years in 127 IBM cases from the UK and USA.44  
The IBMFRS includes 10 measures (swallowing, handwriting, cutting food and 
handling utensils, fine motor tasks, dressing, hygiene, turning in bed and adjusting 
covers, changing position from sitting to standing, walking, and climbing stairs), each 
graded on a Likert scale from 0 (being unable to perform) to 4 (normal). Sum of the 10 
items gives a value between 0 and 40, with a higher score representing less functional 
limitation.   
3.1.5 Importance of the Study and Any Relevant Treatment Issues or Controversies 
In the US, the true prevalence of IBM is unknown, but is conservatively estimated at 5-10 
cases per million and the upper end of the prevalence estimate range is 71 per million.8 
There are no effective treatments for IBM; the patient’s disease continues to progress 
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exposed to inflammatory mediators, suggesting lower levels of cell stress. Indeed, both 
β-APP over-expression and inflammatory mediators induced cell death, which was 
significantly reduced by arimoclomol. 
Nuclear translocation of the NFkB subunit p65 was examined as an indication of NFkB 
activation, which was observed following exposure to IL1β and TNFα. β-APP 
over-expression also induced NFκB activation, in keeping with cellular models of 
Alzheimer’s disease, in which Aβ42 has been shown to activate the inflammatory 
cascade.46 Arimoclomol had an inhibitory effect on NFκB activation in both models, which 
is likely to reflect HSR augmentation, given the established ability of HSPs to 
down-regulate the NFκB cascade.47
Arimoclomol also significantly reduced the disruption in ER calcium homeostasis induced 
in both IBM models and consequently reduced the ER stress response, a key mechanism 
involved in handling aberrant proteins.6 This was reflected by restoration of cytosolic 
calcium levels towards control levels. Indeed, in TNFα treated cultures, the reduction in 
cytosolic calcium was entirely prevented by arimoclomol, as was the expression of the 
ER stress mediator CHOP. This protective effect of arimoclomol is likely to reflect, at least 
in part, the chaperone activity of augmented HSP70 levels which serves to improve the 
efficiency of protein handling and repair or degradation of misfolded proteins. 
Examination of the two major protein degradation pathways in the culture models 
revealed disruption in both proteasome function and increased autophagy. However, 
arimoclomol had no effect on proteasome function, although formation of mature 
autophagosomes was reduced, suggesting a reduced misfolded protein load in the 
lysosomal pathway.  
In vivo, treatment of mVCP mice with arimoclomol between 4-14 months of age 
significantly improved the pathological features and functional deficits characteristic of the 
inclusion body myopathy.6 Thus, in arimoclomol-treated mVCP mice an increase in 
muscle strength was observed and a reduction in key pathological hallmarks of IBM, 
including a decrease in ubiquitin expression and a reduction in cytoplasmic 
mis-localisation of TDP-43, accompanied by an increase in HSP expression. 
Previous experimental clinical trials in IBM have only tested agents directed at the 
inflammatory component of pathology and all were ineffective.10,13,48-50 Whether the 
degenerative aspect of IBM is primary to the pathogenesis or not, it very likely plays a 
role in the deleterious effects in muscle, and may be a potential therapeutic target. Protein 
homeostasis (proteostasis) is essential for normal cellular functions3 and in conditions of 
cellular stress, proteins can become unfolded or misfolded, leading to their aberrant 
aggregation.4 
Protein misfolding is normally managed by endogenous chaperone proteins5, which 
prevent aberrant protein-protein interactions and promote correct protein folding. HSPs 
are a family of ubiquitously expressed protein chaperones, which are up-regulated 
following stress-induced activation of the heat shock response (HSR), an endogenous 
cytoprotective mechanism. Since the HSR declines with advanced age2, up-regulation of 
the HSR in disorders in which there is evidence of protein mishandling, such as IBM, may 
be of therapeutic value. 
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A randomized controlled pilot study was conducted in 24 IBM subjects, 18 of whom 
received arimoclomol 100 mg PO TID for four months and 8 were on placebo. The IBM 
functional rating scale (IBMFRS) decline at 1 year was less in the arimoclomol group 
compared to placebo with the p value approaching significance at 8 months. Results from 
the clinical proof-of-concept trial in IBM patients showed that arimoclomol was both safe 
and well tolerated, and identified a promising positive trend of effect on disease outcome 
measures although the study was not powered for efficacy. 
These findings provide compelling evidence of the beneficial effects of arimoclomol in in 
vitro and in vivo models of IBM, which support clinical assessment of its effects in IBM 
patients. However, up-regulation in HSP expression by arimoclomol was clearly 
established in both the in vitro and in vivo models, as previously reported.42 
A Type C guidance (written responses only) was received under IND 076773 from the 
Food and Drug Administration (FDA) with regards to a Phase 2/3 protocol with on 
21 June 2016 (Reference ID 3948721). Initially, the Sponsor proposed 0 mg (placebo), 
100 mg t.i.d and 200 mg t.i.d. as the doses for the protocol. FDA recommended to select 
a higher dose that may be closer to the maximum tolerated dose. Therefore, clarification 
was sought on behalf of the Sponsor of the IND regarding the proposed doses for the 
protocol, where the doses of 0 mg (placebo), 200 mg t.i.d and 400 mg t.i.d. were 
proposed. The Agency agreed to the higher dosing of 400 mg t.i.d. and the proposal to 
increase the lower dose to 200 mg t.i.d. Statistical evaluation has shown that to perform 
a three arm study, we would need to double our sample size to demonstrate the same 
efficacy as with a two arm study. Given this is a rare disease with limited total patients, 
the current study design is a two-arm study comparing placebo versus arimoclomol 
400 mg t.i.d. 
This proposal for higher dosing (400 mg t.i.d.) is based on nonclinical safety data and 
previous human exposure; the nonclinical and clinical study reports are submitted to 
IND 071269; study numbers included in parenthesis are summarized below: 
Nonclinical: 
In vitro data 
•
Dose proportionality is established in relevant in human cell line over a wide range,
10-400 μM.
•
No effect on human ether-a-go-go-related gene (hERG) potassium channels
(ARIM-SF-001)
•
No CYP Inhibition (ARIM-AD-003)
•
Weak inhibitor of the OCT 2 transporter; IC50 at 10 μM (CYP0882_R1)
Toxicity data 
•
19 nonclinical toxicological studies have been performed with arimoclomol in mice,
rats and dogs
•
Dogs: no-observed-adverse-effect-level (NOAEL) at 160 mg/kg/day (80 mg/kg
BID) PO determined in 52 weeks study (ARIM-TX-004)
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•
Rats: NOAEL at 375 mg/kg/day PO determined in 28 day toxicology study in rats
•
Lethal dose 1800 mg/kg PO QD. The test item arimoclomol administered orally to
rats in doses 200, 400 and 900 mg/kg respectively over 180 days did not cause
any toxic lesions detectable by histological examination (PREST-013)
Clinical: 
Extensive human exposure to arimoclomol 
•
7 (seven) Phase I studies were completed with dose levels ranging from 50 mg to
1800 mg
•
Maximum single dose administered in human being was 800 mg
•
Maximum repeated dose was 600 mg t.i.d. for 5 days (AALS-005)
•
Renal safety was assessed in a 28 day Phase I study with 400mg t.i.d (1200 mg
daily) or placebo t.i.d. administered for 28 days was safe and well tolerated. There
were no deaths, no serious adverse events (AEs) and no other significant AEs.
(AALS-010)
•
Cmax observed at 1628 ng/ml (3.2 µM) (Healthy male volunteers) (AALS-010)
•
Higher metabolite exposure in animals than humans
Based on the minimum safety factor of 10 for calculating the human equivalent doses, 
the current study highest dose of 1200 mg daily (~ 17 mg/kg based on average human 
body weight of 70 kg) is much lower than the calculated highest safe dose of 6300 mg 
daily, i.e. 70 kg x 90 mg (1/10 of safe dose tested in Pre-ST-013). The proposed dose of 
400 mg t.i.d. was also well tolerated in the 28-day Phase I study in healthy human 
volunteers. The maximum tolerated dose for humans is not known but the highest dose 
used in healthy volunteers is 1800 mg/day.  
Preliminary data from the pilot Phase II clinical study indicate that arimoclomol 100 mg 
p.o. t.i.d. is safe and well-tolerated in IBM.6 Given the observed positive IBMFRS and
MMT trends from the pilot study, further investigation of arimoclomol in a larger IBM
patient population is warranted. While a dosage of 100 mg t.i.d. was used in the pilot
Phase 2 study, a 400 mg t.i.d. dosage will be used in the Phase 2/3 clinical study.
3.1.6 Potential Risks and Benefits 
3.1.6.1 Safety and Tolerability 
A total of 10 clinical studies with arimoclomol have been conducted: 7 studies in healthy 
subjects, 2 studies in patients with ALS, and 1 study in sIBM.  
Data from the completed studies indicate that arimoclomol may lead to a drug-related 
increase in serum creatinine and a decrease in mean creatinine clearance. There was no 
change in glomerular filtration rate (GFR) and serum cystatin C, suggesting an inhibitory 
effect of arimoclomol on tubular secretion of creatinine. The increase in serum creatinine 
may be explained by a weak interaction of arimoclomol with the OCT2 transporter. See 
the current version of the Investigator’s Brochure for further information. 
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In a completed investigator initiated study in sIBM (10656), there were no significant 
differences between treatment groups regarding the rate, type, and severity of AEs. There 
were 8 possibly treatment-related AEs in the placebo group and 14 with arimoclomol, the 
most common being gastrointestinal.6 
Increases in transaminases (ALT/AST) have been observed in a minority of patients 
treated with blinded IMP in ongoing trials with arimoclomol. The maximum increase has 
been above 20x upper limit of normal (ULN). The values have returned to baseline either 
during treatment or after discontinuation of blinded IMP. 
3.1.6.2 Known Potential Benefits 
Trials assessing immunotherapeutic agents have not demonstrated significant efficacy 
against IBM. In experimental cellular and animal models, arimoclomol ameliorates key 
degenerative and inflammatory features of IBM pathology. In a randomized, 
placebo-controlled safety and tolerability trial, arimoclomol (300 mg/day) was found to be 
safe and well tolerated in sIBM patients. There was a trend in favor of arimoclomol in 
secondary endpoints of muscle function and functional IBM scales.6 If arimoclomol were 
found to be beneficial for the treatment of IBM, this would represent the only effective 
treatment for this otherwise progressive disease. 
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4 
TRIAL OBJECTIVES AND PURPOSE 
4.1 Objectives 
4.1.1 Primary Objective  
• To evaluate the efficacy of arimoclomol at a daily dosage of 1200 mg (400 mg t.i.d)
compared to placebo in the treatment of sporadic IBM at 20 months.
4.1.2 Safety Objective 
•
To evaluate the safety and tolerability of arimoclomol at a daily dosage of 1200 mg
(400 mg t.i.d.) compared to placebo in the treatment of sporadic IBM over 20
months.
4.2 Estimands 
4.2.1 Primary Estimand 
The primary estimand – “Treatment policy” is defined as follows: 
Treatment difference of change from baseline in the IBMFRS instrument’s total score 
between arimoclomol and control at 20 months for all randomised patients regardless 
of exposure, adherence to randomised treatment and changes in standard of care  
The treatment policy estimand assesses the expected benefit on the IBMFRS 
instrument in a future population that results from patients being offered treatment with 
arimoclomol as add-on to standard-of-care as compared to standard-of-care alone after 
20 months of follow-up. 
Generalisation of this estimand depends among other things on the extent to which the 
standard-of-care provided in this trial reflects clinical practice and whether the 
adherence to trial product administration in this trial reflects the behaviour of the target 
population. Accordingly, data collected regardless of discontinuation of trial product or 
background therapy will be used to draw inference. 
In line with the primary estimand, the term “missing data” will be used to cover data that 
are planned to be collected but are not present in the database. This implies that data 
that are missing due to death are considered missing and thus could meaningfully have 
been collected. The premise for using this counterfactual while-alive approach is that 
deaths are assumed relatively rare and unrelated to the disease. Details on how 
missing data are handled further and imputed are detailed in Section 
4.2.2 Secondary Estimand 
The secondary and supportive estimand – “Hypothetical” estimand, is defined as 
follows: 
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Treatment difference of change from baseline in the IBMFRS instrument’s total score 
between arimoclomol and control at 20 months for all randomised and exposed 
patients if all patients adhered to treatment. 
The hypothetical estimand assesses the benefit on the IBMFRS instrument that a future 
population would be expected to experience if the patients did not discontinue 
arimoclomol when compared to standard-of-care. It is considered a clinically relevant 
estimand as it provides information to treating clinicians about the expected efficacy of 
arimoclomol compared to standard-of-care for purposes of treating individual patients. 
Generalisation of this estimand depends among other things on the extent to which the 
adherence to trial product administration in this trial could reflect the behaviour of the 
target population. Accordingly, only data collected while patients were exposed to trial 
IMP will be used to draw inference.
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5 
OVERALL STUDY DESIGN 
5.1 Description of the Study Design 
The clinical study will be a Phase 2/3 randomized, double-blind, placebo-controlled 
international study in 150 patients with sporadic IBM followed for 20 months. Total 
duration of the study per patient is approximately 22 months including screening and the 
end of study phone call. In this study there will be two treatment groups of 75 patients 
each, i.e., 75 patients receiving arimoclomol 400 mg t.i.d and the remaining 75 patients 
receiving placebo. There will be approximately 11 sites in the United States and 1 site in 
the United Kingdom.   
Arimoclomol will be administered at 400 mg orally three times a day in this study. 
Capsules are 200 mg so each patient will take 2 capsules three times a day. Every effort 
should be made to allow approximately 6 to 7 hours between dosing. As arimoclomol 100 
mg PO TID was a well-tolerated dosage in our pilot study and 200 mg PO TID was 
well-tolerated for 1 year in a familial ALS study, and safety data support the use of 400 mg 
PO TID, and since the latter dosage is felt to be appropriate based on extrapolation from 
our animal VCP IBM model data, we will initiate participants on the 400 mg PO TID 
dosage or matching placebo. The main adverse events recorded in previous studies were 
mild to moderate gastrointestinal events.  
If a patient experiences an intolerable adverse event, dosing may be interrupted and 
supportive therapy administered as required. Detailed description of the dose reduction 
is located in Section 7.7. The patient will be followed up as planned per protocol for 
adverse events recording. Every effort will be made to continue to follow up and evaluate 
all subjects enrolled in this study.  
Upon completion of this study, qualified patients may enter an open-label extension study 
at their last treatment visit (Month 20). 
5.2  Study Endpoints 
5.2.1 Primary Endpoint 
The primary endpoint is the change from baseline to Month 20 in the Inclusion Body 
Myositis Functional Rating Scale (IBMFRS) total score.   
5.2.2 Secondary Endpoints 
Secondary endpoints of this study will involve objective endpoints that could translate into 
the functional strength abilities of these patients. The quadriceps muscles are targeted in 
this Phase 2/3 trial because of their preferential weakness in IBM and their contribution 
to gait impairment and falls.52 There is a correlation between quadriceps muscle strength 
and function including the distance walked at the 2- and 6-minute walk tests and timed 
tests of stair climbing, standing from a chair, and stepping up on curbs. Subjects with the 
best-preserved quadriceps strength exhibited the highest IBMFRS scores. 
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Secondary efficacy endpoints will include changes from baseline to Months 12 and 20 in 
the following measures of strength and function: 
•
IBMFRS total score (Month 12)6 minute walk test with 2 minute distance captured
•
Modified Timed Up and Go (mTUG)
•
Muscle Strength Testing
o
Manual Muscle Testing (MMT)
o
Isometric Contraction Testing of bilateral quadriceps strength using the
MicroFET
•
Health Assessment Questionnaire (HAQ- DI)
•
Grip strength using the Jamar device
•
SF-36
•
Falls and near falls
•
Patient Global Impression of Severity (PGIS) and Patient Global Impression of
Change (PGIC)
•
Clinician Global Impression of Severity (CGIS) and Clinician Global Impression of
Change (CGIC)
5.2.2.1 Six Minute Walk Test 
The distance an IBM patient can walk in 6 minutes will be assessed. Subjects will be 
instructed to walk down one side of the track and back along the opposite side as quickly 
and safely as possible for 6 minutes. Subjects will be allowed to take breaks as needed 
during the walking period, but timing will continue during breaks. The distance walked in 
meters will be recorded after 2 minutes and 6 minutes. Use of assistive device and the 
type of device during this test will be documented each time. Instructions for 
administration of the test are provided in the Clinical Evaluator’s Manual. 
5.2.2.2 Modified Time Up and Go 
Patient’s ability to get up from a chair allowing subjects to use their arms (since most with 
sIBM cannot perform the task without pushing off), walk 3 meters, turn around and walk 
back to the chair and sit down. The use of nearby walls, or assistance from a caregiver, 
will not be allowed. This test will be performed twice and the fastest time will be used in 
the data analysis. Instructions for administration of the test are provided in the Clinical 
Evaluator’s Manual. This objective endpoint represents a skill that is one of the first things 
that patients lose. This also can be the most debilitating loss that they will endure. Losing 
this function greatly hinders their ability to transfer.  
5.2.2.3 Muscle Strength Testing 
Muscle testing will be performed by three different methods. The first method is by Manual 
Muscle testing. 24 number of muscles will be tested. This method is routinely performed 
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in a clinical setting and has been shown to be reliable (see the Clinical Evaluator’s 
Manual).  
The second method involves using the MicroFET hand myometer of quadriceps muscle. 
This is a hand-held device that allows the examiner to push against a muscle while the 
patient resist. Unlike the manual muscle test which provides a range, this device will 
provide an actual number. One muscle group will be tested bilaterally (i.e., quadriceps). 
Each muscle is tested twice while the patient is encouraged by the clinical evaluator (CE) 
to exert maximal effort. Record the two trials generated by the patient. Effort should be 
made to keep the variability down to 15% between the two trials (see the Clinical 
Evaluator’s Manual). 
The third strength method is the use of a Jamar Dynamometer that will measure grip 
strength. Two trials should be performed on each side (see the Clinical Evaluator’s 
Manual). 
5.2.2.4 Health Assessment Questionnaire 
The health assessment questionnaire (HAQ-DI) is a self-report functional status 
(disability) measure based on the five patient-centered dimensions (death, disability, 
discomfort, drug toxicity and dollar costs). The HAQ domain of disability is assessed by 
the eight categories of dressing, arising, eating, walking, hygiene, reach, grip, and 
common activities. Discomfort is determined by the presence of pain and its severity. 
5.2.2.5 Number of Falls and Near Falls 
Falls are common events in the lives of IBM patients. We will record the number of falls 
and near falls every month.  
5.2.2.6 SF-36 
The SF-36 will be performed as described in Section 8. 
5.2.2.7 Patient Global Impression of Severity and Change 
The PGIS and PGIC will be performed as described in Section 8. 
5.2.2.8 Clinician Global Impression of Severity and Change 
The CGIS and CGIC will be performed as described in Section 8. 
5.2.2.9 Safety Endpoints  
The safety endpoints are as follows: 
•
Adverse events (AEs);
•
Hematology;
•
Clinical chemistry;
•
Vital signs;
•
Columbia Suicide Severity Rating Scale (C-SSRS)
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6 
STUDY ENROLLMENT AND WITHDRAWAL 
6.1 Trial Conduct 
This clinical trial will be conducted in compliance to this protocol, the ethical and scientific 
principles governing clinical research as set out in the Declaration of Helsinki and the 
International Conference on Harmonization (ICH) guidelines on Good Clinical Practice 
(GCP). 
6.2 Inclusion Criteria 
Study subjects must meet all of the following criteria which must be documented in the 
study site source documents: 
1. Meet any of the European Neuromuscular Centre Inclusion Body Myositis research
diagnostic criteria 2011 categories for IBM.1 (see Appendix 1)
2. Demonstrate being able to arise from a chair without support from another person or
device
3. Able ambulate at least 20 ft/6 meters with or without assistive device. Once arisen
from the chair, participant may use any walking device, i.e. walker/frame, cane,
crutches, or braces. They cannot be supported by another person and cannot use
furniture or wall for support.
4. Age at onset of weakness > 45 years
5. Body weight of > 40 kg
6. Able to give informed consent.
6.3 Exclusion Criteria 
Study subjects must not meet any of the following criteria which must be documented in 
the study site source documents: 
1. History of any of the following excludes subject participation in the study: chronic
infection particularly HIV or Hepatitis B or C; cancer other than basal cell cancer less
than five years prior; or other chronic serious medical illnesses.
2. Presence of any of the following on routine blood screening: WBC<3000; platelets
< 100,000; hematocrit < 30%; BUN > 30 mg/dL; creatinine > 1.5 x upper limit of
normal; symptomatic liver disease with serum albumin < 3 g/dL.
3. History of most recent creatine kinase >15x the upper limit of normal without any
other explanation besides IBM.
4. History of non-compliance with other therapies.
5. Use of testosterone except for physiologic replacement doses in case of androgen
deficiency. Participants must have documented proof of the androgen deficiency.
6. Coexistence of any other disease that would be likely to affect outcome measures.
7. Drug or alcohol abuse within past three months. Patient has recent history (within
6 months before Screening) of chronic alcohol or drug abuse which may
compromise the patient’s safety or ability to participate in study activities. Cannabis
for IBM symptoms will be allowed (where legal).
8. Participation in a recent drug study in the last 30 days prior to the screening visit or
use of a biologic agent less than 6 months prior to the screening visit.
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9. Women who are lactating or pregnant, or sexually active female subjects of child-
bearing potential* intending to become pregnant or unwilling to use a highly effective
method of contraception** during the trial through 1 month after the last dose of trial
medication. Sexually active males with female partners of child-bearing potential*
unwilling to use a condom with or without spermicide in addition to the birth control
used by their partners during the trial until 3 months after the last dose of trial
medication unless surgically sterile (vasectomy).
* Non child-bearing potential is defined as post-menopausal (minimum of 12 months
with no menses and follicle-stimulating hormone in the post-menopausal range) or
sterilisation (hysterectomy, oophorectomy, or bilateral tubal ligation). 
** Highly effective methods of contraception include combined (oestrogen and 
progestogen containing) hormonal contraception associated with inhibition of 
ovulation (oral, intravaginal, or transdermal); progestogen-only hormonal 
contraception associated with inhibition of ovulation (oral, injectable, or implantable); 
intrauterine device; intrauterine hormone-releasing system; bilateral tubal occlusion; 
and vasectomised partner. 
According to the recommendations from the Clinical Trial Facilitation Group (CTFG, 
2014), sexual abstinence is considered a highly effective birth control method only if 
it is defined as refraining from heterosexual intercourse during the trial until 1 month 
after the last dose of trial medication (for female subjects of child-bearing potential) 
and for 3 months after the last dose of trial medication (for male subjects with female 
partners of child-bearing potential). The reliability of sexual abstinence needs to be 
evaluated by the investigator in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the subject. 
10. Participants taking >7.5mg prednisolone or equivalent or participants on intravenous
immunoglobulin (IVIg) or other immunosuppressants within the last 3 months.
Topical, nasal, and ocular corticosteroids are allowed unless they are being widely
applied or the severity of the underlying condition makes them unsuitable in the
Investigator’s opinion. Local steroid injections are allowed.
11. Clinically significant renal or hepatic disease, as indicated by clinical laboratory
assessment (results ≥3 times the upper limit of normal [ULN] for alanine
aminotransferase combined with bilirubin ≥2 times the ULN; symptomatic liver
disease with serum albumin < 3 g/dL; or creatinine ≥1.5 times the ULN). Laboratory
tests may be repeated once at screening. Reasons to repeat laboratory tests may
include that the medication causing laboratory abnormality was suspended, any
other suspected cause may no longer exist, or to rule out laboratory error.
6.4 Strategies for Recruitment and Retention 
The sample size will be 75 participants per group (150 total). 
There will be approximately 11 sites within the US and 1 site within the UK. The UK 
anticipates recruiting approximately 50 patients and each site within the US believes that 
they can recruit up to 10 patients per site.  
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Each site involved in this study has a large database of IBM patients and since there are 
no other current drug treatment trials involving IBM patients, we anticipate that each site 
would be able to recruit their patients within 1 year of start up. The study is currently listed 
on clinicaltrials.gov.  
If necessary, letters to neurologists within each sites region will be sent if enrollment is 
slow. The Myositis Association will be contacted to assist with recruitment. 
6.5 Participant Withdrawal or Termination 
6.5.1 Reasons for Withdrawal or Termination 
The patient will be advised in the ICF that they have the right to withdraw from the study 
at any time without prejudice, and may be withdrawn at the Investigator’s, or the 
Sponsor’s discretion at any time. In addition, early withdrawal may occur for any of the 
following reasons: 
•
Patient requests (withdrawal by subject)
•
Investigator decides that it is in the patient’s interest (physician decision)
•
Serious AE that is probably or definitely related to the study medication
•
Death
•
Failure to meet eligibility criteria
•
Lost to follow-up
•
Significant protocol violation
•
Breaking of the blind
•
Pregnancy
•
Commencing systemic treatment with prednisolone >7.5 mg or equivalent
(except if short course [up to 4 weeks] administration not related to IBM e.g. due
to an asthma attack), IVIg, or other immunosuppressants
•
Commencing other experimental or prohibited treatments
•
Study terminated by Sponsor
•
Other
6.5.2 Handling of Participant Withdrawals or Discontinuation of Study Treatment 
In the event that the patient permanently discontinues study treatment, the patient will be 
encouraged to continue attending the protocol-specified study visits for continued 
assessments. 
According to the FDA Guidance for Industry on Drug-Induced Liver Injury (DILI) (64), IMP 
must be permanently discontinued in the case of the following: 
•
ALT or AST >8 x ULN
•
ALT or AST >5 x ULN for more than 2 weeks
•
ALT or AST >3 x ULN and bilirubin >2 x ULN or International Normalised Ratio
(INR) >1.5)
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•
ALT or AST >3 x ULN with the appearance of fatigue, nausea, vomiting, right upper
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
Re-challenge in case of increased transaminases: 
If in the Investigator’s judgement, a temporary halt in IMP is instituted because of elevated 
transaminases, a re-challenge must not occur if the patient had the following: 
•
ALT or AST > 5 x ULN
•
ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
•
ALT or AST > 3 x ULN AND bilirubin >2 x ULN
IMP must also be discontinued for subjects with elevated transaminases where close 
observation (repeated laboratory tests) is not possible, see Section 6.5.2 
In the event that the patient drops out of the study or is withdrawn from the study, the end 
of study/discontinuation page in the patient’s case report form (CRF) should be 
completed. On the end of study/discontinuation page, the Investigator (or designee) 
should record the date of the withdrawal, the person who initiated withdrawal and the 
reason for withdrawal. Withdrawn patients will not be replaced.   
If a patient is unable to return to the center, a phone call will be made to the patient in 
order to complete assessments and retrieve any outstanding data. All attempts to make 
contact with the patient should be documented in source notes. In the event of a loss to 
follow up, information about the patient will be sought from the family or family physician. 
For patients who leave the study or when the study ends, normal standards of care, 
according to local practice, will continue as necessary. 
6.5.2.1 Premature Termination of the Study 
The Scientific Steering Committee and the Sponsor may jointly decide to terminate the 
trial at any time for any reason. 
The Sponsor will terminate the study if the Sponsor determines that its investigational 
drug presents an unreasonable and significant risk to patients. Time permitting, the 
Sponsor will notify the Steering Committee and involve the Steering Committee in its 
decision. 
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The Independent Ethics Committees (IECs)/Institutional Review Boards (IRBs) may 
recommend to the Sponsor, and the regulatory authorities may require from the Sponsor, 
that the study is terminated for reasons pertaining to efficacy, safety or quality of the 
investigational product (arimoclomol). A decision to prematurely terminate the study will 
be binding to all Site Investigators of all study centers. IECs/IRBs and regulatory 
authorities will be informed about the reason and timing of such termination according to 
the applicable laws and regulations.  
6.5.2.2 Premature Discontinuation of Study Participation at Individual Centres 
The Sponsor and the Scientific Steering Committee may jointly decide to discontinue this 
study in one particular or several study centre(s) for reasonable cause, including but not 
limited to one of the following reasons: 
•
Non-compliance with GCP and/or regulatory requirements.
•
Inability of the site to be activated in a timely fashion.
•
Centre cannot recruit an adequate number of patients in a timely fashion.
•
False documentation in the CRF, either deliberately or due to carelessness.
•
Inadequate co-operation with the Sponsor or its representatives.
•
The Investigator requests closure of his/her study centre.
If the study participation is prematurely discontinued in one or more study centers, site 
Investigators must inform their patients and take care of appropriate follow-up and further 
treatment of the patients. Independent Ethics Committees (IECs) / Institutional Review 
Boards (IRBs) and regulatory authorities will be informed about reason and time of 
discontinuation according to the applicable laws and regulations.  
For patients who leave during the study or when the study ends, normal standards of 
care, according to local practice, will continue as necessary. 
6.5.2.3 Regular Termination of Study 
End of study will be 22 months after recruitment of the last patient (1 month screening 
period, 20 months treatment, 1 month follow-up), or earlier if all patients have completed 
or withdrawn from the study prior to this time point.    
Within 90 days of the end of a clinical study, the Sponsor will notify IECs/IRBs and 
regulatory authorities about the regular termination of the study as required according to 
national laws and regulations.  
If the study has to be terminated early, this period shall be reduced to 15 days and the 
reasons clearly explained. 
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7 
STUDY TREATMENT 
7.1 Study Agent(s) and Control Description 
In this parallel-group randomized trial, subjects who meet trial entry criteria will be 
randomly assigned in a 1:1 ratio to arimoclomol or placebo. The randomization schedule 
will be computer generated using a permuted block algorithm and will randomly allocate 
IMP to randomization numbers. The randomization numbers will be assigned sequentially 
as subjects are entered into the trial.  
When all screening procedures are completed and the site investigator believes that the 
subject is eligible, the site will contact the KUMC project manager (or delegate) who will 
confirm completeness of the eCRF data prior to randomization. If the data is confirmed 
as complete, the KUMC project manager (or delegate) will perform the randomization 
before the baseline visit. A randomization confirmation email will automatically be 
generated to the study site staff and management team. Study medication bottle numbers 
to be dispensed at the baseline visit will already have been distributed to the site in 
advance of randomization. 
7.2 IMP Manufacturing 
The drug substance will be manufactured and released by Patheon (US) and will be 
utilized to prepare hard capsules of arimoclomol citrate containing standard compendial 
excipients. Arimoclomol capsules are manufactured by Patheon (FR). The IMP is 
labelled, packed and released according to the IMPD.  
7.3 Formulation, Appearance, and Packaging 
Arimoclomol is an odourless, crystalline powder of white or off-white colour supplied in 
hard capsules of 200 mg. For each strength, capsule fill will be a powder mix of active 
pharmaceutical ingredient (API), with the remainder made of 
 and 
. Arimoclomol is formulated into 
size “0”, white hard capsules for oral administration. For this Phase 2/3 clinical trial, 
capsule strength is 200 mg.  
The placebo capsule is visually indistinguishable from the arimoclomol capsule in size 
and appearance. The placebo of the same size (size 0) will be presented with an identical 
weight capsule fill in identical white hard capsules and packaged and labelled as 
described for arimoclomol. The excipient composition, texture, appearance, solubility, 
smell and flavour of the placebo are carefully matched to mask the identity of the active 
capsule (arimoclomol). In the placebo formulation, the API is exchanged to Bitrex® 
(denatonium benzoate) as placebo flavour masking.  
The capsules are packed in high density polyethylene (HDPE) bottles each containing 
84 capsules. 
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7.4 Product Storage and Stability 
Clinical batches of active and placebo capsules will be placed in a stability study in 
accordance to International Conference on Harmonization (ICH) stability program. The 
stability testing will be performed on packaged product in bottles as applicable.  
In-use stability data following pre-mixing of the capsules contents into a suitable beverage 
or soft food vehicle (e.g. water, apple juice, and yogurt) as well as feeding-tube recovery 
are documented. 
Based on the available stability data, the IMP capsules are recommended to be stored at 
USP controlled room temperature, i.e., store  at 15º to 25ºC with excursions permitted 
between 2º and 30ºC.  
7.5 Preparation 
Arimoclomol citrate is a highly soluble compound with an aqueous solubility of 
14 g/100 mL. Arimoclomol is formulated in size “0”, white hard capsules for oral 
administration.  
All the excipients are listed in the FDA’s inactive ingredients database. 
Arimoclomol capsules are available as oral capsules in strengths of 25 mg, 50 mg, 
100 mg, and 200 mg, but only 200 mg capsules will be used for this study. The dose in 
the Phase 2/3 clinical trial is 400 mg t.i.d.  
7.6 Dosing Route and Regimen 
The IMP (arimoclomol and placebo) may be dispensed only by the site Investigator or by 
a staff member assigned by the site Investigator, as appropriate. The IMP will be 
dispensed to the patient during site visits or may be shipped to the patient’s house (as 
appropriate). 
The contents of the hard capsules can be dispersed in 10-30 mL (i.e. 1-2 tablespoons) of 
water, milk or juice or sprinkled on foods like apple sauce, or yogurt etc. to promote dose 
compliance. 
In aqueous dispersed state, the capsule content can be administered through a gastric 
tube. The tube should be flushed with 5 mL of water. 
7.7 Starting Dosage, IMP interuption, rechallenge and permanent 
discontinuation 
Dosing will start at 400 mg 3 times a day. If a patient experiences an intolerable adverse 
event, dosing may be interrupted and supportive therapy administered as required. All 
dosing interruptions must be discussed with the contract research organization (CRO)’s 
medical monitor. 
An interruption of up to 4 weeks (calculated from the first day of interruption) is permitted 
following discussion with the CRO’s medical monitor prior to resuming IMP. The 
interruption of the dose should be as short as possible. 
If the patient experiences the same intolerable adverse event after re-challenge with the 
full dose of IMP, the dose can be reduced to half, i.e., 200 mg t.i.d., following discussion 
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with the CRO’s medical monitor. The patient must continue this dose for the remaining 
part of the study. If this dose is not tolerated, the IMP must be discontinued permanently. 
This sequence of events can be implemented only once for intolerable AEs within a given 
organ/body system. If the patient experiences a different intolerable adverse event within 
a different organ/body system, this sequence of events can be repeated for that AE. 
According to the FDA Guidance for Industry on Drug-Induced Liver Injury (DILI) (64), IMP 
must be permanently discontinued under circumstances related to elevated 
transaminases. IMP must also be discontinued for subjects with elevated transaminases 
where close observation (repeated laboratory tests) is not possible, see Section 6.5.2 
If in the Investigator’s judgement, a temporary halt in IMP is instituted because of elevated 
transaminases, a re-challenge must not occur if criteria described in Section 6.5.2 are 
met. 
7.8 Duration of Therapy 
Patients will receive the study medication for 20 months. 
7.9 Investigational Product Accountability 
Site Investigator or pharmacist, or an approved representative, should maintain records 
of the product’s delivery to the study center, the inventory at the centre, the administration 
to each patient, and will ensure that all investigational products are stored in a secure, 
limited access area. These records should include dates, quantities, batch/serial 
numbers, expiration dates (if applicable), and the unique code numbers assigned to the 
investigational product(s) and study patients.   
A temperature log should also be kept and should be made available when the monitors 
arrive on site or does remote monitoring.  
Investigators should maintain records that document adequately that the patients were 
administered the dose specified by the Protocol and reconcile all investigational 
product(s) received from the Sponsor. 
To ensure adequate records, all study treatments will be accounted for on an ongoing 
basis throughout the study in drug accountability forms at the study centre.   
Subjects will receive study medication at clinic visits at baseline, Months 1, 4, 8, 12 and 
16. Subjects will use a medication log and will be instructed to return all unused study
medication at each clinic visit. Compliance will be assessed by review of the medication
log at each visit and by documentation of unused study medication. A subject who is not
adherent (taking less than 80% of assigned capsules) will be counseled at each visit on
the importance of taking IMP as instructed.
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8 
STUDY PROCEDURES AND SCHEDULE 
8.1 Study Specific Procedures 
Please refer to the Schedule of Events in Table 2. 
8.1.1 Consent 
Patients will be given opportunity to read, ask questions, have those questions answered 
and sign the consent before any study procedures are performed. The consenting 
procedure must be documented. 
For competent trial subjects who have lost dexterity in the hands and cannot personally 
sign and date the informed consent form, an impartial witness signature may be used to 
document that the participant understands the study, the consent process, and has 
consented to continue to participate in the trial (if permitted by local regulations). 
8.1.2 Inclusion/Exclusion/Eligibility/Screen Failure 
Each patient must satisfy inclusion/exclusion criteria and must be eligible for the study 
before they can be randomized. Once a patient is randomized eligibility checks will not 
be repeated at the baseline visit.  
If a patient is found not to be eligible due to exclusion criteria # 2, 5, or 10, the specific 
eligibility criterion can be reassessed and out-of-range laboratory results can be redrawn 
within the 30-day screening window. For subjects outside of the screening window, 
rescreening is allowed only once and only if approved by the medical monitor. 
Rescreening will be conditional on medical monitor approval if it is considered to be due 
to one of the following three reasons: 
•
Subject failing to satisfy exclusion criteria # 2, 5, or 10 which according to the
opinion of the medical monitor is for an unrelated or reversible reason
•
Out of window baseline visit
•
If a concurrent medical condition in the opinion of the investigator requires initiation
of treatment or optimization of treatment. The subject can be rescreened when the
condition is stabilized.
8.1.3 Medical History Including IBM history 
All past medical history that might affect the results of the study, such as muscle, bone, 
and degenerative disease that might affect performance on the outcome measures, must 
be recorded. Information specific to IBM including date of onset and site of onset must be 
obtained. 
8.1.4 Physical Examination 
A general physical examination must be performed by a physician; in countries where 
accepted, this task can be delegated when documented on a delegation log. 
At months 3, 5 and 6 the physical examination may be conducted in a short-form. As a 
minimum, the examination must include assessments of right upper quadrant pain or 
tenderness and rash. 
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8.1.5 IBM Functional Rating Scale 
The IBMFRS is a quickly administered (10-minute) ordinal rating scale used to determine 
participants' assessment of their capability and independence. It includes 10 measures 
(swallowing, handwriting, cutting food and handling utensils, fine motor tasks, dressing, 
hygiene, turning in bed and adjusting covers, changing position from sitting to standing, 
walking, and climbing stairs), graded on a Likert scale from 0 (being unable to perform) 
to 4 (normal). The sum of the 10 items gives a value between 0 and 40, with a higher 
score representing less functional limitation. 
8.1.6 Patient Global Impressions of Severity and Change 
The Patient Global Impression of Severity (PGIS) is a patient-reported assessment of the 
impact of IBM on a patient’s ability to complete activities of daily living right now. The 
scale ranges from ‘none’ to ‘very mild,’ ‘mild,’ ‘moderate,’ ‘severe,’ and ‘very severe’ 
impact. The Patient Global Impression of Change (PGIC) is an assessment by the subject 
of self-perceived change in ability to conduct daily activities since the start of study 
medication. The scale ranges from ‘very much worse’ to ‘much worse,’ ‘a little worse,’ ‘no 
change,’ ‘a little improved,’ ‘much improved,’ and ‘very much improved’. 
8.1.7 Clinician Global Impressions of Severity and Change 
The Clinician Global Impression of Severity (CGIS) is a clinician-reported assessment of 
the severity of the patient’s IBM symptoms right now. The scale ranges from ‘none’ to 
‘very severe’. The Clinician Global Impression of Change (CGIC) is an assessment by 
the clinician of change in the patient’s IBM since the start of study medication. The scale 
ranges from ‘very much worse’ to ‘very much improved’.  
8.1.8 Muscle Strength Testing 
Muscle testing will be performed by three different methods. The first method is by Manual 
Muscle testing. 24 muscles will be tested. This method is routinely performed in a clinical 
setting and has been shown to be reliable.  
The second method involves using the MicroFET hand myometer. This is a hand-held 
device that allows the examiner to push against a muscle while the patient resists. Unlike 
the manual muscle test which provides a range, this device will provide an actual number. 
One muscle group will be tested bilaterally (i.e., quadriceps). Each muscle is tested twice 
while the patient is encouraged by the Clinical Evaluator (CE) to exert maximal effort. The 
maximum force generated by the patient from the two trials is used for each muscle group. 
The third strength method is the use of a Jamar Dynamometer that will measure grip 
strength. The maximum force generated by the patient from the two trials is used for each 
muscle group. 
8.1.9 Modified Timed Up and Go (mTUG) 
We will measure the patient’s ability to get up from a chair allowing participants to use 
their arms (since most with sIBM cannot perform the task without pushing off), walk 
3 meters, turn around and walk back to the chair and sit down. The use of nearby walls, 
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or assistance from a caregiver is not allowed. This test will be performed twice and the 
fastest time will be used in the data analysis.52,56  
8.1.10 6 Minute Walk Test with 2 Minute Distance Captured 
We will assess the distance IBM participants can walk in 6 minutes. Participants will 
be instructed to walk down one side of the track and back along the opposite side as 
quickly and safely as possible for 6 minutes. Participants will be allowed to take break 
as needed during the walking period, but timing will continued during breaks. Time to 
complete each 50-meter lap and distance walked in meters will be recorded after 
2 minutes and 6 minutes. We will capture use of assistive devices during the test. 
8.1.11 Falls Diary 
Each subject will record the number and date of falls and near falls within each month 
period. 
8.1.12 Health Assessment Questionnaire – Disability Index (HAQ- DI) 
This is a self-report functional status (disability) measure based on the five 
patient-centered dimensions (death, disability, discomfort, drug toxicity and dollar 
costs).57-58  
8.1.13 Columbia Suicide Severity Rating Scale 
The Columbia Suicide Severity Rating Scale (C-SSRS), will be administered to the 
subject by study personnel at the screening visit using the “baseline/screening” version 
of the scale. The “since last visit” version will be administered at all other clinic visits. 
8.1.14 Vital Signs 
Vital signs, including weight, heart rate, respiratory rate, and sitting blood pressure will 
be measured after the subject has been in a sitting position for 5 minutes. Temperature 
will also be measured. Any clinical significant abnormality must be reported as an AE. 
8.1.15 ECG 
A standard 12-lead ECG will be performed after the subject has been lying down for at 
least 5 minutes. All ECG recordings will be identified with the subject number, date, 
and time of the recording. The ECG interpretation will be recorded in the subject’s 
eCRF. Any abnormality at screening will be listed as medical history; any subsequent 
clinically significant abnormality must be reported as an AE. 
8.1.16 SF-36 
The Short Form-36 Health Survey is a 36-item, patient-reported survey of health. The 
SF-36 is a measure of health status. 
8.1.17 
Samples of 2 mL of serum will be collected to obtain 
 levels. Serum samples 
will be obtained, frozen at -70 degrees Celsius, and shipped. 
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8.1.18 Biobanking 
We will collect approximately 12 mL of blood at screening and approximately 6 mL of 
blood at Months 4, 8, 12, and 20 for potential future testing. 
8.1.19 POP PK 
Samples of blood will be drawn as specified in the laboratory manual at month 1 pre-dose 
and then 0.5 hours (+ 60 min) post-dose, and month 8 pre-dose and then 1.5 hours (+ 60 
min) post-dose. A total of 4 samples per subject will be drawn; 2 samples at Month 1 and 
2 samples at Month 8. Patients will be asked to confirm the mode of administration (as 
per section 7.6) of the last dose taken at home before the POP PK blood draw. 
8.1.20 Laboratory Procedures/Evaluations 
For each in-person visit, except for the Baseline visit, the following lab procedures will be 
performed:  
Hematology 
with differentials 
hemoglobin; hematocrit; mean corpuscular volume (MCV); red 
blood cells (RBC/erythrocytes); white blood cells 
(WBC/leukocytes); and differential count (basophils, eosinophils, 
lymphocytes, monocytes, neutrophils [% and absolute count], and 
platelets) 
Biochemistry 
albumin; alkaline phosphatase; alanine aminotransferase 
(ALT/SGPT); aspartate aminotransferase (AST/SGOT); bilirubin 
(total); calcium; chloride; cholesterol; creatine kinase ); creatinine; 
gamma-glutamyl transferase (GGT); glucose (random); iron; 
lactate dehydrogenase (LDH); phosphate; potassium; protein total; 
sodium; triglycerides; BUN; uric acid 
Other 
cystatin C 
A urine pregnancy test will be performed on women of childbearing potential before the 
study medication is given to them at baseline and at each visit. 
All laboratory results must be signed and dated by the physician in a timely manner. All 
abnormal results will be classified as either clinically significant or not clinically significant. 
All clinically significant abnormal values must be recorded as medical history or AEs, as 
appropriate. All of the above mentioned laboratory tests will be performed by a central 
laboratory.  
If the subject cannot attend the trial site for specific laboratory follow-up, the analyses 
may be conducted at a local laboratory. For guidance on follow-up of specific laboratory 
abnormalities, see section 9.6  
8.1.20.1 
Specimen Preparation, Handling and Shipment 
All laboratory samples will be handled and shipped as per the Central Laboratory Manual. 
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8.2 Study Schedule 
This study is co-funded by a 4-year FDA-OPD grant and Orphazyme. We anticipate 
approximately 15 months of active screening and enrollment, and 21 months of treatment 
and follow-up. 
The planned sequence and maximum duration of the trial periods will be as follows: 
1. Screening: up to 1 month
2. Treatment: 20 months
3. Post-treatment Follow-up Call: 1 month after last dose of IMP
The maximum treatment duration for each subject is approximately 20 months.
The maximum trial duration for each subject is approximately 22 months.
Following the screening and baseline visits, Visits 3 to 7 are to occur every 30 days 
(± 7 days) and the remaining visits are to occur every 60 days relative to baseline 
(± 7 days). In-person follow up visits at the trial site are to occur at Months 1, 2, 3, 4, 5, 6, 
8, 12, 16, and 20. Phone calls will be made at Months 10, 14, 18, and 21. If a patient must 
stop the trial medication for any reason, every effort will be made to have the patient 
participate in each subsequent visit as scheduled. 
8.2.1 Screening (30 Day Window) (Visit 1) 
The subject must be screened within 30 days before enrollment in the trial. The following 
procedures will be performed at screening: 
•
Obtain written informed consent and/or assent.
•
Assess inclusion/exclusion criteria.
•
Collect demographic information.
•
Record IBM history and medical history, including current therapies (e.g.,
prescription and nonprescription medications).
•
Perform a physical examination.
•
Measure vital signs, including weight, pulse, sitting blood pressure, respiratory
rate, and temperature.
•
Perform a 12-lead ECG.
•
Collect blood for safety laboratory tests, anti-
 levels, and biobanking. 
•
Complete the C-SSRS “baseline/screening” (lifetime) assessment.
8.2.1.1 Randomization 
The site investigator will review and sign off on all inclusion and exclusion criteria and 
safety laboratory tests prior to randomization. Completeness of eCRF and safety 
laboratory data will be reviewed by the KUMC project manager (or delegate) before 
randomization can occur as detailed in Section 7.  
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8.2.2 Baseline (Visit 2, Day 1) 
The following procedures will be performed at Visit 2 (baseline): 
•
Measure vital signs, including weight.
•
Perform a urine pregnancy test for female subjects of childbearing potential.
•
Record concomitant medications and concomitant therapies.
•
Assess and record AEs occurring since signing of informed consent.
•
Complete the PGIS, IBMFRS, MMT, MVICT of quadriceps and grip, mTUG, grip
assessments, 6 minute walk test with 2 minute distance, HAQ-DI, SF-36, and
CGIS.
•
Administer the first dose of IMP and observe for 1 hour after the dose.
•
Dispense IMP for the initial one-month period, and give the patient instructions
regarding dosing schedule and trial requirements.
•
Provide the subject with a falls diary.
•
Remind patient not to take the morning dose of the study medication on the day of
the Month 1 visit (to allow for pre-dose PK blood sampling).
8.2.3 Ongoing Treatment Visits (Visits 3 to 13, Months 1 to 18) 
8.2.3.1 Months 1 and 2 
The following procedures will be performed at the site visits at Months 1 and 2: 
•
At Month 1 only, to enable a pre-dose PK sample, the patient must not have taken
study medication approximately 8 hours prior to the site visit.
•
Measure vital signs, including weight.
•
Perform a physical examination.
•
Collect blood for clinical safety laboratory tests and (at Month 1 only) for PK
(pre-dose).
•
At Month 1 only, the patient takes dose of study medication in the clinic.
•
At Month 1 only, collect blood for PK 0.5 hours post-dose as per protocol section
8.1.19.
•
Record concomitant medications and concomitant therapies.
•
Assess and record AEs occurring since the last evaluation. Follow up ongoing AEs.
•
Complete the IBMFRS.
•
Complete the C-SSRS (“since last visit” assessment).
•
Perform a urine pregnancy test for female subjects of childbearing potential.
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•
At Month 1 only, collect empty IMP packaging and unused IMP, and dispense
additional IMP.
•
Collect and review the falls diary and give the subject a new falls diary.
8.2.3.2 Months 3, 5, and 6 
The following procedures will be performed at the site visits at Months 3, 5 and 6: 
•
Collect blood for clinical safety laboratory tests
•
Record concomitant medications and concomitant therapies.
•
Perform a physical examination.
•
Assess and record AEs occurring since the last evaluation. Follow up ongoing AEs.
•
At Month 3 and 6 only, complete the IBMFRS
•
Complete the C-SSRS (“since last visit” assessment).
8.2.3.3 Months 4, 8, 12, and 16 
The following procedures will be performed at the site visits at Months 4, 8, 12, and 16: 
•
At Month 8 only, to enable a pre-dose PK sample, the patient must not have
taken study medication approximately 8 hours prior to the site visit.
•
Measure vital signs, including weight.
•
Perform a 12-lead ECG (Month 12 only).
•
Perform a physical examination.
•
Collect blood for clinical safety laboratory tests, anti-
 levels (Month 12 
only), biobanking (Months 4, 8, and 12 only), and PK (Month 8 only; pre-dose). 
•
At Month 8 only; the patient takes dose of study medication in the clinic.
•
At Month 8 only; collect blood for PK 1.5 hours post-dose as per protocol section
8.1.19.
•
Record concomitant medications and concomitant therapies.
•
Assess and record AEs occurring since the last evaluation. Follow up ongoing AEs.
•
Complete the PGIS, PGIC, IBMFRS, MMT, MVICT of quadriceps and grip, mTUG,
grip assessments, 6 minute walk test with 2 minute distance, HAQ-DI, SF-36,
CGIS, and CGIC.
•
Complete the C-SSRS (“since last visit” assessment).
•
Collect empty IMP packaging and unused IMP, and dispense additional IMP.
•
Perform a urine pregnancy test for female subjects of childbearing potential.
•
Collect and review the falls diary and give the subject a new falls diary.
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8.2.3.4 Months 10, 14, and 18 
The following procedures will be performed at the telephone visits at Months, 10, 14, 
and 18: 
•
Record concomitant medications and concomitant therapies.
•
Assess and record AEs occurring since the last evaluation.
•
Complete the IBMFRS.
•
Ensure the subject has sufficient IMP and arrange for additional IMP supplies if
needed.
•
Review the falls diary.
8.2.4 Final In-person Study Visit and Follow-Up Phone Call 
The following procedures will be performed at the final in-person trial visit at Month 20: 
•
Measure vital signs, including weight.
•
Perform a 12-lead ECG (Month 20 only).
•
Perform a physical examination.
•
Collect blood for safety laboratory tests, anti-
 levels, and biobanking. 
•
Record concomitant medications and concomitant therapies.
•
Assess and record AEs occurring since the last evaluation.
•
Perform a urine pregnancy test for female subjects of childbearing potential.
•
Complete the PGIS, PGIC, IBMFRS, MMT, MVICT of quadriceps and grip, mTUG,
grip assessments, 6 minute walk test with 2 minute distance, HAQ-DI, SF-36,
CGIS, and CGIC.
•
Complete the C-SSRS (“since last visit” assessment).
•
Collect empty IMP packaging and unused IMP.
•
Collect and review the falls diary.
Upon completion of this study, qualified patients may provide informed consent and enter 
an open-label extension study at the Month 20 visit. Assessments recorded at this visit 
will also constitute the first assessments of such open-label extension study. 
The following procedures will be performed at the final telephone visit at Month 21: 
•
Record updates to any concomitant medications or therapies that were ongoing at
the previous visit.
•
Record updates to any AEs that were ongoing at the previous visit.
•
Record any new SAEs.
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8.2.5 Early Termination Visit 
If the patient wishes to withdraw from the study and they do not wish to continue in the 
study visits (see Section 6.5.2), you must bring them in for the Month 20 (Visit 14) study 
procedures. This will need to be followed by the visit 15 (30 day post-visit) phone call. 
8.2.6 Unscheduled Visits 
Unscheduled visits to evaluate potential adverse events can occur at any time. Vital signs, 
physical examinations, safety laboratory, C-SSRS, adverse events and concomitant 
medications will be collected during this visit. If this visit is greater than 1 week before 
their regularly scheduled appointment, they must also attend the regularly scheduled 
appointment. Unscheduled visits that are solely for the purpose of refilling medication do 
not require any of the safety assessments. 
8.2.7 Exceptional Circumstances Preventing Patient From Attending In-Person Visits 
In the exceptional circumstance that a patient cannot attend a scheduled or an 
unscheduled visit at the site information about adverse events, concomitant medications 
and IBMFRS can be obtained via telephone. Such an exceptional circumstance should 
be discussed with the CRO’s medical monitor.  
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8.3 Concomitant Medications, Treatments, and Procedures 
Concomitant medication use, including over-the-counter supplements, will be 
documented throughout the study. The entry will include the dose, regimen, route, 
indication, and dates of use. Antioxidants and vitamins will be allowed. There may be 
soreness from the strength and functional tests that the patients must undergo.  
Concomitant procedures (e.g. ultrasound investigation of the liver) must be recorded in 
the CRF. 
8.4 Precautionary Medications, Treatments, and Procedures 
Arimoclomol is an in vitro inhibitor of the OCT2, MATE-1, and MATE-2K transporters and 
consequently may inhibit the elimination of cationic drugs that are significantly eliminated 
by tubular secretion. In addition, arimoclomol is an in vitro substrate of the MATE-1 and 
MATE-2K transporters. Arimoclomol undergoes renal tubular secretion, and concomitant 
treatment with drugs that are MATE-1 or MATE-2K inhibitors may therefore lead to 
increased exposure of arimoclomol. Consequently, the concomitant use of cationic drugs 
that are significantly eliminated by tubular secretion as well as drugs that are MATE-1 or 
MATE-2K inhibitors should be administered with caution. These include, but are not 
limited to, amantadine, amiloride, cimetidine, dopamine, famotidine, memantine, 
metformin, pindolol, procainamide, ranitidine, varenicline, oxaliplatin, dofetelide, 
trimethoprim, 
quinidine, 
verapamil, 
levofloxacin, 
ciprofloxacin, 
moxifloxacin, 
pyrimethamine, and ondansetron. 
Additionally, in vitro studies show that arimoclomol is a direct inhibitor of CYP2D6 and 
may potentially cause increase in exposure of co-administered medications that are 
substrates of CYP2D6 when arimoclomol is dosed at 400 mg t.i.d.   
Since, the magnitude of the potential increase cannot be predicted from in vitro data 
caution is advised if arimoclomol is co-administered with medicinal products that are 
metabolised by CYP2D6. This may for examples be relevant for class I anti-arrhytmics, 
tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRI’s)  particularly 
if they are known to be sensitive and moderate sensitive CYP2D6 substrates and/or have 
a narrow therapeutic index.  
The product information for co-administered medicinal products should be consulted for 
guidance on concomitant treatment with a CYP2D6 inhibitor as dose adjustment of the 
CYP2D6 substrate may be appropriate. For compounds metabolised by CYP2D6 the 
dose may be reduced and for pro-drugs that are converted to the active compound by 
CYP2D6 the dose may be increased to ensure efficacy.  
Animal studies have indicated a possible interaction with furosemide (additive effect) and 
enalapril (decreased effect), both at high doses, and consequently concomitant dosing 
should be done with caution. 
8.4.1 Prohibited Medications, Treatments, and Procedures 
The following medications are prohibited during the study and for specified durations prior 
to enrollment as noted in the exclusion criteria: 
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•
Use of testosterone except as allowed in the exclusion criteria.
•
Cannabis except as allowed in the exclusion criteria.
•
Prednisone, IVIg, or other immunosuppressants except as allowed in the exclusion
criteria. A short course [up to 4 weeks] of systemic treatment with prednisolone
>7.5 mg or equivalent is allowed for conditions not related to IBM (e.g. due to an
asthma attack). Topical, nasal, and ocular corticosteroids are allowed unless they
are being widely applied or the severity of the underlying condition makes them
unsuitable in the Investigator’s opinion. Local steroid injections are allowed.
•
Other experimental treatments
Should there become a medication, treatment, or procedure that is either precautionary 
or prohibited, all patients will be notified immediately. IRB/IEC’s will be notified as soon 
as possible; also include any IMP or any product not approved by the European Medicines 
Agency (EMA) or the United States Food and Drug Administration. 
8.4.2 Prophylactic Medications, Treatments, and Procedures 
There may be soreness from the strength and functional tests that the patients must 
undergo. They may take normal prophylactic medications, treatments or procedures to 
ease the soreness. 
8.4.3 Rescue Medications, Treatments, and Procedures  
Currently there are no rescue medications, treatments and procedures to treat IBM. 
8.4.4 Participant Access to Study Drug At Study Closure 
Upon completion of this study, qualified patients may provide informed consent and enter 
an open-label extension study. 
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9 
ASSESSMENT OF SAFETY 
9.1 Adverse Events 
9.1.1 Adverse Event Definition 
An AE is defined as: Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to 
have a causal relationship with this treatment.  
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product.  
An AE can also refer to an untoward response to the administration of the IMP, but can 
also occur as a result of the protocol-required procedures or be unrelated to both and 
include worsening of pre-existing conditions, for example.  
AEs include the following: 
• Suspected adverse medication reactions;
• Reactions from medication overdose, abuse, sensitivity, or toxicity;
• Apparently unrelated illnesses, including the worsening of a pre-existing illness;
• Injury or accidents;
Note: If a documented medical condition is known to have caused the injury or accident, 
only the accident should be reported as an AE;  
• New or aggravated clinically relevant abnormal medical finding at a physical
examination as compared with previous assessments;
• Laboratory abnormalities or other abnormal assessments (e.g. physical examination,
vital signs, ECG) that require clinical intervention or further investigation (beyond
ordering a repeat [confirmatory] test) unless they are associated with an already
reported clinical event.
9.1.2 Definition of a Serious Adverse Event  
A serious adverse event (SAE) is defined as any untoward medical occurrence that: 
• Results in death;
Note: Death is an outcome of an AE, and not an AE in itself. Event which led to death
should be recorded with fatal outcome. In reports of death due to “Disease
Progression”, where no other information is provided, the death will be assumed to
have resulted from progression of the disease under investigation.
All deaths occurring on the study or patient withdrawal must be reported.
• Is life-threatening;
A life-threatening event places the patient at risk of death at the time of the event. It
does not refer to an event which hypothetically might have caused death if it were
more severe).
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• Requires inpatient hospitalization or prolongation of existing hospitalization;
Note: In general, hospitalization signifies that the patient has been detained (usually
involving at least an overnight stay) at the hospital or emergency ward for observation
and/or treatment that would not have been appropriate in the physician’s office or
outpatient setting. Complications that occur during hospitalization are AEs. If a
complication prolongs hospitalization or fulfils any other serious criteria, the event is
serious. When in doubt as to whether other events meet the serious criteria, the event
is to be considered serious. When in doubt as to whether “hospitalization” occurred
or was necessary, the AE should be considered serious. Hospitalization for elective
treatment of a pre-existing condition that did not worsen from baseline is not
considered an AE.
• Results in persistent or significant disability/incapacity;
Note: The term “significant disability” means a substantial disruption of a person’s
ability to conduct normal life functions. This definition is not intended to include
experiences of relatively minor medical significance such as uncomplicated
headache, nausea, vomiting, hospital, influenza, and accidental trauma (e.g.,
sprained ankle) which may interfere or prevent everyday life functions, but do not
constitute a substantial disruption.
• Is a congenital anomaly/birth defect;
• Is an important medical event(s) that may not be immediately life threatening or result
in death or hospitalization but that may jeopardize the patient or require intervention
to prevent one of the above outcomes. Examples of such events are intensive
treatment in an emergency room or at home for allergic bronchospasm; blood
dyscrasias or convulsions that do not result in hospitalization; or development of drug
dependency or drug abuse. Medical and scientific judgement should be exercised in
deciding whether expedited reporting is appropriate in such circumstances.
9.2 Recording and Reporting of Adverse Events 
All AEs and SAEs, as defined above, encountered during the clinical study will be reported 
in the appropriate section of the CRF. Information will include the following:  
• Duration of the AE (onset/resolution dates);
• Relationship to the IMP (refer to Section 9.2.2);
• Severity (refer to Section 9.2);
• Concomitant therapy given (or other action taken);
• Action taken with respect to the IMP.
If an AE increases in severity it will be recorded as a new record with the same AE 
identifier.  
AE data should be obtained through observation of the patient, from any information 
volunteered by the patient and through patient questioning. The patient may be asked 
“Do you have any health problems?” or “Have you had any health problems since your 
last site visit?”  
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Reporting of Signs and Symptoms versus a Diagnosis 
Recording a diagnosis (when possible) is preferred to recording a list of associated signs 
and symptoms. However, if a diagnosis is known but there are associated signs or 
symptoms not generally attributed to the diagnosis, the diagnosis and each sign or 
symptom must be recorded separately.  
Pregnancy 
Should a pregnancy occur in a female patient or the partner of a male patient, it must be 
reported promptly, within 24 hours of the site first becoming aware of the pregnancy, by 
entering the pregnancy as a non-serious AE in the CRF and completing, signing, and 
dating the pregnancy report form. The pregnancy report form should be sent to the safety 
vendor   using the contact details in Section 9.2.3. A pregnant patient should discontinue 
treatment, but remain in the study for ongoing assessments until the birth of the baby. 
9.2.1 Definition of Severity of Adverse Events  
Severity of any AE will be graded using the definitions below. 
Definition of Severity 
of Adverse Events 
Mild 
Does not interfere with patient’s usual function (awareness 
of symptoms or signs, but easily tolerated [acceptable]). 
Moderate 
Interferes to some extent with patient’s usual function 
(enough discomfort to interfere with usual activity 
[disturbing]) 
Severe 
Interferes significantly with patient’s usual function 
(incapacity to work or to do usual activities [unacceptable]). 
Note: Severe is a measure of intensity whereas an event must meet one of the criteria 
for serious events listed in Section 9.1.2 to be considered serious; thus, a severe 
reaction is not necessarily a serious reaction. For example, a headache may be severe 
in intensity, but would not be classified as serious unless it met one of the criteria for 
serious events listed in Section 9.1.2. An AE that is assessed as severe should not be 
confused with a SAE.  
9.2.2 Definition of Relationship of AEs to a Medicinal Product and/or Study Procedure 
Site Investigator must assess the possible relationship between the AE and the IMP  and 
record that assessment in the CRF.  
The Sponsor will evaluate all SAEs with respect to expectedness according to the IB. 
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The relationship should be assessed according to the criteria below: 
Probably Related 
AEs that are temporally linked and for 
which the study product is more likely to be 
the explanation than other causes, which 
may improve when not using study product 
Possibly Related 
AEs that could equally well be explained by 
study product or other causes, which are 
usually temporally linked and may improve 
when not using study product but do not 
reappear when using study product  
Not Related 
AEs that can be clearly explained by 
extraneous causes and for which there is 
no plausible association with study product, 
or AEs for which there is no temporal 
relationship  
9.2.3 SAE Reporting Procedure for Site Investigators 
The Investigator must report (by fax or email) all SAEs to the safety vendor within 24 
hours of awareness of an SAE by completing, signing and dating the Serious Adverse 
Event Report Form, verifying the accuracy of the information recorded in the form with 
the source documents and CRF, and sending the SAE form to the safety vendor by one 
of the following methods: 
Study Contact for Reporting Serious Adverse Events 
Please refer to the SAE Reporting Contact Details document. 
If, for any reason, it is not possible to complete all sections of the SAE form within 
24 hours, transmission of the form must not be delayed and the outstanding information 
should be sent on a follow-up SAE form.  
Information on SAEs will be recorded on a SAE form. Blank copies are included in the 
study Investigator’s file.  
The SAE form must be completed as fully as possible with information relevant to the 
SAE(s) being reported. All fields should be populated or marked accordingly if no 
information is available.  
The investigator is required to comply with applicable regulations (including local laws 
and guidances) regarding the notification of his or her health authorities, IRB/IEC, 
principal and coordinating investigators, trial investigators, and institutions. Each 
investigator is obligated to learn about the reporting requirements for investigators in 
his/her country. 
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9.2.4 Follow-up SAE Reports 
For all SAEs where important or relevant information is missing, active follow-up should 
be undertaken. The follow-up information must be presented on an SAE form marked as 
follow-up. It is necessary only to provide the new information, together with the following 
minimal information (initial report, adverse event, date of occurrence, subject identification 
(ID), study ID, IMP, and site number); this will allow the follow-up information to be linked 
to the initial SAE report, with the SAE form signed by an Investigator.  
Specific information may be requested by the safety vendor using a follow-up request 
form. 
Investigators or other site personnel should send relevant or requested anonymized 
supporting documentation (e.g. ECG, laboratory results, autopsy report) to the safety 
vendor.  
The Investigator will ensure that all the necessary information is provided within the 
timelines stipulated by the safety vendor when the request for information is made.  
Follow-up reports (as many as required) should be completed and submitted following 
the same procedure above.  
9.3 Reporting Serious Adverse Events to the IEC/IRB 
The Investigator is responsible for informing local IECs/IRBs of the applicable safety 
reports in compliance with local regulations. Copies of all correspondence relating to 
reporting of any safety reports to the IEC/IRB should be maintained in the Investigator’s 
files and provided to Premier Research.  
9.4 Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) 
A suspected unexpected serious adverse reaction (SUSAR) is an SAE, the nature or 
severity of which is not consistent with the reference safety information of the study drug 
in the IB and for which there is at least a reasonable possibility of a causal relationship 
with the study drug.  
The Sponsor shall ensure that all relevant information about SUSARs that are fatal or 
life-threatening is recorded and reported as soon as possible to the concerned authorities, 
central IECs/IRBs and Investigators, and in any case no later than seven days after 
knowledge by the Sponsor of such a case, and that relevant follow-up information is 
subsequently communicated within an additional eight days. 
All other SUSARs shall be reported to the concerned authorities, central IECs/IRBs and 
Investigators as soon as possible but within a maximum of fifteen days of first knowledge 
by the Sponsor. The Sponsor will report all SUSARs via FDA, the EudraVigilance Clinical 
Trials (CT) Module or Council for International Organizations of Medical Sciences 
(CIOMS) forms.  
The Investigator is responsible for informing local IECs/IRBs of the applicable safety 
reports in compliance with local regulations. Copies of all correspondence relating to 
reporting of any safety reports to the IEC/IRB should be maintained in the Investigator’s 
files and provided to Premier Research. 
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9.5 Adverse Event Reporting Period 
AEs will be collected from the time of written informed consent until the end of the trial or 
patient withdrawal. All ongoing AEs will be followed until the follow-up telephone visit and 
SAEs will be followed up until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the patient is lost to follow-up, whichever occurs first.  
Any increase in transaminases > 3x ULN will be followed up (see section 9.6.2) until the 
the values have stabelised or the baseline level of the patient has been reestablished.  
Any SAE (including an AE that leads to death) that occurs after the end of the trial, which 
the Investigator assesses as related to a trial procedure and/or medicinal product, should 
also be reported.  
All new AEs or the worsening of any ongoing events from the time of informed consent 
will be recorded on the AE pages of the CRF.  
9.6 Follow-up for specific laboratory abnormalities 
9.6.1 Increased serum creatinine 
Serum creatinine values > 2-3 fold compared to the patient’s baseline value should be 
further investigated for signs of kidney injury. Estimation of the patient’s GFR based on 
BUN, creatinine, and cystatin C should be performed. In addition, follow-up should be 
done according to local hospital guideline. Follow-up may include measurement of 
oliguria, urine analysis, glomerular filtration rate, vital signs, ultrasound of the kidney, 
blood sampling for parathyroid hormone, metabolic status, and investigation of other 
markers of kidney dysfunction and alternative causes of increased creatinine. 
9.6.2 Increased transaminases 
Transaminases (AST, ALT) > 3 x ULN must be further investigated in line with the FDA 
Guidance on Drug-Induced Liver Injury (64).  
IBM patients may exhibit elevation in transaminases, and according to exclusion criteria 
11, subjects are only excluded with clinically significant hepatic disease indicated by 
clinical laboratory assessment (results ≥3 times the upper limit of normal [ULN] for alanine 
aminotransferase combined with bilirubin ≥2 times the ULN. A consequence of this criteria 
is that subjects with ALT elevation not in the presence of bilirubin elevation may be eligible 
for the trial.  
The investigator may apply clinical judgement to the threshold of transaminases that 
qualify for close monitoring. This will be based on the subject’s baseline clinical safety 
laboratory results and the expected variability of such parameters under repeat measure. 
Exceptions to the guidance for close monitoring must be discussed with the medical 
monitor and the rationale behind any clinical judgement overruling the below definitions 
must be documented in the subjects medical/source records. Note that investigator 
judgment may not be applied to the guidance regarding IMP interruption or 
discontinuation (see Section 6.5.2). 
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Upon first observation of transaminases (AST, ALT) > 3 x ULN, a repeat test must be 
performed within 48-72 hours (ALT, AST, ALP, bilirubin) and the subject should be 
enquired for presence of symptoms (fatigue, nausea, vomiting, right upper quadrant pain 
or tenderness, fever, or rash). 
If the increase is confirmed, close observation must be performed: 
•
Repeating of ALT, AST, ALP, GGT, bilirubin, eosinophils (differential count) 2-3
times weekly. Frequency of retesting may be decreased to once a week or less
(after agreement with the medical monitor) if abnormalities stabilize or the trial drug
has been discontinued and the subject is asymptomatic. The values should be
monitored until the values have stabelised or the baseline level of the patient has
been re-established.
•
Obtaining/confirming detailed history of symptoms and prior or concurrent
diseases.
•
Obtaining/confirming concomitant drug use (including nonprescription medications
and herbal and dietary supplement preparations), alcohol use, recreational drug
use, and special diets.
•
Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic
hepatitis; NASH; hypoxic/ischemic hepatopathy; and biliary tract disease (e.g.
performing 
an 
abdominal 
ultrasound 
or 
Magnetic 
resonance
cholangiopancreatography (MRCP)).
•
Obtaining a history of exposure to environmental chemical agents.
•
Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR,
direct bilirubin).
•
Considering gastroenterology or hepatology consultations.
If close observation is not possible, IMP must be interrupted or discontinued (see section 
6.5.2.2) 
If the subject cannot attend the trial site for close monitoring, the analyses may be 
conducted at a local laboratory. 
At the earliest possible opportunity, a single serum sample should be taken for use in 
case further analyses to explore possible mechanisms behind the transaminase 
elevations are conducted. 
The sample may be processed and shipped under ambient or frozen conditions and will 
be stored frozen at the central laboratory. This sample will be discarded as soon as it is 
decided that such analyses are not warranted or after sample processing and analysis is 
completed which will be no longer than 2 years after the completion of the trial. 
All local laboratory assessments and other assessment performed in relation to increased 
transaminases must be recorded in the CRF including the appropriate reference ranges. 
For scenarios where a permanent halt in the IMP is required, see Section 6.5.2.2 
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9.7 Study Halting Rules 
All attempts will be made to enhance patient compliance (see Section 7.9). Early 
withdrawal may occur for any of the reasons listed in Section 6.5.1.  
If the patient needs to discontinue study medication, every effort will be made to 
encourage the patient to continue with the study visits until study completion. If a patient 
is unable to return to the center, a phone call will be made to the patient. In the event of 
a loss to follow-up, information about the patient will be sought from the family or family 
physician. 
9.8 Study Discontinuation 
Please see Section 6.5.2. 
9.9 Safety Oversight 
The Premier Research medical monitor will be responsible for independent review of the 
safety laboratory tests and adverse events, will be responsible for monitoring the real-time 
reporting of SAEs, and will review laboratory reports and adverse events monthly, or more 
frequently as needed. The medical monitor will be blinded to treatment assignment. If the 
medical monitor has concerns regarding the safety data, they may notify the DMC. The 
medical monitor may request additional or clarifying information from the coordinating 
center of the treating physician. The medical monitor will prepare a report to present to 
the DMC prior to their meetings. 
9.10 Data Monitoring Committee 
A DMC will assess safety and tolerability at regular intervals.  The responsibilities of the 
DMC are further described in a DMC charter. 
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10 CLINICAL MONITORING 
Premier Research is responsible for ensuring the proper conduct of the clinical trial with 
regard to protocol adherence and validity of the data recorded in the CRFs. Premier 
Research will conduct site visits to monitor the trial and ensure compliance with the 
protocol, GCP, and applicable regulations and guidelines. The assigned clinical research 
associate(s) will visit the investigator and trial site at periodic intervals and maintain 
periodic communication.  
The site Investigator will be informed of anticipated in-person monitoring visits. He/she 
will also receive a notification prior to each monitoring visit during the course of the study. 
It is expected that the Investigator and/or his/her Sub-investigator(s) and other 
appropriate staff will be available on the day of the visit to discuss study conduct.  
For additional information, please refer to the clinical monitoring plan. 
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11 STATISTICAL CONSIDERATIONS 
11.1 General Considerations 
This section presents a summary of the planned statistical analyses. A statistical analysis 
plan (SAP) that describes the details of the analyses to be conducted will be written prior 
to database lock.  
Unless otherwise indicated, a two-sided significance level of 5% will be used for all 
hypothesis testing. 
Every effort will be made to retain subjects in this trial, to promote adherence to the study 
protocol, and to collect all data at every visit. If a subject cannot tolerate (even after 
tapering down) or refuses to continue taking study medication, we will continue to follow 
and evaluate that subject. If a subject withdraws from the trial, attempts will be made to 
bring the subject in for a final evaluation. Compliance with trial procedures, subject 
disposition, and reasons for subject withdrawal will be carefully tracked throughout the 
study. 
11.2 Statistical Hypotheses 
The primary outcome variable is the change from baseline to Month 20 in the total score 
on the IBMFRS. The null hypothesis to be tested is that the mean value of this outcome 
variable is the same in the arimoclomol and placebo groups. The alternative hypothesis 
is that the mean value differs between the groups (two-sided). 
11.3 Analysis Populations 
The following analysis populations are planned for this trial: 
•
Intent-To-Treat Population (ITT) or Full analysis set (FAS): The ITT/FAS
population includes all randomized patients. Patients in the ITT population will
contribute to the evaluation ‘as randomized’.
•
Safety Population (SAF): The SAF population includes all patients who receive
any amount of trial medication. Patients in the SAF population will be analysed
according to treatment actually received. The definition of “actually received” will
be based on simple couting the number of days on either of the two treatments.
Further details will be provided in the SAP.
11.4 Description of Statistical Methods 
11.4.1 Baseline Descriptive Statistics 
The distributions of demographic and clinical characteristics will be described for the 
treatment groups as well as the overall cohort using standard summary statistics. 
11.4.2 Analysis of the Primary Efficacy Endpoint(s) 
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Analysis of the Primary Estimand 
The analyses will be based on the FAS using all observations from schedueld visits (see 
SAP for details) regardless of treatment adherence and used of concomittant medication. 
The analysis is a Mixed Model for Repeated Measurements (MMRM). The independent 
effects included in the model are treatment interacting with visit, trial centre as a separate 
main effect and baseline IBMFRS interacting with visit. An unstructured covariance matrix 
for IBMFRS measurements within the same patient will be used, hereby assuming that 
measurements from different subjects are conditionally independent. 
The MMRM is a well-established method that accounts for the uncertainty pertaining to 
missing data. The model assumed that data are missing at random (MAR). Under this 
assumption, the statistical behaviour of the missing data can be described by the 
observed data included in the model, thus, observed IBMFRS responses at all visits and 
the observed effects adjusted for in the model. Consequently, MAR will reflect adherence 
to protocol (not nessesarily adherence to treatment). Of note, an analysis based on MAR 
may attribute benefits to patients who withdraw from trial altogether regardless of the 
reason for discontinuation. By assuming MAR but allowing patients to remain under 
observation while no longer exposed to trial IMP means that the primary statistical 
analysis evaluates effectiveness of arimoclomol, thus targeting the primary estimand. 
The null hypothesis to be tested is that the mean difference in the primary endpoint 
between arimoclomol and placebo is zero. The alternative hypothesis is that it differs from 
zero. If the null-hypothesis is rejected (two-sided p-value < 0.05), and if the estimated 
mean difference in the primary endpoint between arimoclomol and placebo is greater than 
zero, then the primary objective of the trial will be confirmed. 
The analysis of the primary estimand and other methods for handling missing data 
(including imputation models) are further specified in the SAP. 
Analysis of the Secondary Estimand 
The change from baseline in IBMFRS total score will be assessed for the secondary 
estimand using an MMRM analysis like the one detailed above. The difference lie in the 
data used for analysis: This MMRM will be based on all observed IBMFRS-data from 
scheduled visits while patients were exposed to trial mediction (i.e. before treatment 
discontinuation (see SAP for further details)). 
Explorative analysis 
To explore the IBMFRS in further details, indiviual items and domains will be presented 
based on both in-clinic and telephone assessments. The planned analysis is further 
specificed in the SAP. 
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11.4.3 Analysis of the Secondary Endpoint(s) 
The secondary outcome variables of efficacy including; 6MWT distance walked (at 
minutes 2 and 6) strength outcomes (quantitative quadriceps strength and MMT scores, 
grip strength), HAQ-DI, SF-36 scores, falls and near falls, CGIS, CGIC, PGIS, PGIC, and 
modified timed up and go (mTUG) will be analysed at month 12 and 20 for both the 
primary and secondary estimands. Further details on the analysis methods wil be 
provided in the SAP. 
11.5 Safety Analyses 
Adverse events will be summarized by treatment group, maximum severity, and 
perceived relationship to study medication.  
Continuous measures of safety (vital signs, laboratory test results) will be presented using 
descriptive statistics and the C-SSRS will be summarized. 
See the SAP for the full specification of the safety and tolerability analysis. 
11.6 Adherence and Retention Analyses 
Compliance data (pill counts) will be summarized by treatment group, overall and by visit. 
Subject disposition (study completion, study completion on a reduced dosage or off of 
study drug, withdrawal) will also be summarized by treatment group. 
11.7 Planned Analyses 
11.7.1 Safety Review 
The sponsor will monitor blinded safety data on an ongoing basis and the DMC will 
monitor safety and tolerability according the DMC charter. 
11.7.2 Additional Sub-Group Analyses 
We will investigate the interactions between treatment group and selected baseline 
variables including site, IBMFRS score, 6-minute walk test distance, site of onset, and 
 status. This will be done by adding the appropriate main effect and interaction 
terms to the primary analysis model. Since the power to detect potentially meaningful 
interactions will be limited, the magnitudes of treatment effects in the relevant subgroups 
will be examined. The observation of clinically important subgroup differences in 
treatment effects (e.g., in those with low vs. high IBMFRS scores at baseline) will serve 
as hypothesis generation for possible future studies designed to specifically address the 
issue of differential therapeutic response. 
11.7.3 Sensitivity Analyses 
To investigate the sensitivity of the primary and secondary analysis results, complementary and 
separate analyses will be performed for each of the two estimands. In particular. these sensitivity 
analyses will be used to evaluate the sensitivity of the results due to the impact of missing data. 
Further details are provided in the SAP. 
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11.8 Sample Size Considerations 
The primary outcome variable is the change from baseline to Month 20 in the IBMFRS. 
In the arimoclomol pilot study, the standard deviation of the 12-month change in IBMFRS 
was 2.9. The mean change in the placebo group was -3.5 and the mean change in the 
arimoclomol group was -2.1. A sample size of 68 subjects per group (136 total) will 
provide 80% power to detect a treatment group difference in mean response of 1.4 points, 
using a two-sample t-test and a 5% significance level (two-tailed). To account for an 
anticipated 10% drop-out rate, the sample size will be inflated to 75 participants per group 
(150 total). Although this calculation strictly applies only to a trial with 12-month follow-up, 
it will also apply to this trial if, as expected, the magnitude of the treatment effect relative 
to the magnitude of the standard deviation of the change in IBMFRS score does not 
diminish over time. 
11.9 Measures to Minimize Bias 
11.9.1 Breaking the Study Blind/Participant Code 
Each site will receive documentation to break the randomization code if needed. The site 
investigators will not have access to the randomization codes. The investigator or 
pharmacist at the site will have access to the unblinded information for the double-blind 
treatment for each subject via code envelopes. 
The investigator may only break the code for a subject if knowledge of the IMP is 
necessary to provide optimal treatment to the subject in an emergency situation. If 
possible, the investigator should consult the Medical Monitor before breaking the code. 
The investigator must record the date, time, and reason for breaking the code on the code 
envelope and sign it. The subject must be immediately withdrawn from IMP and followed 
up according to Section 6.5.   
11.9.2 Unblinding for Data Monitoring Committee 
Periodic safety review by the Data Monitoring Committee will be facilitated by an 
unblinded statistician from Premier not otherwise involved in the study. The sponsor and 
all other study personnel will remain blinded. Safety reports will be reviewed by the DMC 
in a closed session. If the recommendation by the DMC is to continue the study, the 
detailed results of the safety review will not be conveyed to the sponsor until the end of 
the study. In the event that the DMC recommends stopping the study, communications 
between the DMC and the sponsor will be strictly limited to a small number of designated 
sponsor representatives. The sponsor will share DMC recommendations with the 
Steering Committee promptly. The details of the DMC process, including communications 
with the sponsor, will be detailed in the DMC charter and the statistical analysis plan. 
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12 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
A CRF is required and should be completed for each included (consented) patient. The 
Investigator will be responsible for the accuracy of the data entered into the CRF. All data 
must be entered in English and must be completed by designated study personnel. The 
completed CRFs must be reviewed, and electronically signed/dated by the Investigator in 
a timely fashion. If a change is made on any of the eForms after the Investigator has 
signed that eForm, the Investigator must re-sign the CRF. Relevant completed eForms 
must be available for review at each scheduled monitoring visit.  
The Investigator will allow designated sponsor representatives and regulatory bodies to 
have direct access to the source documents to verify the data reported in the CRFs.  
Source documents (e.g., medical records, raw data collection forms, pharmacy 
dispensing records, recorded data from automated instruments, laboratory data) are the 
originals of any documents used by the Investigator or hospital/institution that allow 
verification of the existence of the patient and substantiate the integrity of the data 
collected during the trial. Source documents should be available to support all the data 
recorded in the CRF. The Investigator will prepare and maintain adequate and accurate 
source documents. These documents are designed to record all observations and other 
pertinent data for each patient included in this clinical trial. 
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13 QUALITY ASSURANCE AND QUALITY CONTROL 
An independent audit of the study may be conducted during the study or after completion. 
The audit may be conducted by either Orphazyme or an independent auditor or a 
regulatory authority.  
13.1 Quality Control 
Quality Control (QC) is defined as the operational techniques and activities undertaken 
within the QA system to verify that the requirements for quality of the trial-related activities 
have been fulfilled. QC should be applied to each stage of data handling to ensure that 
all data are reliable and have been processed correctly.  
13.2 Quality Assurance 
Quality Assurance (QA) is defined as the planned and systematic actions that are 
established to ensure that the trial is performed and the data are generated, documented 
(recorded) and reported in compliance with GCP and the applicable regulatory 
requirements.  
13.3 Audit 
The Investigator will permit an audit mandated by the Sponsor after reasonable notice. 
The purpose of an audit is to confirm that the study is conducted as per protocol, GCP 
and applicable regulatory requirements, that the rights and well-being of patients enrolled 
have been protected and that all data relevant for the evaluation of the IMP have been 
captured, processed and reported in compliance with the planned arrangements. The 
Investigator will permit direct access to all study documents, IMP accountability records, 
medical records and source data. The Investigator and his/her study team will also be 
available for discussion regarding study progress and procedures during the audit (both 
during the audit and at the end of the audit for an “exit” discussion). 
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14 ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1 Institutional Review Board 
It is the responsibility of the local site Investigator to obtain approval of the trial 
protocol/amendments from the IEC/IRB. Prior to the initiation of the study, each site 
Investigator will submit the following documents to the appropriate IECs/IRBs for 
approval:  
• The study protocol and any amendments;
• The IB;
• Details of any compensation to patients;
• The current curriculum vitae of the Principal Investigator;
• Any other requested document(s).
A copy of the approval will be sent to Premier Research along with all other 
correspondence with the IEC/IRB, including the submission documents. The Investigator 
should file all correspondence with the IEC/IRB in the Investigator site file.  
The study will not start and no subject may undergo any procedure not part of routine 
care for the subject’s condition until approval of the protocol and the consent form has 
been obtained from the appropriate IEC/IRB. The letter of approval should be dated, and 
should specify the protocol number and date of the protocol or amendment which was 
reviewed and approved. It should also specify the date the ICF was reviewed and 
approved. 
A dated list of the voting members of the IEC/IRB who were present when the protocol 
was reviewed and approved, including their titles/occupations and institutional affiliations 
should be provided where possible by the Investigator to Premier Research prior to study 
initiation. The Investigator will make all attempts to ensure that the IEC/IRB is constituted 
and operates in accordance with the ICH-GCP and any local regulations.  
The Investigator will submit any protocol amendments to the IEC/IRB (and other local 
authorities, according to local regulations) prior to implementation.  
The Investigator will submit required progress reports to the IEC/IRB that approved the 
protocol at least annually, as well as report any SAEs, life-threatening problems or deaths, 
to comply with ICH-GCP. The Investigator must inform the IEC/IRB of the termination of 
the study.   
14.2 Regulatory Body Approval 
The study will not be started until the sponsor has received approval from relevant 
regulatory bodies. The sponsor will provide the Investigator with a copy of the relevant 
document.  
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14.3 Informed Consent and Screening Data 
Any changes requested by the IEC/IRB must be approved by the IEC/IRB prior to the 
documents being used. A copy of the final, IEC/IRB-approved consent form must be 
submitted to Premier Research prior to initiation of this study.  
Written informed consent will be obtained from each patient prior to inclusion in the trial, 
and prior to any study-related assessments are performed.  
14.3.1 Confidentiality 
Participant confidentiality and privacy is strictly held in trust by the participating 
investigators, their staff, and the sponsor and their representatives. This confidentiality is 
extended to cover testing of biological samples and genetic tests in addition to the clinical 
information relating to participants. Therefore, the study protocol, documentation, data, 
and all other information generated will be held in strict confidence. No information 
concerning the study or the data will be released to any unauthorized third party without 
prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of 
the IRB, regulatory agencies, or companies supplying study product may inspect all 
documents and records required to be maintained by the investigator, including, but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
participants in this study. The clinical study sites will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept 
in a secure location for as long a period as dictated by the reviewing IRB, institutional 
policies, or sponsor requirements. 
Study participant research data for purposes of statistical analysis and scientific reporting 
will be transmitted to and stored at Premier Research and the University of Rochester. 
This will not include the participant’s contact or identifying information. Rather, individual 
participants and their research data will be identified by a unique study identification 
number. The study data entry and study management systems used by clinical sites and 
by Premier Research and University of Rochester staff will be secured and password 
protected. At the end of the study, all study databases will be de-identified and archived. 
The Investigator must ensure that the patients’ anonymity will be maintained. 
The Investigator should keep a separate log (Patient Master List) of patient’s codes 
(assigned patient number), names, addresses, telephone numbers and hospital numbers 
(if applicable). Documents not for submission to the sponsor (e.g. signed informed 
consent forms) should be maintained by the Investigator in strict confidence.  
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14.3.2 Staff Information and Responsibilities 
It is the responsibility of the local site Investigator to ensure that all personnel involved in 
the study are fully informed of all relevant aspects of the study, including detailed 
knowledge of and training in all procedures to be followed to allow collection of accurate, 
consistent, complete and reliable data.  
The local site Investigator will provide a list of delegated responsibility to Premier 
Research, detailing the various study tasks to be performed by each member of his/her 
study staff. Each staff member should sign in agreement to their performing each of the 
tasks delegated to them on the list. The local site Investigator should ensure that the staff 
have the required knowledge and training for the tasks delegated to them.  
14.3.3 Essential Document Retention 
All clinical information shall be recorded, handled and stored in such a way that it can be 
accurately reported, interpreted and verified, while ensuring confidentiality of the trial 
patients’ personal data. Documents that enable both the conduct of the clinical trial and 
the quality of the data produced to be evaluated; and show whether the trial is, or has 
been, conducted in accordance with ICH-GCP and applicable regulatory requirements 
are considered essential documents. 
The Investigator will retain copies of all the essential documents (as defined by ICH-GCP) 
until at least 2 years after the last approval of a marketing application in an ICH region, 
and until there are no pending or contemplated marketing applications in an ICH region, 
or at least 2 years have elapsed since the formal discontinuation of clinical development 
of the IMP. The period of document retention is, however, also dependent on the 
applicable regulatory requirements (e.g. EEC Directive 91/507 requires retention of 
patient codes for at least 15 years after the completion or discontinuation of a trial and 
retention of hospital records and other source data for the maximum time permitted by 
the institution where the study takes place). The Investigator should take measures to 
prevent accidental or premature destruction of these documents.  
The essential documents include: the signed protocol, copies of the completed CRFs, 
hospital records and other source documents, IEC/IRB approval and all related 
correspondence, including approved documents, and all other documentation included in 
the Investigator site file.  
The Investigator will inform the Sponsor of the storage location of these essential 
documents and must contact the Sponsor before disposing of any. If the Investigator 
wishes to assign the files to someone else (e.g. if he/she retires) or to remove them to 
another location, the Sponsor Project Manager should be consulted about this change.  
The Sponsor will inform the Investigator in writing when these documents no longer need 
to be retained. 
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14.4 Data Handling and Record Keeping 
14.4.1 Data Collection and Management Responsibilities 
Data will be collected and entered into an electronic data capture system (Datalabs) 
provided by Premier Research Inc. Datalabs is a web-based 21 CRF Part 11-compliant 
database system which will be customized specifically for this clinical trial. Premier 
Research will be responsible for managing the database. Drug dispensing logs will be 
kept to record the total amount of medication received from and returned to the site. 
Completed informed consent forms from each subject will be available in the subject’s file 
and verified for proper documentation.  
Data collection is the responsibility of the clinical trial staff at the site under the supervision 
of the local site PI. The investigator is responsible for ensuring the accuracy, 
completeness, legibility, and the timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. Black or blue ink is required to ensure clarity of reproduced copies. 
When making changes or corrections, cross out the original entry with a single line, and 
initial and date the change. DO NOT ERASE, OVERWRITE, OR USE CORRECTION 
FLUID OR TAPE ON THE ORIGINAL. 
Source documents will be stored at each of the clinical sites in double locked storage. 
Data reported in the CRF derived from source documents should be consistent with the 
source documents or the discrepancies should be explained and captured in a progress 
note and maintained in the participant’s official study record. 
Clinical data (including AEs, concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into Datalabs. The data system includes 
password protection and internal quality checks, such as automatic range checks, to 
identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be 
entered directly from the source documents.  
The site investigators will be responsible for insuring that all blank data spaces on each 
CRF are filled in. The Premier DM group will notify each investigator of any missing or 
inconsistent data. All completed CRFs are to be reviewed by the site investigator.  
14.4.2 Protocol Adherence 
The study PI will work closely with PIs at all other sites to ensure adherence of the protocol 
by the study sites and study data integrity. The Sponsor PI will be responsible for 
communicating with all sites to ensure smooth conduct of the study and prompt data 
submission. The PI will coordinate e-mail and conference call communications and work 
with the data coordinator to prepare monthly reports from each site indicating the status 
of the study and problems that might arise. Serious adverse events will be reported 
immediately to the Sponsor PI and reviewed promptly by the medical safety monitor. 
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Based upon our previous experience in managing multicenter studies of neuromuscular 
disorders at KUMC, we will again assemble a communications and computing 
infrastructure and technical staff to ensure the success of this study. We will use 
strategies for intra- and inter-site communication, data entry, storage, management, and 
analysis similar to those we have previously used and currently use. We will have several 
ways to ensure adequate communication between the data center and the individual 
clinical sites. Telephone, fax, and electronic mail will be the primary modes of inter- and 
intra-site communication for investigators and study staff. The existing infrastructure at 
each site includes sophisticated telephone networks, voice messaging systems, fax 
machines and Ethernet connections to the Internet to support this strategy. All study 
computers at the data center and each of the clinical sites will be password protected, 
and kept in locked offices. The evaluators performing the monthly studies will complete a 
CRF after each visit. The PI/study coordinator will be responsible for dispensing and 
accounting for all study medication. The PI at each study site is responsible for all aspects 
of the study at the site. The investigator agrees to cooperate fully with monitors.  
14.4.3 Data Storage and Backup 
Data backup, restore and security will be handled as per Premier Research’s Data 
Management Plan 
14.4.4 Study Records Retention 
Study records must be retained for 5 years after the close of the study or until the drug is 
approved for two years by the FDA. 
14.4.5 Protocol Deviations  
The trial must be conducted in accordance with: 
• The protocol;
• Applicable regulatory requirement(s) or conditions linked to the approval(s) of the
study;
• Applicable IEC/IRB requirement or conditions linked to the approval(s) of the study;
• Any particulars or documents, other than the protocol, accompanying the regulatory
or IEC/IRB request or that application.
Protocol waivers will not be granted. Any amendment(s) to the protocol must be approved 
by both Orphazyme A/S and the IEC/IRB which granted the original approval of the study 
prior to their implementation (unless only logistical or administrative aspects of the trial 
are involved). All substantial amendments to the protocol must be approved by the 
applicable regulatory bodies prior to their implementation.  
However, in the event of any medical emergency, the Investigator is free to institute any 
medical procedure he/she deems appropriate. Such events and procedures must be 
promptly reported to the Orphazyme A/S representatives. 
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15 STUDY ADMINISTRATION 
15.1 Study Leadership 
A Scientific Steering Committee will govern the conduct of the study and provide scientific 
direction. The Steering Committee composition is given in protocol section 2. The 
Steering Committee will meet and act according to the Steering Committee Charter. 
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16 CONFLICT OF INTEREST POLICY 
Any actual conflict of interest of persons who have a role in the design, conduct, analysis, 
publication or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts 
managed in a way that is appropriate to their participation in the trial. The study leadership 
in conjunction with the FDA-OPD has established policies and procedures for all study 
group members to disclose all conflicts of interest and will establish a mechanism for the 
management of all reported dualities of interest.  
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17 CORONAVIRUS (COVID) OPERATIONAL CHANGES 
The document (COVID-19) Addendum 1.0 dated 24-Mar-2020 shall remain in effect with this 
Clinical Trial Protocol. The Addendum to the Clinical Trial Protocol is designed to mitigate the 
operational impact resulting from COVID-19, and shall only be applied as an interim solution 
during the period that normal Clinical Trial Protocol logistics cannot be adhered to. Once 
containment measures have ceased and operations return to normal on both a site and subject 
level, procedures will resume as per the site’s currently approved Clinical Trial Protocol.  
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18 LITERATURE REFERENCES 
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31. Salajegheh M, Pinkus JL, Taylor JP, et al. Sarcoplasmic redistribution of nuclear
TDP-43 in inclusion body myositis. Muscle Nerve 2009;40(1):19–31
32. Subourg O, Wanschitz J, Maisonobe T, et al. Diagnositic value of markers of
muscule degeneration in sporadic inclusion body myositis. Acta Myol. 2011
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Arimoclomol 
Module   5.3.5.1: Phase 2/3 Study of Arimoclomol in IBM 
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08 JUN 2020 
33. Askanas V, Engel WK. Molecular Pathology and Pathogenesis of Inclusion-Body
Myositis. Microscopy Research and Technique. 2005; 67: 114-120.
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degenerative muscle disease associated with aging, impaired muscle protein
homeostasis and abnormal mitophagy. Biochim Biophys Acta. 2015; Apr
1852(4):633-43.
35. Askanas V, Engel WK. Inclusion-bodymyositis: amyodegenerative conformational
disorder associated with Abeta, protein misfolding, and proteasome inhibition.
Neurology 2006;66(2, Suppl 1):S39–S48.
36. Ozturk A, McFerrin J, Engel WK, Askanas V. HSP70 chaperone machinery in
sporadic inclusion-body myositis muscle fibers. Neurology. 2004; 62: 168.
37. Fratta P, Engel WK, McFerrin J, Davies KJA, Lin SW, Askanas V. Proteosome
inhibition and aggresome formation in sporadic inclusion-body myositis and in
amyloid-B precursor protein-overexpressing cultured human muscle fibers. Am J
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38. Engel WK, and Askanas, V. Inclusion-body myositis: Clinical, diagnostic, and
pathologic aspects. Neurology. 2006; 66(Suppl 1): S20-S29.
39. Forloni G, Terreni L, Bertani I et al. Protein misfolding in Alzheimer's and
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40. Hartl F, Hayer-Hartl M. Molecular chaperones in the cytosol: from nacent chain to
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41. Sherman MY, Goldberg AL. Cellular defenses against unfolded proteins: a cell
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42. Kieran D, Kalmar B, Dick JR et al. Treatment with Arimoclomol, a coinducer of heat
shock proteins, delays disease progression in ALS mice. Nat Med. 2004;10:402-
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43. Morrow JM, Ramdharry GR, Machado P, Burns T, Amato A, Barohn R, Phillips L,
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44. Jackson CE, Barohn RJ, Gronseth G, Pandya S, Herbelin L; Muscle Study Group.
Inclusion body myositis functional rating scale: a reliable and valid measure of
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45. Rohn TT. Caspase-cleaved TAR DNA-binding protein-43 is a major pathological
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Arimoclomol 
Module   5.3.5.1: Phase 2/3 Study of Arimoclomol in IBM 
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47. Feinstein DL, Galea E, Aquino DA, Li GC, Xu H, Reis DJ. Heat shock protein 70
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body myositis: treatment with intravenous immunoglobulin. Neurol 1994; 44(8):
1516-1518.
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study of intravenous immunoglobulin combined with prednisone in the treatment
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Rheumatol Rep 2013; 15(5): 329.
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Group (MSG).   Inclusion body myositis functional rating scale.  Neurology 2007;68
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52. Lowes LP, Alfano L, Viollet L, Rosales XQ, Sahenk Z, Kaspar BK, Clark KR,
Flanigan KM, Mendell JR, McDermott MP. Knee extensor strength exhibits
potential to predict function in sporadic inclusion-body myositis.Muscle Nerve.
2012 Feb;45(2):163-8.
53. Salajegheh M, Lam T, Greenberg SA. Autoantibodies against a 43 KDa muscle
protein in inclusion body myositis. PLoS One. 2011; 6(5):e20266
54. Benjamin Larman H, Salajegheh M, Nazareno R, Lam T, Sauld J, Steen H, et al.
Cytosolic 5'-nucleotidase 1A autoimmunity in sporadic inclusion body myositis.
Ann Neurol. 2013 Mar; 73(3):408-418.
55. Pluk H, van Hoeve BJ, van Dooren SH, Stammen-Vogelzangs J, van der Heijden
A, Schelhaas HJ, et al. Autoantibodies to cytosolic 5'-nucleotidase 1A in inclusion
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58. Fries JF, Spitz PW, et al. The dimensions of health outcomes: the health
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59. Molenberghs G, Thijs H, Jansen I, Beunckens C, Kenward MG, Mallincdrodt C,
Carroll RJ. Analyzing incomplete longitudinal clinical trial data. Biostatistics 2004;
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60. Cox FM, Titulaer MJ, Sont JK, et al. A 12-year follow-up in sporadic inclusion body
myositis: An end stage with major disabilities. Brain 2011;134(11):3167–75.
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, M.D. (KUMC) 
Arimoclomol 
Module   5.3.5.1: Phase 2/3 Study of Arimoclomol in IBM 
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61. Price MA, Barghout V, Benveniste O, et al. Mortality and causes of death in
patients with sporadic inclusion body myositis: Survey study based on the clinical
experience of specialists in Australia, Europe and the USA. J Neuromuscul Dis.
2016;Mar 3;3(1):67-75.
62. Lilleker JB, Rietveld A, Pye SR, et al.Cytosolic 5'-nucleotidase 1A autoantibody
profile and clinical characteristics in inclusion body myositis. Ann Rheum Dis.
2017;Jan 25. pii: annrheumdis-2016-210282. doi: 10.1136/annrheumdis-2016-
210282 [Epub ahead of print].
63. Carpenter JR, Roger JH, Kenward MG.  Analysis of longitudinal trials with protocol
deviation: a framework for relevant, accessible assumptions and inference via
multiple imputation.  J Biopharm Statist 2013; 23:1352-1371.
64. FDA Guidance for Industry on Drug-Induced Liver Injury: Premarketing Clinical
Evaluation, July 2009
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, M.D. (KUMC) 
Arimoclomol 
Module   5.3.5.1: Phase 2/3 Study of Arimoclomol in IBM 
Page 94 
08 JUN 2020 
APPENDIX 1: EUROPEAN NEUROMUSCULAR CENTRE INCLUSION 
European Neuromuscular Centre Inclusion Body Myositis research diagnostic criteria 
2011 
Diagnostic sub-group 
Clinico-
pathologically 
defined IBM 
Clinically 
defined IBM 
Probable 
IBM 
Clinical features 
Duration of weakness > 12 
months 
X 
X 
X 
Age at onset > 45 years 
X 
X 
X 
Creatine kinase ≤ 15x ULN 
X 
X 
X 
FF weakness > SA weakness 
AND/OR KE weakness ≥ HF 
weakness 
X 
- 
- 
FF weakness > SA weakness 
 AND KE weakness ≥ HF 
weakness 
- 
X 
- 
FF weakness > SA weakness 
 OR KE weakness ≥ HF 
weakness 
- 
- 
X 
Pathological features 
Endomysial inflammatory 
infiltrate 
X 
≥1, but not all 
of the 4 
pathological 
features 
≥1, but not all 
of the 4 
pathological 
features 
Rimmed vacuoles 
X 
Protein accumulation* or 15-
18nm filaments 
X 
Up-regulation of MHC Class I 
- 
*Demonstration of amyloid or other protein accumulation by established methods (e.g.
for amyloid Congo red, crystal violet, thioflavin T/S, for other proteins p62, SMI-31, TDP-
43). FF, Finger flexion; HF, Hip flexion; KE, Knee extension; SA, Shoulder abduction;
MHC Class I, Major histocompatibility complex class I; ULN = Upper limit of normal.
CONFIDENTIAL


, M.D. (KUMC) 
Arimoclomol 
Module   5.3.5.1: Phase 2/3 Study of Arimoclomol in IBM 
Page 95 
08 JUN 2020 
APPENDIX 2: IBM FUNCTIONAL RATING SCALE 
1. SWALLOWING
4 Normal
3 Early eating
problems – 
occasional 
choking 
 2 Dietary 
consistency 
changes 
 1 Frequent choking 
 0 Needs tube 
feeding 
2. HANDWRITING
(with dominant
hand prior to IBM
onset)
4 Normal
3 Slow or sloppy; all
words are legible
2 Not all words are
legible
1 Able to grip pen
but unable to 
write 
 0 Unable to grip 
pen 
3. CUTTING FOOD
AND HANDLING
UTENSILS
4 Normal
3 Somewhat slow
and clumsy, but 
no help needed 
 2 Can cut most 
foods, although 
clumsy & slow; 
some help 
needed 
 1 Food must be cut 
by someone but 
can still feed 
slowly 
 0 Needs to be fed 
4. FINE MOTOR TASKS
(opening doors, using
keys, picking up small
objects)
 4 Independent 
 3 Slow or clumsy in  
completing task 
 2 Independent but requires 
modified techniques or 
assistive devices 
 1 Frequently requires 
assistance from 
caregiver 
 0 Unable 
5. DRESSING
4 Normal
3 Independent but with
increased effort or 
decreased efficiency 
 2 Independent but requires 
assistive devices or 
modified techniques 
(Velcro snaps, shirts 
without buttons, etc.) 
 1 Requires assistance from 
caregiver for some 
clothing items 
 0 Total dependence 
6. HYGIENE (Bathing and
toileting)
 4 Normal 
 3 Independent but with 
increased effort or 
decreased activity 
 2 Independent but requires 
use of assistive devices 
(shower chair, raised toilet 
seat, etc.) 
 1 Requires occasional 
assistance from caregiver 
 0 Completely dependent  
7. TURNING IN BED &
ADJUSTING COVERS
4 Normal
3 Somewhat slow & clumsy
but no help needed
2 Can turn alone or adjust
sheets but with great 
difficulty 
 1 Can initiate but not turn 
or adjust sheets alone 
 0 Unable or requires total 
assistance 
8. SIT TO STAND
4 Independent (without use
of arms)
3 Performs with substitute
motions (leaning forward, 
rocking) but without use 
of arms) 
 2 Requires use of arms 
 1 Requires assistance from 
device/person 
 0 Unable to stand 
9. WALKING
4 Normal
3 Slow or mild
unsteadiness
2 Intermittent use of
assistive device (AFO, 
cane, walker) 
 1 Dependent on assistive 
device 
 0 Wheelchair dependent 
10. CLIMBING STAIRS
4 normal
3 Slow with hesitation or
increased effort; uses 
handrail intermittently 
  2 Dependent on handrail 
  1 Dependent on handrail 
and additional support 
(cane or person) 
  0 Cannot climb stairs 
CONFIDENTIAL


, M.D. (KUMC) 
Arimoclomol 
Module 5.3.5.1: Phase 2/3 Study of Arimoclomol in IBM 
APPENDIX 3: - SUB-STUDY 
This was an exploratory sub-study and the details are not relevant for the primary or
secondary endpoints and therefore not included here.
Page 96 
08JUN2020 
CONFIDENTIAL


Protocol number: IBM4809 
Date: 23-Sep-2020 
Version: Final 1.0 
Addendum 1.0 to 
Clinical Trial Protocol v9.0 dated 08-Jun-2020 
Phase 2/3 Study of Arimoclomol in Inclusion Body 
Myositis (IBM) 
A Randomized, Double-blind, Placebo-Controlled Trial
Sponsor: Orphazyme A/S, Ole Maaløes Vej 3, DK-2200 Copenhagen N, Denmark 
International Coordinating investigator: 
, MD, Professor of 
Neurology 
Protocol number: IBM4809 
EudraCT No.: 2017-004903-33 
ClinicalTrials.gov Identifier: NCT02753530
Trial product name: Arimoclomol Capsules 
Date of Addendum: 23-Sep-2020 
The trial will be conducted according to the protocol and in compliance with Good Clinical Practice (GCP), with the 
Declaration of Helsinki and with other applicable regulatory requirements 
Orphazyme A/S - Strictly Confidential 
(IB, CYP2D6 DDI) Addendum 1.0 to CTPv9.0, dated 23-Sep-2020 
Page 1 of 6 
This document contains information which is the property of KemPharm Denmark A/S and 
is provided here as part of the results registration on clinicaltrials.gov. It is understood that 
this information cannot and will not be disclosed to others without written approval from 
KemPharm Denmark A/S.


Protocol number: IBM4809 
Date: 23-Sep-2020 
Version: Final 1.0 
Orphazyme A/S - Strictly Confidential 
(IB, CYP2D6 DDI) Addendum 1.0 to CTPv9.0, dated 23-Sep-2020 
Page 2 of 6 
Contents 
Acknowledgement Statement Investigators ..................................................... Error! Bookmark not defined.
Justification for Addendum ............................................................................................................................ 3
Modification to the Clinical Trial Protocol due to update of Investigator Brochure version 4.0 dated 
15-SEP-2020 ..................................................................................................................................................... 4


Protocol number: IBM4809 
Date: 23-Sep-2020 
Version: Final 1.0 
Orphazyme A/S - Strictly Confidential 
(IB, CYP2D6 DDI) Addendum 1.0 to CTPv9.0, dated 23-Sep-2020 
Page 3 of 6 
Justification for Addendum 
Results from an in vitro study showed that arimoclomol is a direct inhibitor of CYP2D6 with an IC50 of190 
µM which is > 25 times higher than clinical exposure (Cmax) 
The investigator’s Brochure was previously updated with these findings and correspondingly the Clinical 
trial Protocol (CTP) was updated to indicate that concomitant treatment with CYP2D6 substrates should be 
done with caution (since their exposure could increase as a result of their metabolism being inhibited). 
By using mechanistic static modelling, instead of basic equations, it has since been evaluated that the in vitro  
CYP2D6 inhibition is not clinically relevant. These findings have been included in the annual update of the 
Investigator’s Brochure and the updated guidance on use of concomitant medications are included in this 
CTP addendum. 
The changes described are done to ensure continued safety and well-being of the subjects and the integrity of 
the clinical trial. A sponsor risk assessment has concluded that the changes in this addendum are not likely to 
affect the safety and well-being of the participants or the scientific value of the trial. Therefore, the Sponsor 
confirms that the benefit-risk evaluation for arimoclomol in IBM is not changed. 







SAP_001.pdf: 
Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 1 of 51
Sponsor:
Orphazyme A/S
Protocol Title:
Phase 2/3 Study of Arimoclomol in Inclusion Body Myositis 
(IBM) A Randomized, Double-blind, Placebo-Controlled Trial
Protocol Number:
IBM4809 
Premier Research PCN:
ORPA177146
Document Version:
FINAL Version 1.0
Document Date: 
02 March 2021
Approvals 
Role
Signatures
Date
Biostatistician
Print Name:
Sign Name:
Peer Reviewer
Print Name: 
Sign Name:
Orphazyme A/S 
Print Name: 
Sign Name:
		

		
		

Page 2 of 52
ClinicalTrials.gov Identifier: NCT02753530
This document contains information which is the property of KemPharm Denmark A/S and is provided 
here as part of the results registration on clinicaltrials.gov. It is understood that this information cannot 
and will not be disclosed to others without written approval from KemPharm Denmark A/S.
CONFIDENTIAL


Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 2 of 51
Document History
Not applicable 
Page 3 of 52
CONFIDENTIAL


Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 3 of 51
Table of Contents
Approvals...................................................................................................................................1
Document History......................................................................................................................2
Table of Contents.......................................................................................................................3
List of Tables .............................................................................................................................6
List of Figures............................................................................................................................6
Notification on Arimoclomol Strength......................................................................................6
1.
Trial Objectives and Endpoints......................................................................................7
1.1.
Trial Objectives........................................................................................................7
1.1.1. Primary Objective ....................................................................................................7
1.1.2. Safety Objectives .....................................................................................................7
1.2.
Trial Endpoints.........................................................................................................7
1.2.1. Efficacy Endpoints...................................................................................................7
1.2.2. Safety Endpoints......................................................................................................8
1.2.3. Exploratory Endpoints .............................................................................................8
1.2.4. Pharmacokinetic/Pharmacodynamic Variable(s).....................................................8
2.
Overview........................................................................................................................9
3.
Estimands.....................................................................................................................10
3.1.
The Primary Estimand (Treatment Policy)............................................................10
3.2.
The Secondary Estimand (Hypothetical)...............................................................10
4.
Overall Trial Design and Plan......................................................................................11
4.1.
Overall Design .......................................................................................................11
4.2.
Sample Size and Power..........................................................................................11
4.3.
Trial Population .....................................................................................................11
4.4.
Treatments Administered.......................................................................................12
4.5.
Method of Assigning Patients to Treatment Groups..............................................12
4.6.
Blinding and Unblinding........................................................................................12
4.6.1. Breaking the Trial Blind/Participant Code ............................................................12
4.6.2. Unblinding for Data Monitoring Committee.........................................................12
4.7.
Schedule of Events.................................................................................................12
5.
Statistical Analysis and Reporting...............................................................................14
5.1.
Introduction............................................................................................................14
6.
Analysis Populations & Treatment Durations .............................................................15
6.1.
Analysis Populations..............................................................................................15
6.2.
Observation Periods...............................................................................................15
7.
Statistical Analysis.......................................................................................................17
7.1.
Baseline..................................................................................................................17
Page 4 of 52
CONFIDENTIAL


Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 4 of 51
7.2.
Adjustments for Covariates....................................................................................17
7.3.
Analysis Visit Windows ........................................................................................17
7.4.
Multiple Comparisons............................................................................................20
7.5.
Analysis of Primary Endpoint................................................................................20
7.5.1. Analysis of Primary Estimand (Treatment Policy)................................................20
7.5.2. Analyses of Secondary Estimand (Hypothetical) ..................................................27
7.5.3. Sub-Group Analysis of IBMFRS...........................................................................27
7.5.4. Explorative Analyses of IBMFRS .........................................................................27
7.6.
Analyses of Secondary Endpoints .........................................................................28
7.6.1. Confirmatory Secondary Endpoints.......................................................................28
7.6.2. Other Secondary Endpoints ...................................................................................29
7.7.
Derived Variables ..................................................................................................32
7.8.
Data Adjustments/Handling/Conventions .............................................................32
8.
Trial Patients and Demographics.................................................................................34
8.1.
Disposition of Patients and Withdrawals...............................................................34
8.2.
Protocol Violations and Deviations .......................................................................34
8.3.
Demographics and Other Baseline Characteristics................................................34
8.4.
Exposure and Compliance .....................................................................................34
8.4.1. Exposure ................................................................................................................34
8.4.2. Calculation of capsules taken.................................................................................35
8.4.3. Dose de-escalation .................................................................................................35
8.4.4. Compliance ............................................................................................................36
9.
Safety and Tolerability Analysis..................................................................................37
9.1.
Adverse Events ......................................................................................................37
9.2.
Adverse Events Leading to Withdrawal ................................................................37
9.3.
Deaths and Other Serious Adverse Events ............................................................38
9.4.
Clinical Laboratory Evaluations ............................................................................38
9.5.
Vital Signs..............................................................................................................40
9.6.
Electrocardiograms ................................................................................................40
9.7.
Physical examination results..................................................................................40
9.8.
Columbia Suicide Severity Rating Scale (C-SSRS)..............................................40
9.9.
Concomitant Medication........................................................................................41
10.
Changes from Planned Analysis and clarifications .....................................................42
11.
Other Planned Analysis................................................................................................43
11.1.
Pharmacokinetic Analysis......................................................................................43
12.
References....................................................................................................................44
13.
Tables, Listings, and Figures .......................................................................................45
Page 5 of 52
CONFIDENTIAL


Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 5 of 51
Appendix 1: Abbreviations List...............................................................................................46
Appendix 2: List of Concomitant Medications........................................................................50
Appendix 3: Overview of estimands and sensitivity analyses.................................................51
Page 6 of 52
CONFIDENTIAL


Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 6 of 51
List of Tables
Table 1: Schedule of Events ......................................................................................................... 13
Table 2: Window bounds for scheduled IBMFRS assessments (visits 2 to 14)........................... 18
Table 3: Window bounds for ECG scheduled assessments (visits 2, 10 and 14)......................... 19
Table 4: Window bounds for scheduled assessments pattern at visits 2, 6, 8, 12 and 14............. 19
Table 5: Window bounds for scheduled assessments pattern at visits 2, 3, 4, 5, 6, 6a, 8, 10 12 and 
14........................................................................................................................................... 19
Table 6: Window bounds for scheduled assessments pattern at visits 2, 3, 4, 6, 8, 10 12 and 14 20
List of Figures
N/A.
Notification on Arimoclomol Strength
The dose of arimoclomol is expressed as the base strength throughout this document, whereas in 
the protocol, the dose is expressed as the citrate salt. This implies, that the dose of 1200 mg 
arimoclomol citrate stated in the protocol is represented as 744 mg arimoclomol free base in this 
document.
The comparison of base strength to citrate salt for various doses which are commonly referred to,
is as follows:

62 mg arimoclomol (equivalent to 100 mg arimoclomol citrate)

124 mg arimoclomol (equivalent to 200 mg arimoclomol citrate)

248 mg arimoclomol (equivalent to 400 mg arimoclomol citrate)

744 mg arimoclomol (equivalent to 1200 mg arimoclomol citrate)
Reporting of results from trial IBM4809 will be done using the arimoclomol free base strengths. 
Page 7 of 52
CONFIDENTIAL


Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
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1.
Trial Objectives and Endpoints
1.1.
Trial Objectives
1.1.1.
Primary Objective
The primary objective is to evaluate the efficacy of arimoclomol at a daily dosage of 744 mg/day 
(248 mg t.i.d) compared to placebo in the treatment of sporadic IBM at 20 months.
1.1.2.
Safety Objectives
The safety objective is to evaluate the safety and tolerability of arimoclomol at a daily dosage of 
744 mg/day (248 mg t.i.d.) compared to placebo in the treatment of IBM over 20 months.
1.2.
Trial Endpoints
1.2.1. Efficacy Endpoints
1.2.1.1. Primary Efficacy Endpoint
The primary efficacy endpoint of this trial is the change from baseline to Month 20 in the 
Inclusion Body Myositis Functional Rating Scale (IBMFRS) total score. 
1.2.1.2. Secondary Efficacy Endpoints
1.2.1.2.1 Confirmatory secondary endpoints
Change from baseline to Month 20 in:
1.
Grip Strength using the Jamar device
2.
Modified Timed Up and Go (mTUG)*
3.
Manual Muscle Testing (MMT) total score
4.
6 Minutes Walking distance test; distance at 6 minutes (6MWD)
5.
SF-36 – Physical component
* The mTUG parameter is analysed through its reciprocal value, multiplied by the planned total
distance of 6 meter. This corresponds to analysing the velocity of the walking speed expressed in
meters per seconds (m/s), including the time spent for standing up and sitting down again.
1.2.1.2.2 Other secondary endpoints
Change from baseline to Month 12 and Month 20 in:
6.
Isometric Contraction Testing of bilateral quadriceps strength using the MicroFET
7.
Health Assessment Questionnaire (HAQ- DI)
8.
2 Minutes Walking distance test; distance at 2 minutes (2MWD)
Page 8 of 52
CONFIDENTIAL


Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 8 of 51
9.
SF-36 – Mental component
10. Patient Global Impression of Severity (PGI-S)
11. Patient Global Impression of Change (PGI-C)
12. Clinician Global Impression of Severity (CGI-S)
13. Clinician Global Impression of Change (CGI-C)
Accumulated number since baseline of:
14. Falls
15. Near falls
For IBMFRS and the parameters listed under confirmatory endpoints, the change from baseline 
to Month 12 are also secondary endpoints.
1.2.2. Safety Endpoints
The safety endpoints of this trial include the following:
16. Adverse events (AEs)
17. Haematology
18. Clinical chemistry
19. Vital signs
20. Columbia Suicide Severity Rating Scale (C-SSRS)
1.2.3. Exploratory Endpoints
The exploratory endpoints of this trial include the following:
21. Presence of
22.
 (sub-trial in selected sites only; in a subset of patients [see 
Appendix 3 of the protocol])*
23. IBMFRS sum over the 5 upper limb domain items (2, 3, 4, 5, 6)
24. IBMFRS sum over the 4 lower limb domain: items (7, 8, 9, 10)
25. IBMFRS sum over the 9 limb items, excluding swallowing.
* Analysis details
will be described in a separate SAP to the extent that they are not 
covered by the exhaustive description in the Appendix 3 of the protocol. 
1.2.4. Pharmacokinetic/Pharmacodynamic Variable(s)
The pharmacokinetic (PK) endpoints of the trial constitutes arimoclomol plasma concentrations.
The calculation of parameters for population PK analysis will be described in a separate PK 
analysis plan (PKAP).
Page 9 of 52
CONFIDENTIAL


Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 9 of 51
2.
Overview
This statistical analysis plan (SAP) describes the planned analysis and reporting for Orphazyme 
A/S protocol number IBM4809 (Phase 2/3 Study of Arimoclomol in IBM, A Randomized, 
Double-blind, Placebo-Controlled Trial) and any updates hereof. Reference materials for this 
statistical plan include the protocol and the accompanying sample data collection documents. 
Operational aspects related to collection and timing of planned clinical assessments are not 
repeated in this SAP unless relevant to the planned analysis.
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration (FDA), European Medicines Agency (EMA), 
and International Conference on Harmonization (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical 
Trials (1). All work planned and reported for this SAP will follow internationally accepted 
guidelines, published by the American Statistical Association (2) and the Royal Statistical 
Society (3), for statistical practice.
The planned analyses identified in this SAP may be included in clinical trial reports (CTRs), 
regulatory submissions, or future manuscripts. Also, post-hoc exploratory analyses, not 
necessarily identified in this SAP, may be performed to further examine trial data. Any post-hoc,
or unplanned, exploratory analysis performed will be clearly identified as such in the final CTR.
The statistical plan described hereafter is an a priori plan. It will be finalized and approved prior 
to database lock (DBL), i.e. prior to any unblinded inferential or descriptive analysis of the data 
pertaining to the IBM4809 trial.
Page 10 of 52
CONFIDENTIAL


Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 10 of 51
3.
Estimands
A comprehensive set of estimands and sensitivity analyses is described in the following, and 
further presented on tabular form in Appendix 3.
3.1.
The Primary Estimand (Treatment Policy)
The primary estimand – “Treatment Policy” is defined as follows:

Treatment difference of change from baseline in the IBMFRS instrument’s total score
between arimoclomol and control at 20 months for all randomized patients regardless of
exposure, adherence to randomized treatment and changes in standard of care
The treatment policy estimand assesses the expected benefit on the IBMFRS instrument in a 
future population that results from patients being offered treatment with arimoclomol as add-on 
to standard-of-care as compared to standard-of-care alone.
Generalization of this estimand depends among other things on the extent to which the standard-
of-care provided in this trial reflects clinical practice and whether the adherence to trial product 
administration in this trial reflects the behaviour of the target population. Accordingly, data 
collected regardless of discontinuation of trial product or background therapy will be used to 
draw inference.
In line with the primary estimand, the term “missing data” will be used to cover data that are 
planned to be collected but are not present in the database. This implies that data that are missing 
due to death are considered missing and thus could meaningfully have been collected. The 
premise for using this counterfactual while-alive approach is that deaths are assumed relatively 
rare and unrelated to the disease. Details on how missing data are handled further and imputed 
are detailed in Section 7.
3.2.
The Secondary Estimand (Hypothetical)
The secondary and supportive estimand – “Hypothetical” estimand, is defined as follows:

Treatment difference of change from baseline in the IBMFRS instrument’s total score
between arimoclomol and control at 20 months for all randomized and exposed patients
if all patients adhered to treatment.
The hypothetical estimand assesses the benefit on the IBMFRS instrument that a future 
population would be expected to experience if the patients did not discontinue arimoclomol 
when compared to standard-of-care. It is considered a clinically relevant estimand as it provides 
information to treating clinicians about the expected efficacy of arimoclomol compared to 
standard-of-care for purposes of treating individual patients. Generalization of this estimand 
depends among other things on the extent to which the adherence to trial product administration 
in this trial could reflect the behaviour of the target population. Accordingly, only data collected 
while patients were exposed to trial IMP will be used to draw inference.
Page 11 of 52
CONFIDENTIAL


Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 11 of 51
4.
Overall Trial Design and Plan
4.1.
Overall Design
This is a phase 2/3 randomized, double-blind, placebo-controlled international trial in patients
with IBM followed for 20 months. In this trial there will be two treatment groups:

75 patients receiving arimoclomol 744 mg/day (248 mg t.i.d)

75 patients receiving placebo t.i.d.
There will be approximately 11 sites in the United States and 1 site in the United Kingdom.
Arimoclomol will be administered as 248 mg orally three times a day in this trial. Capsules are 
124 mg so each patient will take 2 capsules three times a day. An interruption of up to 4 weeks 
(calculated from the first day of interruption) is permitted due to AEs. If the patient experiences 
the same intolerable AE after re-challenge with the full dose of IMP, the dose can be reduced to 
half, i.e., 124 mg t.i.d.
 sub-trial is also planned. 
4.2.
Sample Size and Power
The primary outcome variable is the change from baseline to Month 20 in the IBMFRS. In the 
arimoclomol pilot trial, the standard deviation of the 12-month change in IBMFRS was 2.9. The 
mean change in the placebo group was -3.5 and the mean change in the arimoclomol group 
was -2.1. A sample size of 68 patients per group (136 total) will provide 80% power to detect a 
treatment group difference in mean response of 1.4 points, using a two-sample t-test and a 5% 
significance level (two-tailed). To account for an anticipated 10% drop-out rate, the sample size 
will be inflated to 75 participants per group (150 total). Although this calculation strictly applies 
only to a trial with 12-month follow-up, it will also apply to this trial if, as expected, the 
magnitude of the treatment effect relative to the magnitude of the standard deviation of the 
change in IBMFRS score does not diminish over time.
4.3.
Trial Population
Patients with sporadic IBM according to the protocol/meeting the eligibility criteria.
Page 12 of 52
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Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 12 of 51
4.4.
Treatments Administered
In this trial there will be two treatment groups of 75 patients each, i.e., 75 patients receiving 
arimoclomol 744 mg/day (248 mg t.i.d) and the remaining 75 patients receiving placebo.
4.5.
Method of Assigning Patients to Treatment Groups
The randomization schedule was computer generated using a permuted block algorithm which 
randomly associated a treatment to a randomization number. The randomization number was 
then assigned to a patient sequentially. The randomization was thus stratified by centre with the
blocking implemented to provide balance.
The general method for assigning randomized treatment to patients was a telephone-based 
system provided by Telerx Marketing Inc. / C3i Solutions. This system was a help-desk style 
service manned by a call-centre as opposed to an IVRS. Randomization code lists and by site and 
bottle code lists were used in a manual fashion to assign IMP numbers in sequential order. 
Subsequent treatment dispensation was handled in a similar fashion.
For the first 13 randomized patients at the KUMC site 01, the general system was not yet
available, and these patients were assigned to their treatment via RedCap, which is a stand-alone 
web-based application provided by the University of Rochester Data Management Centre.
4.6.
Blinding and Unblinding
4.6.1. Breaking the Trial Blind/Participant Code
Each site will receive documentation to break the randomization code if needed. The investigator 
or pharmacist at the site will have access to the unblinded information for the double-blind 
treatment for each subject via code envelopes.
The investigator may only break the code for a subject if knowledge of the IMP is necessary to 
provide optimal treatment to the subject in an emergency situation. If possible, the investigator 
should consult the Medical Monitor before breaking the code. The investigator must record the 
date, time, and reason for breaking the code on the code envelope and sign it. The patient must 
be immediately withdrawn from IMP and followed up according to Section 6.5 of the protocol.  
4.6.2. Unblinding for Data Monitoring Committee
Periodic safety review by the Data Monitoring Committee will be facilitated by an unblinded 
statistician from Premier not otherwise involved in the trial. The sponsor and all other trial
personnel will remain blinded. See the SAP for the DMC and the DMC charter for further detail.
4.7.
Schedule of Events
A detailed schedule of events for the trial is provided in Table 1 below.
Page 13 of 52
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Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 13 of 51
Table 1: Schedule of Events
Visit #
1
2
3
4
5
6
6a
7
8
9
10
11
12
13
14
15
Month
-1
(Sc)
0 (Base)
1
2
3
4
5
6
8
10
12
14
16
18
20‡
21
Consent
X
Eligibility
X
Medical History
X
IBM History
X
Vital signs, including 
weight
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
X
X
X
X
Safety Labs
X
X
X
X
X
X
X
X
X
X
X
Urine Preg**
X
X
X
X
X
X
X
X
Blood for 
 levels
X
X
X
Blood for biobanking
X
X
X
X
X
POP PK 
X
X
ECG
X
X
X
Randomization
X
Dispensing of Medication
X
X
X
X
X
X
Return of Medication
X
X
X
X
X
X
PGI-S/PGI-C
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
X
Muscle Testing (MMT, 
MVICT)
X
X
X
X
X
X
6 min walk test
X
X
X
X
X
X
SF-36
X
X
X
X
X
X
HAQ-DI
X
X
X
X
X
X
Falls diary
X
X
X
X
X
X
X
X
Grip 
X
X
X
X
X
X
IBMFRS
X
X
X
X
X
X
X
X
X
X
X
X
X
mTUG
X
X
X
X
X
X
CGI-S/CGI-C
X
X
X
X
X
X
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X*
Phone visits are shaded gray.
Note: Visit windows for all visits are ± 7 days relative to baseline.
* only stop dates for ongoing AEs and new SAEs
** = Urine pregnancy prior to dispensing trial medication
‡ = Upon completion of this trial, qualified patients may provide informed consent and enter an open-label extension
trial at the Month 20 visit. Assessments recorded at this visit will also constitute the first assessments of such open-
label extension trial.
Page 14 of 52
CONFIDENTIAL


Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 14 of 51
5.
Statistical Analysis and Reporting
5.1.
Introduction
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations, except for PK parameter estimation, will be performed primarily using 
SAS (release 9.4 or higher). If the use of other software is warranted, the final statistical 
methodology report will detail what software was used for what purposes.
Continuous (quantitative) variable summaries will include the number of patients (n) with 
non-missing values, mean, standard deviation (SD), median, minimum, maximum, quartile 1 and 
quartile 3. 
Categorical (qualitative) variable summaries will include the number of patients (n) with non-
missing values, frequency and percentage of patients who are in the particular category or each 
possible value. In general, the denominator for the percentage calculation will be based upon the 
total number of patients in the relevant analysis population for the treatment groups, unless 
otherwise specified. The denominator for by-visit displays will be the number of patients in the 
relevant analysis population with non-missing data at each visit.
The minimum and maximum will be reported with the same degree of precision (i.e., the same 
number of decimal places) as the observed data. Measures of location (mean and median) will be 
reported to 1 degree of precision more than the observed data and standard deviation (SD) will 
be reported to 2 degrees of precision more than the observed data.
Percentages will be presented to 1 decimal place, unless otherwise specified.
Unless otherwise indicated, all statistical tests will be conducted at the 0.05 significance level 
using 2-tailed tests, and p-values will be reported. Corresponding 95% confidence intervals (CIs) 
will be presented for statistical tests.
Section 7.3 describes rules for deciding which visits/assessments are eligible for which analysis. 
Please note that all data will appear in lists and for analysis non-eligible datapoints will be 
highlighted in the lists.
Page 15 of 52
CONFIDENTIAL


Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 15 of 51
6.
Analysis Populations & Treatment Durations
6.1.
Analysis Populations
The following analysis populations are planned for this trial: 

Intent-To-Treat Population (ITT): The ITT population includes all randomized
patients, except for patients that are randomized in error and do not receive any
investigational medicinal product (IMP). Furthermore, randomized patients not
complying to the inclusion criteria will be excluded from the ITT population. Violations
of exclusion criteria will not lead to exclusion from the ITT population. Patients in the
ITT population will contribute to the evaluation ‘as randomized’. This will be the main
population for all efficacy analyses unless otherwise specified.

Safety Population (SAF): The SAF population includes all patients who receive any
amount of trial medication. Patients in the SAF population will be analysed according to
treatment actually received. This will be the population used for all safety analyses unless
otherwise specified.
o
If a patient receives mixed treatments during the study, then patients will be assigned
to the arimoclomol arm as their actual treatment if they receive at least 1 capsule of
arimoclomol. Otherwise patients will be assigned to the originally randomized arm. If
a placebo patient erroneously receives arimoclomol, adverse events from the date of
the erroneous treatment will be assigned to arimoclomol. Events prior to the given
date will be flagged as non-treatment emergent and further be presented in a separate
listing. Other safety assessments prior to the given data will be flagged as not to be
analysed (having analysis flag ANL0XFL = “”).
6.2.
Observation Periods
Patients and data to be used in an analysis will be selected in a two-step manner.

Firstly, patients will be selected based on the specified analysis set (ITT vs SAF)

Secondly, data points from the selected patients from the first step will be selected based
on the specified observation period
Two observation periods are defined:

In-Trial: This observation period represents the time period where patients are
considered to be randomized and enrolled in the trial, regardless of adherence to trial
protocol. The in-trial period starts at randomization and ends at the date of below
(whichever comes first); (all inclusive):
o
the last direct subject-site contact
o
trial withdrawal for patients who withdraw their informed consent
o
the last subject-investigator contact as defined by the investigator for patients who are
lost to follow-up
Page 16 of 52
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Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 16 of 51
o
death for patients who die before any of the above
Data assessed at the randomization Visit 2 or screening data considered as baseline belongs to 
the in-trial period.

On-Treatment: This observation period represents the time period where patients are
considered treated with IMP. The on-treatment period is a subset of the in-trial period. It
starts at the date of first administration of IMP. The end of the on-treatment period is
defined slightly different for the purpose of the safety and efficacy presentations:
o
Safety endpoints: In order to report safety assessments during IMP interruptions in a
consistent manner relative to assessments after termination of IMP, a patient is
considered to be on-treatment at any time point up to 14 days since the latest
preceding administration of IMP or the end-date for the in-trial period, whichever
comes first. This means that a safety assessment occurring 15 days (or later) within
an IMP interruption period will not be considered to occur on-treatment. The
definition implies that the on-treatment time for a given patient potentially may be
composed by several periods separated by interruption intervals.
o
Efficacy endpoints: The on-treatment evaluation of efficacy endpoints is intended to
reflect an effect that can be attributed as close as possible to a continuous treatment
regimen (i.e. without interruptions that potentially can weaken the effect following an
interruption). For that reason, the on-treatment period used for efficacy evaluation
ends at the first time point where a patient has not administered IMP for 15 days or
more, or at or the end-date for the in-trial period, whichever comes first.
Unless otherwise specified, the primary estimand is associated with analyses on the ITT
population and in-trial period while the secondary estimand is associated with analyses on the 
SAF population and the on-treatment period.
Page 17 of 52
CONFIDENTIAL


Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 17 of 51
7.
Statistical Analysis
7.1.
Baseline
The last observation recorded prior to first dose up to and including visit 2 will be used as the 
baseline value.
7.2.
Adjustments for Covariates
Trial centre will be taken into account by including them in the primary analysis model. In 
addition to sites, baseline of the endpoint under analysis will be included as a covariate in the 
model.
All least square (LS) mean estimates of change from baseline and least square mean estimates of 
absolute values will be reported adjusted according to observed baseline distribution, see Section 
7.5.1.
7.3.
Analysis Visit Windows
The summary and analysis of the trial endpoints by visit is conditioned on each patient 
contributing no more than one observation per visit. As some parameters may have assessments 
occurring very close in time and thus may be attributable to the same planned visit, an algorithm 
whereby maximally 1 (one) is being selected for summary analysis is detailed below: 
Visit windows vary depending on the specific assessment. The visit windows for each 
assessment are shown in Table 2 to Table 5 below.
In the presented tables, the rule for calculating the nominal day (ADY) for a given visit I with a 
given nominal month mi is given as ADY=30∙mi +1. Also as a general rule, the upper bound for 
a visit is the mean of the nominal day of the given visit and the nominal day the next visit i+1
(15∙(m + mi+1)). The lower bound is the upper bound of the preceding visit + 1. As an exception 
from the general rule, windows are restricted by the exception that a window for a given 
parameter cannot exceed +/- 60 days (2 months) and can also not extend beyond the nominal 
time of a neighbouring visit, at which the given parameter is scheduled to be collected
Scheduled assessments will be assigned to the visit at which they are scheduled. If they are 
outside the acceptable windows shown in the tables below, they will be flagged such that they 
are not used in analyses and summary statistics.
Unscheduled visits will be mapped to the appropriate visit depending on which visit window 
they fall within, except for efficacy assessments (for which only scheduled visits will be used for 
windowing, c.f. protocol Section 11.2.4). The final in-person visit is normally scheduled for 
month 20, but may be done earlier for early dropouts. In those cases, the observations at the final 
in-person visit are also mapped to the appropriate visit based on the visit window. If unscheduled 
visits or the final in-person visit do not fall within any visit window, they will be left described 
as "unscheduled".
Page 18 of 52
CONFIDENTIAL


Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 18 of 51
If there is more than one observation per assessment within the same visit window, then the 
observation with the closest day to the nominal day will be selected for analysis and any other 
observations will be disregarded. If 2 observations have the same distance from the nominal day, 
then a scheduled visit will be preferred to an unscheduled visit, and if both observations are of 
the same type, then the earlier visit will be preferred.
7.3.1. Note on Falls and Near Falls
Because falls and near falls represent count data rather than findings at specific points in time, 
falls and near falls will be handled differently. The number of falls reported at each visit since 
the previous visit will be calculated, including any out of window reports of falls between the 
visit and the previous visit. If multiple records are present for a given visit, then a total is 
calculated of all the records since the previous visit. This allows for calculating a simple 
incidence rate of fall events per year in the period between two visits, using as the time period 
the time between the last record of falls for the current visit and the last record of falls for the 
previous visit. The incidence rate will be calculated as the total number of fall events for the visit 
divided by the number of days in the time period multiplied by 365.25. The total incidence rate 
of fall events for the entire study period will be calculated similarly based on the total number of 
fall events during the study and the number of days from baseline until the final assessment of 
falls.
Table 2: Window bounds for scheduled IBMFRS assessments (visits 2 to 14)
Visit
Month
Nominal time
(ady)
Lower bound
(ady)
Upper bound
(ady)
V2
0
1
NA
1
V3
1
31
2
46
V4
2
61
47
76
V5
3
91
77
106
V6
4
121
107
151
V7
6
181
152
211
V8
8
241
212
271
V9
10
301
272
331
V10
12
361
332
391
V11
14
421
392
451
V12
16
481
452
511
V13
18
541
512
571
V14
20
601
572
661
Page 19 of 52
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Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 19 of 51
Table 3: Window bounds for ECG scheduled assessments (visits 2, 10 and 14)
Visit
Month
Nominal time
(ady)
Lower bound
(ady)
Upper bound
(ady)
V2
0
1
NA
1
V10
12
361
301
421
V14
20
601
541
661
Table 4: Window bounds for scheduled assessments pattern at visits 2, 6, 8, 12 and 14
Visit
Month
Nominal time
(ady)
Lower bound
(ady)
Upper bound
(ady)
V2
0
1
NA
1
V6
4
121
61
181
V8
8
241
182
301
V10
12
361
302
421
V12
16
481
422
541
V14
20
601
542
661
Covers the following parameters: MMT, Grip Strength, 2MWD, 6MWD, SF-36, HAQ-DI, MTUG, PGI-S/PGI-C, 
CGI-S, CGI-C.
Table 5: Window bounds for scheduled assessments pattern at visits 2, 3, 4, 5, 6, 6a, 8, 10 12 
and 14
Visit
Month
Nominal time
(ady)
Lower bound
(ady)
Upper bound
(ady)
V2
0
1
NA
1
V3
1
31
2
46
V4
2
61
47
76
V5
3
91
77
106
V6
4
121
107
136
V6a
5
151
137
166
V7
6
181
167
211
V8
8
241
212
301
V10
12
361
302
421
V12
16
481
422
541
V14
20
601
542
661
Covers the following parameters: Physical exams, Safety Labs and C-SSRS.
Page 20 of 52
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Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 20 of 51
Table 6: Window bounds for scheduled assessments pattern at visits 2, 3, 4, 6, 8, 10 12 and 
14
Visit
Month
Nominal time
(ady)
Lower bound
(ady)
Upper bound
(ady)
V2
0
1
NA
1
V3
1
31
2
46
V4
2
61
47
91
V6
4
121
92
211
V8
8
241
212
301
V10
12
361
302
421
V12
16
481
422
541
V14
20
601
542
661
Covers the following parameters: Vital signs, Falls and Near Falls.
7.4.
Multiple Comparisons
The type I error will be controlled by testing the confirmatory secondary endpoints in the 
following hierarchical sequence in so far as the primary endpoint is significant:
1.
Grip Strength
2.
Modified Timed Up and Go (mTUG)
3.
Manual Muscle Testing (MMT) total score
4.
6 Minutes Walking distance test; distance at 6 minutes (6MWD)
5.
SF-36 – physical component
The confirmatory testing will stop at the first endpoint not meeting statistical significance. For 
any endpoints beyond the first one not meeting clinical significance, as well as all other 
secondary endpoints not included in the above list, the calculated p-value will be treated as 
nominal and not indicative of statistical significance.
7.5.
Analysis of Primary Endpoint
7.5.1. Analysis of Primary Estimand (Treatment Policy)
The analyses will be based on the ITT using all observed in-windowed (scheduled) data (see 
Section 7.3) regardless of treatment adherence and use of concomitant medication, i.e. the 
observed in-trial scheduled assessments. The analysis is a Mixed Model for Repeated 
Measurements (MMRM) of the change from baseline. The independent effects included in the 
model are visit interacting with treatment and baseline IBMFRS interacting with visit. Trial 
centre will further be included as a factor.
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Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
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An unstructured covariance matrix for IBMFRS measurements within the same patient will be 
used, hereby assuming that measurements from different subjects are independent. The degrees 
of freedom will be approximated using Satterthwaite’s approximation and the estimation 
procedure will be restricted maximum likelihood. If the ML optimization fails to converge using 
the unstructured covariance matrix, an AR(1) matrix will alternatively be applied, followed by a 
CS structure, if the approach with an AR(1) structure also fails.
The MMRM is a well-established method that accounts for the uncertainty pertaining to missing 
data. The model assumes that data are missing at random (MAR). Under this assumption, the 
statistical behaviour of the missing data can be described by the observed data included in the 
model, thus, observed IBMFRS responses at all visits and the observed effects adjusted for in the 
model.
To ensure the same representative contribution to the baseline distribution from all patients, 
records for each patient from all visits will be included in the analysis, including visits with 
missing values. For dosed patients in the ITT population without post-dose assessments, the 
baseline IBMFRS value will be carried forward as the value at the first planned post dose visit 
(at Month 1).
Consequently, MAR will reflect adherence to trial procedures/participation and not necessarily
adherence to treatment per se. Of note, an analysis based on MAR may attribute benefits to 
patients who withdraw from trial altogether regardless of the reason for discontinuation. By 
assuming MAR but allowing patients to remain under observation while no longer exposed to 
trial IMP means that the primary statistical analysis evaluates effectiveness of arimoclomol, thus 
targeting the primary estimand.
The null hypothesis to be tested is that the mean difference in the primary endpoint between 
arimoclomol and placebo at month 20 is zero. The alternative hypothesis is that it differs from 
zero. 
If the null-hypothesis is rejected (two-sided p-value < 0.05), and if the estimated mean difference 
in the primary endpoint between arimoclomol and placebo is greater than zero, then the primary 
objective of the trial will be confirmed.
The results of the analysis will be tabulated by visit with least squares means (using the observed 
margins option) in each treatment group and at each timepoint, together with their standard error 
and 95% confidence intervals. In addition, the least squares means of the difference between the 
treatment groups at each timepoint will be presented, together with their standard error, 95% 
confidence interval, and p-value as a test of the null hypothesis that the difference is zero.
The results will further be presented graphically by plotting the least squares means in each
treatment group, including also corresponding 95% confidence intervals as error bars, against 
time.
7.5.1.1. COVID-19 issues
As a consequence of the ongoing COVID-19 pandemic in many countries, a number of patients 
will be unable attend some of their in-clinic visits, either due to restrictions imposed by the 
clinics, country regulations or due to safety concerns expressed by the patients themselves.
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Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 22 of 51
To mitigate the otherwise missing information from a cancelled physical visit, a number of such 
missed visits to the clinic have been conducted as remote phone-based visits (and in a few cases 
video-based visits), including e.g. a remote assessment of the IBMFRS score in the same manner 
as is already done for the planned phone visits 9, 11 and 13 in protocol version 9.0 
(corresponding to Month10, 14 and 18).
The primary analysis of the primary MMRM estimand will include remotely collected IBMFRS 
data at visits originally planned in protocol version 9.0 to be conducted in-person at the clinic but 
made as a remote visit. The inclusion of remote data has been substantiated by an independent 
intra-rater reliability study (OR-REL-IBM-01), demonstrating an Intra Class Correlation (ICC) 
higher than 0.90 between in-clinic and phone assessments of IBMFRS (report under 
preparation).
A sensitivity analysis will be conducted, excluding such remote data from the analysis. In all 
MMRM analyses, data from visits that were intended to be conducted remotely protocol version 
9.0 (months 10, 14, and 18) will be excluded. An additional sensitivity analysis will be made, 
including all data, irrespectively of visit type (i.e. remotely or not remotely).
As a special potentially complicating issue, a high ratio of patients not attending a particular visit 
due to COVID-19 may cause failure of the MMRM analysis to converge. Based on the blinded 
data, this could be an issue for Visit 12 (Month 16). If that turns out to be the case, all data from 
the Month 16 visit will be excluded from the primary MMRM analysis of the primary estimand, 
if the convergence is not achieved after simplifying the covariance structure as outlined 
previously in Section 7.5.1.
The use of remote assessments in the main analysis will also be implemented for secondary 
endpoints that have been collected at such remotely conducted visits (SF-36, HAQ, PGI-S and 
PGI-C).
7.5.2. Sensitivity Analyses of the Primary Estimand
To investigate the sensitivity of the primary analysis results, complementary and separate 
analyses will be performed for the primary estimand. In line with European Medicines Agency
(7) recommendations and with a report from the US National Research Council (9), these
analyses will primarily evaluate the sensitivity of the results due to the impact of missing data.
The following sensitivity analyses will be carried out for the IBMFRS total score.
7.5.2.1. Pattern mixture model – copy to reference
The primary Treatment Policy estimand assesses the treatment effect in a future population that 
results from patients being offered treatment with arimoclomol as add-on to standard-of-care as 
compared to standard-of-care alone.
It is for the primary MMRM analysis of the estimand implicitly assumed that all arimoclomol 
patients who discontinue from treatment and who do not have a Month 20 IBMFRS assessment 
behave similarly to other arimoclomol patients with comparable IBMFRS trajectories (up to the 
point it is assessed). 
The current sensitivity analysis varies this assumption by assuming that arimoclomol treated 
patients that discontinue earlier than 14 days before Month 20 and who do not have a Month 20 
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Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
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IBMFRS assessment behave similarly to placebo patients with comparable IBMFRS trajectories 
(up to the point it is assessed).
This corresponds to assuming that patients withdrawing from trial regardless of the recorded 
reason for withdrawal will remain unexposed to trial medication after withdrawal in the 
hypothetical future population of the primary estimand.
The corresponding analysis model involves first the multiple imputation of missing data in 
accordance with the primary estimand which is then followed by an inferential statistical analysis 
of the multiple imputed datasets. In the following, a description of the imputations and of the 
statistical analysis hereof is provided.
The multiple imputations will be based on the ITT population and include their observed in-trial 
scheduled assessments of the IBMFRS. Regardless of the type of solution with respect to the 
issues relating to COVID-19 and phone visit data, the observed data going into the analysis will 
be the same as that used for the primary analysis. The imputations will be carried out with two 
main steps:
1.
First, intermittent (non-monotone) missing data will be imputed using Monte Carlo
Markov Chain (MCMC). The result of this is data for the specific endpoint with a
monotone missing pattern. A seed of 480901will be used.
2.
To complete the imputations in the second step, the monotone missing data will be
imputed to obtain complete data on all ITT patients based on a modified copy-to-
reference approach using a sequence of regression equations whereby data from a
particular visit, say visit i, get regressed on trial centre as factor, baseline IBMFRS and
the values from the two preceding visits, i.e. i–2 and i–1. A seed of 480902 will be used.
The above two steps are detailed in the below.
Imputation of intermittent missing data
The imputation model for intermittent (non-monotone) missing data is based on the MCMC 
methodology and assumes a multivariate normal distribution over all outcome variables included 
in the imputation model. Trial centre will not be included in this imputation model.
The imputation will be performed within each treatment arm separately. 
The above MCMC algorithm will make 100 replicates of the data where intermittent missing 
data points have been imputed if the percentage of missing data at Visit 14 (Month 20) is less 
than 10%. Otherwise the number of replicates will be 500.
Imputation of monotone missing data
The imputation approach is based on pattern mixture modelling (PMM) assuming the missing 
data mechanism is missing not at random (MNAR). The approach taken is a modified copy-to-
reference: One key aspect hereof is the assumption regarding exposure to active trial medication 
after withdrawal. 
Thus, the imputation of the monotonously missing data will be done within two separate groups 
of patients defined as:
A) Patients randomized to arimoclomol and 1) for whom the scheduled Visit 14 (Month 20)
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Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
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takes places no later than 14 days after date-of last dose or 2) for whom the scheduled 
IBMFRS assessment at Visit 14 (Month 20) is observed. For these subjects the effect 
observed or imputed at Month 20 are assumed to be attributable to arimoclomol.
B) All other patients. These patients will reflect a mixture of patients randomized to
arimoclomol and placebo and are considered to behave at Visit 14 (Month 20) as placebo-
treated patients.
The above categorization into imputation groups will be coded and added to the trial’s ADaM 
ADSL domain including a text field (character variable) detailing reason for categorization.
The implication of this approach is that for in patient group A, imputations will only be for those
with missing IBMFRS at Visit 14 (Month 20) yet actively exposed to arimoclomol. (Most likely, 
this is a very small group of patients.) Moreover, patients randomized to arimoclomol with fully 
observed trajectories will not contribute to imputations in patient group B.
The key to understanding the A-B groups above is that among patients randomized to 
arimoclomol, the only imputations which conditions on that the patients are exposed to 
arimoclomol are for those where it is established that the date of last dose is within two weeks of 
the Visit 14 (Month 20). 
It is implicitly assumed that being withdrawn from trial is similar to being exposed to placebo. It 
is thus further assumed that patients still actively taking placebo (although being blinded to 
treatment) share characteristics with patients who ceased to take trial drug (of either kind) for 
reasons which would have led to treatment discontinuation in the estimand’s hypothetical future 
population. This is an untestable assumption – and although addressing a different scientific 
question – which, at least, seems conservative compared to imputing missing records separately 
with in two randomized treatment arms (corresponding to the secondary estimand).
By performing the imputations in separate groups, the model effectively allows parameters to 
vary freely amongst the two groups. The imputation model will include the preceding two 
endpoint values as predictors and trial centre[*].
More specifically, for every post-baseline visit (i = 1, . . , n) with planned assessments of the 
endpoint under consideration, the missing data will be imputed separately for each of the 
separate imputations and within the two groups detailed above based on a sequence of linear 
regressions:
yi = [trial centre] [y0], [yi–2], [yi–1]
where y0 represents baseline. 
[*]: If the parameters of the sequences of regression models cannot be estimated prior to sampling 
from the posterior, trial centre should be omitted form the imputation model.
Once the imputation part is finalized, the MI data at Visit 14 (Month 20) will be analysed for all 
post baseline visits using an Analysis of Covariance (ANCOVA) model with trial centre,
baseline IBMFRS and randomized treatment as independent variables. Results will be combined 
over imputations using Rubin’s rule (8).
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Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
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7.5.2.2. Pattern mixture model (PMM) – copy to reference, tipping point
This approach reflects a tipping point modification of the PMM analysis described in Section
7.5.2.1 above. It reflects a varied assumption that arimoclomol patients with a missing Month 20 
assessment performs incrementally worse than initially assumed based on the compared patients 
with Month 20 data. The same set of already generated simulated data from the pattern mixture 
model above will be used for this analysis, i.e. no new simulated data will be generated.
For each simulation, imputed changes from baseline in the arimoclomol group will be subtracted 
an incrementally increased sequence of penalties starting from 0 (i.e. corresponding to the 
primary analysis) up to and past the point whereby the analysis tips over and is no longer 
statistically significant. A step of 0.5 should be used, except for the step where outcome becomes 
insignificant, where a step of 0.1 will be used.
If an individual penalized change from baseline becomes numerically larger than the baseline 
value, the change is truncated to the negative baseline value of the individual (implying that the 
outcome of the absolute penalized value cannot be below zero (0). The sequence of penalties is 
further stopped at maximum 40. It follows that this tipping point analysis is only relevant insofar 
as the primary analysis objective is met, and if the primary analysis objective is not met, then the 
tipping point analysis will not be reported.
Once the imputation part is finalized, the MI data will be analysed for the Month 20 visit using 
an ANCOVA model with trial centre; baseline IBMFRS and randomized treatment as 
independent variables. Results will be combined over imputations using Rubin’s rule (8).
7.5.2.3. Retrieved dropouts
This analysis reflects close to the same underlying assumptions as in the primary MMRM 
analysis of the primary estimand. 
For patients without data from some time point on (including the landmark visit), the MMRM 
analysis assumes implicitly similarity with all patients having a landmark visit and a comparable 
IBMFRS trajectory, irrespectively of whether the latter patients have been on treatment or not up 
to the landmark visit. 
In the current sensitivity analysis, similarity is (only) assumed with treatment-discontinued 
patients who do have a landmark assessment (retrieved drop-outs).
Hence, the main difference is that all patients without observed data are assumed to behave as 
patients observed at the landmark visit having discontinued IMP before that (within the same 
treatment arm), while the MMRM analysis implicitly assumes similarity with all patients having 
landmark data, including patients not discontinuing treatment. 
In both treatment arms, the patients used to inform the imputations will be those patients with 
observed Visit 14 (Month 20) but who have discontinued treatment at least two weeks prior to 
their Visit 14 (Month 20), corresponding to the retrieved drop-outs.
Imputations will be performed for each treatment arm separately.
In this imputation it is assumed that regardless of reason for withdrawal, after patient’s 
withdrawal from trial, patients’ trajectories are best represented by patients who remain under 
observation but who do so off IMP. The steps are therefore
Page 26 of 52
CONFIDENTIAL


Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 26 of 51
1. Imputation of intermittent missing data
o
Done as described above in Section 7.5.2.1 using MCMC, establishing a monotone missing
pattern. A seed of 480903 will be used.
2. Imputation of monotone missing data
o
For each treatment arm separately, select retrieved dropouts and all patients with missing
landmark visit and perform imputations based on a similar series/sequence of linear
regressions as detailed above in Section 7.5.2.1. Once the imputations are done, they are
stacked with the data from patients with landmark data observed while exposed to IMP.
(The latter patients should already be repeated 100 times from the first “intermittent” step.).
A seeds of 480904 will be used.
Once the imputation part is finalized, the MI data will be analysed for all post baseline visits 
using an ANCOVA model with trial centre, baseline IBMFRS and randomized treatment as 
independent variables. Results will be combined over imputations using Rubin’s rule (8).
As described above in Section 7.5.2.1, if the parameters of the sequences of regression models 
cannot be estimated prior to sampling from the posterior, trial centre should be omitted form the 
imputation model. If the regression analyses still do not converge, the baseline IBMFRS will 
further be excluded. If convergence is still not reached, e.g. if the number of retrieved drop-out 
patients is less than 5 per treatment group, the analysis will not be made.
7.5.2.4. Random intercept and slope model with in-trial data
This analysis shares the same assumptions as the primary MMRM analysis of the endpoint, with 
the additional assumption that the progression over time is linear.
Using in-trial data from all visits regardless of being “in-windowed”, scheduled or unscheduled,
a random intercept- and slope model of IBMFRS regressed on:
1. Treatment,
2. Trial centre,
3. The interaction between treatment and time (actual time of assessment/visit in year units
including the baseline visit’s records as dependent observations)
4. With intercept and slope being random (with no constraints on the covariance matrix
between random effects of intercepts and slopes).
The output will show the treatment specific slopes and their difference, including Standard Error 
(SE) and CIs. Furthermore, the cumulative distribution (plot) of the estimated patient specific
slopes will be output.
To assess the adequacy of the linear model a quadratic term will be added (γ + γ𝑗) ⋅𝑡2 where γ
represents an overall effect of squared time and the γ𝑗represents treatment specific effects of 
squared time. If either of these effects are significant (first test is omitting the treatment-specific 
term and then the second test is the overall term), outputting the difference between slopes would 
not provide an accurate summary of the treatment effect. Instead, the estimated difference 
between active and placebo will be outputted for time 52 weeks and 76 weeks, respectively.
Page 27 of 52
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Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 27 of 51
7.5.3. Analyses of Secondary Estimand (Hypothetical)
The change from baseline in IBMFRS total score will be assessed for the secondary estimand 
(and based on the SAF population) using the same MMRM model as for primary estimand. The 
MMRM will be based on all observed IBMFRS data from scheduled visits during the on-
treatment period for efficacy (see Section 6.2)
7.5.3.1. Sensitivity analyses of the Secondary Estimand
7.5.3.1.1 Random intercept and slope model with on-treatment data
Using on-treatment data (and based on the SAF population) from all visits regardless of being 
“in-windowed”, scheduled or unscheduled, a random intercept- and slope model with the same 
model specification as detailed for the primary estimand in Section 7.5.2.4 .
7.5.4. Sub-Group Analysis of IBMFRS
Interactions between treatment group and selected baseline variables will be investigated for 
IBMFRS:
1. Country (UK and US)
2. IBMFRS score (high vs. low, split by the median at baseline) (this model will not include
baseline IBMRF as a covariate)
3. 6-minute walk test distance (high vs. low, split by the median at baseline)
4.
(negative vs. positive)
The analysis will be conducted by adding three-way interaction terms to the primary analysis 
model (MMRM) in the primary estimand for IBMFRS between subgroup, treatment and visit. 
The analysis evaluates whether the treatment effect varies across the involved sub-groups for a 
given parameter.
The magnitudes of treatment effects in the relevant subgroups will be presented together with 
their 95% CI.
If the some of the involved sub-categories contains too few patients to facilitate convergence of 
the estimation, the trial centre term will be omitted from MMRM model.
7.5.5. Explorative Analyses of IBMFRS 
To explore the IBMFRS in further details, change from baseline of the following partial 
IBMFRS sum scores will be analysed using the same MMRM model as for the primary analysis
of the primary IBMFRS endpoint.

IBMFRS sum over the 5 upper limb domain items (2, 3, 4, 5, 6)

IBMFRS sum over the 4 lower limb domain: items (7, 8, 9, 10)

IBMFRS sum over the 9 limb items, excluding swallowing.
In addition, the individual 10 items will be summarized by visit and treatment, presenting mean 
descriptive statistics.
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Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
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7.6.
Analyses of Secondary Endpoints
Generally, values will be presented and analysed as observed. 
For endpoints requiring physical activity, some patients may be too weak to complete or 
otherwise unwilling or unable to commence the task, even if they conduct the visit at the site. 
Records missing such patient-related reasons (as reported in the CRF), may be assigned a value 
reflecting a poor outcome, typically zero. This will be addressed for each endpoint, where 
applicable. The referred zero-imputation will not be made at the baseline visit, since an affected 
patient then only can contribute with an improved or a neutral disease progression (i.e. calculated 
change) of the measured property, which is unrealistic.
The secondary endpoint parameters and IBMFRS are typically defined as endpoints at both 
Month 12 and Month 20. The involved MMRM analysis or negative binomial regression (for 
Falls and Near Falls) will be used to provide test outcomes at both time points.
7.6.1. Confirmatory Secondary Endpoints 
All confirmatory secondary endpoints will be analysed using the same MMRM model as for the 
primary analysis of the primary IBMFRS endpoint.
The outcome of the analysis will be presented as a plot of the LS Means estimates by visit, 
including 95% CIs. A corresponding summary by visit will also be presented.
The endpoints will further be summarized by visit and treatment, both as absolute values and 
change from baseline., 
7.6.1.1. Grip strength using the Jamar device 
Grip strength is assessed for both the right and the left hand. Post-baseline data missing due to  
patient-related issues will be analysed as having a zero grip strength value. 
These records are via the CRF identified via two pre-specified reasons for the absence, being 
either “unable to test due to temporary condition” or  “unable to test due to permanent 
condition”. The number of patients being unable to conduct the test according to this pre-
specified criterion will be included in the descriptive summary by treatment and visit.
The result used in the confirmatory analysis will be the result for the strongest hand, which is 
determined at baseline. The right hand will be deemed the strongest if it has a value equal to or 
higher than the left side (at baseline). If both values are missing, the right hand will be assumed 
the strongest.  
During the conduct of the trial, a concern for potential inaccuracy of reporting of units used for
hand grip and knee strength measurements was raised. To mitigate this concern, a question was 
retrospectively added to the relevant CRF, asking whether the site could confirm that the knee 
and hand grip strength results were entered in kg units. The question had thereby the 
characteristics of a data query implemented via the eCRF (EDC). 
In a number of such records, the site answered that they could not confirm the unit used (i.e. they 
did also not reject the originally reported unit).  It will be assumed that the correct unit has been 
reported for these records, but in order to mitigate potential unit errors, a sensitivity analysis 
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Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 29 of 51
excluding the strength test records with non-confirmed units will be conducted. The same type of 
sensitivity analysis will be made for the analysis of knee strength (Isometric Contraction Testing 
of bilateral quadriceps, see further down).
7.6.1.2. Modified Timed Up and Go (mTUG) 
When analysing the Modified Timed Up and Go, the reciprocal of the measured time will be 
used, multiplied by the planned total distance of 6 meter. This corresponds to analysing the 
velocity of the walking speed expressed in meters per seconds (m/s), including the time spent for 
standing up and sitting down again.
Post-baseline data missing due patient-related issues will be analysed as having a zero velocity 
value. Such records will be revealed via the reason given for not conducting the mTUG test and 
will be identified and documented prior to DBL.
7.6.1.3. Manual Muscle Testing (MMT)
MMT is reported using categorical 11 grades of the form 0, 1, 2, 3-, 3, 3+, 4-, 4, 4+, 5- & 5 for 
24 different muscles. These shall be converted to numerical values from 0 to 10 before a total 
score is calculated as an average across the 24 muscles. If more than 25% of the separate muscle 
scores are missing, the total score will not be calculated, thereby becoming missing.
Post-baseline data missing due patient-related issues will be assigned a value of zero (0).  These 
records will be identified according to the reason provided for their absence and documented 
prior to DBL. 
The number of imputed records will be included in the descriptive summary by treatment and 
visit.
7.6.1.4. 6 Minutes Walking distance test; distance at 6 minutes (6MWD)
Post-baseline data missing due patient-related issues will be assigned a distance value of zero (0) 
meters as outcome of the walk test, unless a 2 minute walk test result has been recorded for the 
patient at the given visit. In the latter case, the missing 6 minute walk test result will the imputed 
with the value of the 2 min walk test.
These records will be identified according to the reason provided for their absence and 
documented prior to DBL.
The number of imputed records will be included in the descriptive summary by treatment and 
visit.
7.6.1.5. SF-36 - Physical component
The values of the physical SF-36 component will be analysed as observed and presented in a 
descriptive summary by treatment and visit.
7.6.2. Other Secondary Endpoints
Except for Falls, Near-Falls, PGI-C, CGI-S and CGI-C, other secondary endpoints will be 
analysed using the same MMRM model as for the primary analysis of the primary IBMFRS 
endpoint.
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Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
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The outcome of the analysis will be presented as a plot of the LS Means estimates by visit, 
including 95% CIs. A corresponding summary will also be presented.
The endpoints will further be summarized by visit and treatment. Unless otherwise stated the 
summary will include both as absolute values and change from baseline. For the categorical 
values PGI-S, PGI-C, CGI-S and CGI-S categorical percentages will be presented.
7.6.2.1. 2 Minutes Walking distance test; distance at 2 minutes (2MWD)
Data missing due patient-related issues will be assigned a distance value of zero (0) meters as 
outcome of the walk test. 
These records will be identified according to the reason provided for their absence and 
documented prior to DBL.
The number of imputed records will be included in the descriptive summary by treatment and 
visit.
7.6.2.2. Isometric Contraction Testing of bilateral quadriceps strength using the 
MicroFET 
The isometric strength test is assessed for both the right and the left knee. Data missing due 
patient-related issues will be analysed as having a zero knee strength value. 
These records are via the CRF identified via two pre-specified reasons for the absence, being 
either “unable to test due to temporary condition” or “unable to test due to permanent 
condition”. The number of patients being unable to conduct the test according to this pre-
specified criterion will be included in the descriptive summary by treatment and visit.
The result used in the confirmatory analysis will be the result for the strongest knee, which is 
determined at baseline. The right knee will be deemed the strongest if it has a value equal to or 
higher than the left side (at baseline). If both values are missing, the right knee will be assumed 
the strongest.
7.6.2.3. Health Assessment Questionnaire (HAQ-DI)
For HAQ, both a Standard Disability Index and an Alternative Disability Index will be derived 
and subjected to the MMRM analysis. 
The methodology described in [10] will be applied, calculating an average over the 8 domains, 
with and without consideration of use of aid devises and/or help from other persons. Within each 
of the 8 domains, the score will be the highest (i.e. worst) across the involved subcategory 
scores. In order for a total (average) score to be calculated, scores from at least 6 domains need 
to be available. 
The Alternative Disability Index not incorporating use of aid devices or personal help will be 
used to reflect the HAQ endpoint in the confirmatory hierarchy. The Standard Disability Index
will be analysed as a supportive measurement.
7.6.2.4. SF-36 - Mental component
The values of the Mental SF-36 component will be analysed as observed using MMRM and 
further presented in a descriptive summary by treatment and visit.
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Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
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7.6.2.5. Patient Global Impression of Severity (PGI-S) and Patient Global Impression of 
Change (PGI-C)
PGI-S will be subjected to the same MMRM analysis as for the primary analysis of the primary 
IBMFRS endpoint based on a conversion of the 6 ordinal categorical outcomes to values from 0 
(“None”) to 5 (“Very severe”), but analysing absolute values rather than changes from baseline.
PGI-S and the PGI-C will otherwise be summarized by visit as percentages for each outcome 
within each visit. The number of missing records will also be presented.
7.6.2.6. Clinician Global Impression of Severity (CGI-S) and Clinician Global Impression 
of Change (CGI-C)
CGI-S and the CGI-C will be summarized by visit as percentages for each outcome within each 
visit. The number of missing records will also be presented.
7.6.2.7. Falls and Near Falls
Falls and near falls observed over the entire in-trial period will be analysed as accumulated count 
data using a negative binomial regression model with baseline IBMFRS as covariate and trial 
centre as factor. In-trial observation time will be used as the exposure variable, using log of 
exposure time as offset. This analysis will be repeated for falls and near falls up to 12 months.
A descriptive summary of number of falls recorded at each scheduled visit will further be made 
by treatment, recording also the accumulated (in-trial) observation time across patients since last 
scheduled visit and the rate of falls and near falls (calculated as the number of falls divided by 
the observation time between the dates of two neighbouring nominal visits). The number and 
incidence rate over the whole period of the trial will also be tabulated.
7.6.2.8. Mean hand grip and knee strength
As an exploratory reflection of systemic muscle strength, the mean of the hand grip strength and 
the knee strength (via Isometric Contraction Testing) will be analysed using the same MMRM 
analysis as for the as for the primary analysis of the primary IBMFRS endpoint.
The combined endpoint will be the mean of the strongest side for each original endpoint (as 
identified at baseline). If either of the two components are missing, the available value will be 
used as the mean.
7.6.2.9.
 will be summarized and listed.
The status as positive versus negative is determined based on an initially reported ratio, 
indicating a positive outcome if the ratio is ≥ 1.0 and negative when < 1.0.
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7.7.
Derived Variables
Entity
Definition
Change from baseline
Value at current timepoint – value at baseline
BMI
Weight in kilograms / (Height in meters) ^2
Trial day
assessment date – date of randomization + 1
Treatment day
assessment date – date of first dose + 1
Trial drug exposure
Total dose of the drug (in mg) received during the treatment period
Number of capsules
Total number of capsules dispensed minus the total number of 
capsules returned
TEAE
Any adverse event with reported onset or start date within the on-
treatment period
7.8.
Data Adjustments/Handling/Conventions
All collected data will be presented in listings. Data not included in any analyses according to 
this plan will not appear in any tables or graphs but will be included only in the data listings.
All p-values will be displayed in four decimals and rounded using standard scientific notation 
(e.g., 0.XXXX). If a p-value less than 0.0001 occurs it will be shown in tables as <0.0001.
Adverse events and medical history will be coded using the MedDRA version 20.1.
All medications will be coded using WHO Drug Dictionary (WHODD) v. B2 Sep2017.
A treatment related AE is any AE with a possible or probable relationship to the trial drug.
Anatomical Therapeutic Chemical (ATC) class is defined as ATC level 2. Preferred term is 
defined as ATC level 5.
If partial dates occur in the start dates of events (those observations that have both start and end 
dates, the convention for replacing missing dates for the purpose of statistical analysis is as 
follows: 

If just day is missing then the day assigned is the first day of the month or the date of
first dose (if in the same month), whichever is later

If just month is missing and the year is the same as the first dose, then the month
assigned is the month of the first dose, unless that results in a date prior to the first dose
in which case the month after the first dose is used. If the year is not the same as the first
dose, then the month assigned is January

If both month and day are missing and the year is the same as the first dose, then the
month assigned is the month of the first dose and the day assigned is either the first day
of the month or the first dose date, whichever is later. If the year is not the same as the
first dose, then the date is assigned as 1 of January of the specified year
If partial dates occur in the end dates of events, the conventions are as follows:

If just day is missing, then the day assigned is the last day of the month, or the last date
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PCN Number ORPA177146
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of the in-trial period (as defined in section 6.2), whichever is the earlier

If just month is missing then the month assigned is December, unless that results in a date
after the end of the in-trial period, in which case either the month of the in-trial period is
used if that results in a date within the in-trial period, or otherwise the previous month

If both month and day are missing and the year is the same as the end of the on-treatment
period, then the date is assigned as the end of the on-treatment period. If the year is not
the same as the end of the on-treatment period, then the date is assigned as 31 December
of the specified year
If partial times occur in the start time of events, the convention is as follows: 

If the missing time occurs on the day of the first dose and both the hour and minute are
missing then the time assigned is the time of the first dose, otherwise

If both the hour and minute are missing and the date is not the date of first dose the time
assigned is 12:00;

If the date is the same as the date of the first dose and only hour is missing the hour
assigned is 12 or the hour of first dose, whichever is later, and

If the date is the same as the date of first dose and only the minute is missing the minute
assigned is 30 or the minute of first dose, whichever is later.

Otherwise the hour assigned is 12 if the hour is missing and the date is not the same as
the date of first dose and the minute assigned is 30 if the date is not the same as the date
of first dose.
If partial times occur in the end time of events, no times will be imputed.
These conventions will be applied only to adverse event onset dates and times with the following 
precaution: 

If the missing date and time reflect the date and time of onset of an adverse event, the
modified date and time will be constructed to match the first documented date/time post
drug administration while preserving the order in which the AE was reported in the CRF.
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Protocol Number IBM4809
PCN Number ORPA177146
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8.
Trial Patients and Demographics
8.1.
Disposition of Patients and Withdrawals
The number of patients screened and enrolled will be presented by investigative site.  
Disposition will include tabulations of the number of patients randomized, who completed the 
trial, completed the trial on a reduced dosage, withdrew from trial drug, completed the trial on 
intended dose, had any drug interruptions, by treatment group and overall based on SAF
population. The primary reasons for withdrawal of IMP and from the trial will also be 
summarized by treatment group and overall for the SAF.
The number and percentage of patients in each analysis set will also be summarized.
8.2.
Protocol Violations and Deviations
Protocol deviations are captured in the CRF on a specific protocol deviation CRF page.
Incidences of all protocol deviations will be summarized in the CRF by protocol deviation 
category. Major protocol deviations will be listed.
Protocol deviations representing events that may affect treatment adherence will be considered 
when defining the on-treatment period. 
8.3.
Demographics and Other Baseline Characteristics
Summary statistics for age, gender, race, ethnicity, height, weight, and BMI will be presented by 
treatment group and overall.
Clinical and pathological features of IBM will be described using descriptive summaries. 
For the continuous variables, the number of non-missing values and the mean, standard 
deviation, minimum, median and maximum will be tabulated. 
For the categorical variables, the counts and proportions of each value will be tabulated.   
These analyses will be conducted for the ITT and SAF populations.
The number and percent of patients reporting various medical histories, grouped by MedDRA 
system organ class and preferred term, will be tabulated by treatment group. This analysis will be 
conducted for the SAF population.
8.4.
Exposure and Compliance
8.4.1. Exposure
Exposure to IMP will be calculated as follows: from the date of last dosing minus the first day of 
dosing + 1. The exposure calculation will not take therapy interruptions into account.
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Patient-years of exposure will be calculated as the sum of the above treatment durations by 
treatment group for the SAF divided by 365.25.
8.4.2. Calculation of capsules taken
The term dispensing period will be used to denote the period from the visit a bottle is dispensed 
to the following scheduled visit where the same bottle is planned to be returned. 
The number of capsules taken from a given bottle will generally be calculated based on the 
number of capsules originally dispensed in the bottle minus the number of capsules returned. 
If a bottle is returned too late or not returned, some assumptions will be applied to derive the 
number of capsules used in the dispensing period.

Delayed return of a bottle: The difference between the number of dispensed capsules
and the returned capsules are assumed to have been used in the planned dispensing
period (i.e. up to the first scheduled visit after the dispensing visit).

Non-returned bottles: The amount of used IMP will be calculated based on the
alternative assumptions:
o
Assumption 1: The planned amount of the dispensed (but non-returned) capsules is
assumed to have been used in the planned dispensing period (i.e. up to the first
scheduled visit after the dispensing visit).
o
Assumption 2: None of the dispensed (but non-returned) capsules are assumed to
have been used in the planned dispensing period (i.e. up to the first scheduled visit
after the dispensing visit).
If a bottle is returned with more capsules that were originally dispensed in the bottle, the returned 
bottle will contribute with 0 (zero) capsules to the calculations (i.e. not a negative number).
8.4.3. Dose de-escalation
At any time during the trial, the protocol permits that the IMP may be temporarily halted (e.g., 
interrupted) for up to 4 weeks for an intolerable AE. Following re-challenge at the intended dose 
of 744 mg/day, de-escalation from 744 mg/day (248 mg t.i.d.) to 372 mg/day (124 mg t.i.d.) may 
be considered. The subject will remain on this decreased dose for the remainder of the trial. A 
flag will be created to identify these patients.
Sites record start and stop dates of an interruption, then the sites record if dosing was re-initiated 
and at what dose (744 mg/day or 372 mg/day). It will be assumed the start date of re-initiation is 
the day after stop date of the interruption.
In addition to calculating overall exposure (see above), for patients that do de-escalate, number 
of days exposed to 744 mg/day will be calculated as follows: from day prior to start date of 
interruption that led to de-escalation to dose minus the first day of dosing +1. In addition, 
number of days exposed to 372 mg/day will be calculated as last date of 372 mg/day dose minus 
the day after stop date of interruption + 1.
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PCN Number ORPA177146
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8.4.4. Compliance
Overall and by visit interval treatment compliance will be determined as follows.
Compliance = 100 x (capsules taken/capsules expected to be taken) where capsules taken = 
number of capsules expected to be taken – number of missed capsules (regardless of reason 
including investigator instituted temporary halt). The expected number of capsules to be taken is 
calculated as 6 times the number of days in the relevant period. In this trial, patients can have 
their dose reduced hence number of capsules expected to be taken should be taken into account.
Trial drug administration data will be listed. 
The number of capsules dispensed and returned will be summarized by treatment group, overall 
and by visit, for the ITT population. The number of capsules used will be summarized by 
treatment group and overall for 6, 12, 18, and 20 months trial period. 
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PCN Number ORPA177146
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9.
Safety and Tolerability Analysis
Safety and tolerability will be evaluated from reported AEs, clinical safety laboratory values 
(haematology and clinical chemistry), vital signs, ECG evaluation, physical examinations, and 
C-SSRS.
All safety analyses will be performed on the SAF population for the on-treatment period unless 
otherwise specified.
9.1.
Adverse Events
Adverse events (AEs) will be coded using the MedDRA version 20.1 dictionary.
AEs with onset within the on-treatment period will be considered treatment-emergent adverse 
events (TEAEs). 
Two AE data listings will be prepared; one for TEAEs and one for non-TEAEs.
The incidence of TEAEs (number and percentage of patients with TEAEs), grouped by 
MedDRA system organ class (SOC) and preferred term (PT), will be summarized by treatment 
group and overall for the on-treatment and the in-trial periods. The incidence of TEAEs (number 
and percentage of patients with TEAEs) will also be presented by PT in decreasing order of 
incidence for the on-treatment period. In the case of multiple occurrences of the same event 
within the same subject, each subject will only be counted once for each SOC or PT (the number 
of events will be provided as E).
The incidence of TEAEs (number and percentage of patients with TEAEs), will also be 
summarized by severity and relationship to IMP. 
In the summaries showing severity and relationship to IMP at each level of summarization (SOC 
and PT), patients who reported more than one adverse event will be counted only once for the 
maximum severity (mild, moderate, severe) and strongest relationship (not related, possibly 
related, probably related).  
If a particular event is missing the severity and/or relationship, then the strongest possible 
severity and/or relationship will be assumed for analysis (severity = severe, relationship = 
probably related).
No inferential statistical tests will be performed.
9.2.
Adverse Events Leading to Withdrawal
Summaries of TEAEs leading to withdrawal of IMP, by treatment group, SOC, and PT will be 
prepared for the SAF population. No inferential statistical tests will be performed.
A data listing of TEAEs leading to withdrawal of IMP will also be provided, displaying details 
of the event(s) captured on the CRF.
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Statistical Analysis Plan, 
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PCN Number ORPA177146
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9.3.
Deaths and Other Serious Adverse Events
Any deaths that occur during the trial will be listed. Other (non-fatal) serious treatment emergent 
AEs will be listed. 
Other serious adverse events (non-fatal) will also be tabulated by SOC and PT and presented by 
treatment for the SAF population for the on-treatment and in-trial periods. 
9.4.
Clinical Laboratory Evaluations
For each in-person visit, except for the Baseline visit, the following lab procedures will be 
performed:

Haematology with differentials: haemoglobin, haematocrit, mean corpuscular volume
(MCV), red blood cells (RBC/erythrocytes), white blood cells (WBC/leukocytes), and
differential count (basophils, eosinophils, lymphocytes, monocytes, neutrophils [% and
absolute count], and platelets)

Biochemistry: albumin, alkaline phosphatase, alanine aminotransferase (ALT/SGPT),
aspartate aminotransferase (AST/SGOT), bilirubin (total), calcium, chloride, cholesterol,
creatine kinase (screening visit only), creatinine, gamma-glutamyl transferase (GGT),
glucose (random), iron, lactate dehydrogenase (LDH), phosphate, potassium, protein
total, sodium, triglycerides, BUN, uric acid

Other: cystatin C.
Descriptive statistics of the observed values and change from baseline (continuous data) will be 
presented by treatment group and visit for each haematology, serum chemistry parameter for the 
on-treatment and in-trial periods. Each measurement (continuous data) will be classed as below 
(low), within (normal), or above (high) normal range, based on ranges supplied by the laboratory 
used. 
Number (%) of patients that fall out-side and within range will be reported by visit for the on-
treatment period.
Number (%) of patients that have potentially clinically significant laboratory values overall and 
by visit will be presented for the on-treatment period.
Laboratory test results will be listed. Laboratory values that are outside the normal range will be 
flagged in the data listings. Listings of patients with parameter results considered to be clinically 
significantly abnormal by investigator will be presented for the on-treatment period. The listings 
will include all lab parameter results where at least one value is considered clinically 
significantly abnormal.
The incidence of patients fulfilling the below criteria will be summarized by visit and for the 
whole study and listed:

Post baseline sCr value ≥1.5x baseline value

Post-baseline sCr value ≥2x baseline value

Post-baseline sCr value ≥3x baseline value
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Statistical Analysis Plan, 
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Protocol Number IBM4809
PCN Number ORPA177146
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An additional summary of creatinine over time (mean and change from baseline) will be 
presented according to concomitant use of MATE/OCT-02 medications at any time (see
Appendix 2: List of Concomitant Medications).
The incidence of patients fulfilling the below criteria will be summarized and listed:

ALAT ≥ 3 × ULN

ALAT ≥ 5 × ULN

ALAT ≥ 8 × ULN

ALAT ≥ 20 × ULN

ASAT ≥ 3 × ULN

ASAT ≥ 5 × ULN

ASAT ≥ 8 × ULN

ASAT ≥ 20 × ULN

ALAT or ASAT ≥ 3.0x ULN

ALAT or ASAT ≥ 5.0x ULN

ALAT or ASAT ≥8x ULN

ALAT or ASAT ≥ 20 × ULN

Total Bilirubin≥ 2x ULN

ALP ≥2 x ULN

ALP ≥ 3 × ULN

(ALAT or ASAT ≥3.0x ULN) and Total Bilirubin≥ 2x ULN and ALP ≤1.5x ULN

ALAT ≥ 3 × ULN & Total Bilirubin ≥ 2 × ULN & ALP ≤ 1.5 × ULN

ASAT ≥ 3 × ULN & Total Bilirubin ≥ 2 × ULN & ALP ≤ 1.5 × ULN
The above categorical parameters are to be presented in one table for “by visit” and one table for 
“overall” summaries, respectively.
Furthermore, the following categorical summaries will be summarized descriptively overall:

ALAT or ASAT ≥ 5 × ULN for more than 14 days[§]

(ALAT or ASAT ≥ 3 × ULN) & (Total Bilirubin ≥ 2 × ULN)

(ALAT or ASAT ≥ 3 × ULN) and with ongoing eosinophilia > 5% (in
SDTM.LB$LBTEST=”Eosinophils/Leukocytes”)
[§]: either or both “ALAT ≥ 5 × ULN for 14 days” and/or “ASAT ≥ 5 × ULN for 14 days” corresponding to two
consecutive visits more than 14 days apart.
The above categorical parameters are to be presented in one table for an “overall” summary.
In relation to the last two bullet items above, two AE lists will be presented:

A list of all (in-trial) AEs in patients with ALAT or ASAT ≥ 3 × ULN (in-trial).

A list of all (in-trial) AEs in patients fulfilling criteria {ALAT ≥ 3 × ULN and
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eosinophilia > 5%} or {ASAT ≥ 3 × ULN and eosinophilia > 5%} (in-trial). 
Spaghetti plots: Plots of all individual ALAT and ASAT on-treatment trajectories will be 
presented, separately by treatment group. Lines will be added to the plot to show 3, 5, 8, and 20 x 
the ULN (some of the higher value lines may be omitted if there are no values above the 
previous line).
An eDISH plot by treatment group for SAF in the on-treatment period will be presented. It is a 
scatter plot based on all (both in-windowed and not in-windowed) “on-treatment” pair (identified 
as from the same sampling date) of bilirubin (y-axis) vs ALAT (x-axis) where each parameters 
has been scaled (divided) by its respective ULN-value(s). The x-axis (ALAT) will have a vertical 
line placed at “x = 3” (corresponding to “3 × ULN”) and the y-axis (bilirubin) a vertical line 
located at “y = 2”) (corresponding to “2 × ULN”). Both axes to be displayed as log10.
9.5.
Vital Signs
Descriptive summaries of mean values and changes from baseline will be calculated for weight, 
heart rate, respiratory rate, and sitting blood pressure by treatment group and by visit for 
assessments obtained during the on-treatment period using the SAF population. 
Vital signs will be listed. 
9.6.
Electrocardiograms
The number and percentage of patients with normal, abnormal (not clinically significant) and 
abnormal (clinically significant) ECG results will be summarized by visit and overall, by 
treatment group for assessments obtained during the on-treatment period using the SAF
population. 
ECG results (normal/abnormal) will be listed. Clinically significant abnormalities will be 
flagged.
9.7.
Physical examination results
Physical examination results (normal/abnormal) will be listed.
9.8.
Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS will be tabulated by treatment group and by visit displaying only the highest 
category for each patient for the SAF in the on-treatment period.
Baseline characteristics will further be tabulated for Suicidal Ideation and Suicidal Behavior 
separately, over a life span and the last X months.
All results from the C-SSRS will be listed.
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Protocol Number IBM4809
PCN Number ORPA177146
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9.9.
Concomitant Medication
Prior medications will be presented separately from concomitant medications.
Medications that started prior to the start of the trial drug will be considered prior medications 
whether or not they were stopped prior to the first dose of trial drug. Medications continuing or 
starting post the first dose of trial drug will be considered to be concomitant. If a medication 
starts prior to the first dose of trial drug and continues after the first dose of trial drug, it will be 
considered both prior and concomitant.
Prior and concomitant medications will be summarized descriptively by treatment using counts 
and percentages for the SAF in the on-treatment and in-trial periods. Medications will be coded 
using WHODD v. B2 Sep2017.
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Statistical Analysis Plan, 
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PCN Number ORPA177146
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10.
Changes from Planned Analysis and clarifications
The analyses presented in the SAP generally reflects the analyses in the clinical trial protocol, 
with a few clarifications:

It has been clarified that patients who are randomized in error and do not receive any
investigational medicinal product (IMP) shall not be included in the ITT population.

It has been clarified that it is the physical component of SF-36 endpoint that will be
analysed in the confirmatory testing hierarchy.

It has been clarified that it is the ‘Alternative’ version of the Health Assessment
Questionnaire Disability Index that is used in the confirmatory test hierarchy (as opposed
to the ‘Standard’ version).The analysis of Falls and near falls have been changed from
MMRM of change since baseline to a negative binomial regression of the accumulated
number of events since baseline. The rationale has been that collection of baseline falls
date is over too short a period to meaningfully derive a change from and that the count
data nature of fall events provide weak support for an MMRM analysis.

The analysis of the mTUG endpoint has been adapted to be conducted on reciprocal
values multiplied with the planned distance of 6 meters in order to appropriately reflect
and handle values missing due to inability of patients to initiate the test (not related to
external circumstances). This corresponds approximately to analysing the velocity with
which the mTUG route of 6 meters is accomplished, including the time spent for standing
up and sitting down again.

It was specified in the protocol that a sub-group analysis by site of onset of IBM should
be made (for IBMFRS). Since a patient can report several sites (up to 5 sites), this
analysis is not facilitated by the collected data and therefore not done.

Mean hand grip and knee strength has been added as an additional exploratory endpoint
to be analysed using MMRM, intending to reflect a systemic strength measure.

Due to the exhaustiveness of the description in the protocol of the planned statistical
analysis of 
 data, a separate SAP for 
 data will not pre prepared prior to DBL.
Hence, the protocol describes exhaustively the planned MMRM analyses to be made for
the changes since baseline in various continuous parameters, including the primary
endpoint 
 Technical details related to
treatment periods and missing date information etc. will follow the same principles as
stipulated in this SAP for the main trial.
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PCN Number ORPA177146
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11.
Other Planned Analysis
11.1. Pharmacokinetic Analysis
Plasma concentrations of arimoclomol will be listed. Plasma concentrations will be used for 
population PK analyses and reported separately in a PK analysis plan (PKAP).
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PCN Number ORPA177146
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12.
References
1. US Federal Register. (1998) International Conference on Harmonization; Guidance on
Statistical Principles for Clinical Trials. Department of Health and Human Services: Food and
Drug Administration [Docket No. 97D-0174]. Federal Register Volume 63, Number 179,
pages 49583-49598. September 16, 1998.
2. ASA. (2016) Ethical Guidelines for Statistical Practice. Prepared by the Committee on
Professional Ethics, April 2016. http://www.amstat.org/about/ethicalguidelines.cfm
3. RSS. (2014) The Royal Statistical Society: Code of Conduct, 2014.
http://www.rss.org.uk/Images/PDF/join-us/RSS-Code-of-Conduct-2014.pdf.
4. Allison, Handling Missing Data by Maximum Likelihood. SAS Global Forum 2012, Paper
312-2012
5. Ratitch, O’Kelly, Implementation of Pattern-Mixture Models Using Standard SAS/STAT
Procedures. PharmaSUG2011, Paper SP04
6. Little, R., Yau, L. Intent-to-Treat Analysis for Longitudinal Studies with Drop-Outs.
Biometrics, 1996, vol. 52, 1324-1333
7. Committee for Medicinal Products for Human Use (CHMP). Guideline on Missing Data in
Confirmatory Clinical Trials. EMA/CPMP/EWP/1776/99 Rev. 1. 2 Jul 2010.
8. Little RJA, Rubin DB. Statistical analysis with missing data: New York: John Wiley & Sons.
1987.
9. National Academy of Sciences (NAS). The Prevention and Treatment of Missing Data in
Clinical Trials. Washington D.C.: The National Academies Press. 2010.
10. THE HEALTH ASSESSMENT QUESTIONNAIRE (HAQ) DISABILITY INDEX (DI) OF
THE CLINICAL HEALTH ASSESSMENT QUESTIONNAIRE (VERSION 96.4).
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Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 45 of 51
13.
Tables, Listings, and Figures
All listings, tables, and figures, including presentations by region, are specified in a separate 
shells document. The shells are to be considered for guidance only, and minor deviations from 
the shells are acceptable as long as the outputs are consistent with the text of this SAP.
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CONFIDENTIAL


Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 46 of 51
Appendix 1: Abbreviations List
Abbreviation
Definition
AE
Adverse Event
ANCOVA
Analysis of Covariance
ALT
Alanine Aminotransferase (SGPT)
AST
Aspartate Aminotransferase (SGOT)
BMI
Body Mass Index
CGI-C
Clinician Global Impression of Change
CGI-S
Clinician Global Impression of Severity
CI
Confidence Intervals
CRF
Case Report Form
CS
Clinically Significant
CSA
Cross-Sectional Area
CTR
Clinical Trial Report
C-SSRS
Columbia Suicide Severity Rating Scale
DBL
Database Lock
DMC
Data Monitoring Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
FDA
Food and Drug Administration
GCP
Good Clinical Practice
Page 47 of 52
CONFIDENTIAL


Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 47 of 51
Abbreviation
Definition
GGT
Gamma-Glutamyl Transferase
HAQ-DI
Health Assessment Questionnaire Disability Index
HR
Heart Rate
IBM
Inclusion Body Myositis
IBMFRS
Inclusion Body Myositis Functional Rating Scale
ICH
International Council for Harmonization 
ID
Identification
IMP
Investigational Medicinal Product
ITT
Intent-To-Treat
KUMC
University of Kansas Medical Center
LDH
Lactate Dehydrogenase
LS
Least Squares
MAR
Missing at Random
MCMC
Monte Carlo Markov Chain
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple Imputation
MMRM
Mixed Model Repeated Measures
MMT
Manual Muscle Testing
MNAR
Missing Not At Random
Page 48 of 52
CONFIDENTIAL


Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 48 of 51
Abbreviation
Definition
MTR
Magnetization Transfer Ratio
mTUG
Modified Timed Up and Go
N
Number
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
PK
Pharmacokinetic
PKAP
Pharmacokinetic Analysis Plan
PMM
Pattern Mixture Modelling
PP
Per-Protocol
QOL
Quality of Life
RBC
Red Blood Cells
RMA
Remaining Muscle Area
RR
Respiratory Rate or Relative Rate
SAE
Serious Adverse Event
SAF
Safety Population
SAP
Statistical Analysis Plan
SAS® 
A Software System Used for Data Analysis
SD
Standard Deviation
IBM
Sporadic Inclusion Body Myositis
SOC
System Organ Class
SUSAR
Suspected Unexpected Serious Adverse Reactions
Page 49 of 52
CONFIDENTIAL


Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 49 of 51
Abbreviation
Definition
TEAE
Treatment-Emergent Adverse Event
T.I.D.
Three times a day
WBC
White Blood Cells
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary
UCL
University College London
Page 50 of 52
CONFIDENTIAL


Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 50 of 51
Appendix 2: List of Concomitant Medications
MATE/OCT-02 Medications (inhibitors and substrates)
amantadine
amiloride
cimetidine
dopamine
famotidine
memantine
metformin
pindolol
procainamide
ranitidine
varenicline
oxaliplatin
dofetelide
trimetroprim
verapamil
levofloxacin
ciprofloxacin
moxifloxacin
pyrimethamine
ondansetron
Page 51 of 52
CONFIDENTIAL


Statistical Analysis Plan, 
Orphazyme A/S
Protocol Number IBM4809
PCN Number ORPA177146
AD-ST-33.05  Effective date: 22-Jan-2018
FINAL Version 1.0  | 02 March 2021     |    AD109.01  Effective date 26-Jun-2017
Page 51 of 51
Appendix 3: Overview of estimands and sensitivity analyses
Page 52 of 52
CONFIDENTIAL