Clinical trial NCT04049097
Conditions: Inclusion Body Myositis
Keywords: IBM
Sponsor: ZevraDenmark
Start date: 2019-05-20; Completion date: 2021-11-15
Enrollment: 121 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A multicenter, nonrandomized, open-label, uncontrolled clinical extension trial designed to compare the efficacy and safety of early versus delayed start of arimoclomol in the treatment of Inclusion Body Myositis (IBM)

Detailed description:
This was planned to be a 40-month open-label extension trial of the 20-month randomized, double-blind, placebo-controlled IBM4809 trial. The open-label trial was terminated early by the sponsor as a consequence of the results of IBM4809 which did not meet any of its efficacy endpoints. Therefore, the actual average duration of open-label treatment was approximately 28 weeks.

Arms: arm 1: 248 mg arimoclomol base (equivalent to 400 mg arimoclomol citrate) 3 times daily
Interventions: intervention 1: Arimoclomol
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

Protocol documents:
Prot_000.pdf: 
Protocol version 5.0 dated 18-Jan-2021 
Page 1 of 73 
PROTOCOL 
PRODUCT NAME: 
Arimoclomol 
PROTOCOL NUMBER: 
IBM-OLE 
IND NUMBER: 
076773 
EUDRACT NUMBER: 
2019-000749-11 
DEVELOPMENT PHASE: 
Phase 3b 
PROTOCOL TITLE: 
An open-label, non-randomized trial to investigate the 
efficacy and safety of early versus delayed start of 
arimoclomol in patients with sporadic inclusion body myositis 
who have completed the IBM4809 trial 
PROTOCOL DATE: 
Version 5.0, 18-Jan-2021 
INTERNATIONAL 
COORDINATING 
INVESTIGATOR: 
, MD, Professor of Neurology, 
University of Kansas Medical Center (KUMC) 
University of Kansas Medical Center Research Institute, Inc. 
3901 Rainbow Boulevard, Mailstop 2012 
Kansas City, KS 66160, US 
SPONSORED BY: 
Orphazyme A/S 
Ole Maaløes Vej 3 
DK2200 Copenhagen N 
Denmark  
CONTRACT RESEARCH 
ORGANIZATION: 
Premier Research  
One Park Drive, Suite 150 
Durham, NC 27709 US 
This trial will be performed in compliance with ICH Good Clinical Practices and applicable 
regulatory requirements, including the archiving of essential documents.  
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. 
This document contains information which is the property of Zevra 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 Zevra Denmark A/S.
Clinicaltrials.gov ID: NCT04049097




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1. APPROVAL SIGNATURES 
PROTOCOL NUMBER: 
IBM-OLE (version 5.0) 
PROTOCOL TITLE: 
An open-label, non-randomized trial to investigate the efficacy and 
safety of early versus delayed start of arimoclomol in patients with 
sporadic inclusion body myositis who have completed the IBM4809 
trial 
I, the undersigned, have read this protocol and confirm that to the best of my knowledge it 
accurately describes the planned conduct of the trial. 
 
SIGNATURE 
 
DATE: 
 
 
 
 
 
 
 
, MD 
International Coordinating Investigator 
Professor of Neurology, University of Kansas Medical Center 
(KUMC) 
 
 
 
 
 
 
, MD 
International Coordinating Co-Investigator 
Professor in Clinical Neurology 
University College of London  
 
 
 
 
 
 
, MD 
Medical Director 
Orphazyme A/S 
 
 
 
 
 
19th January 2021


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1.
APPROVAL SIGNATURES
PROTOCOL NUMBER: 
IBM-OLE (version 5.0) 
PROTOCOL TITLE: 
An open-label, non-randomized trial to investigate the efficacy and 
safety of early versus delayed start of arimoclomol in patients with 
sporadic inclusion body myositis who have completed the IBM4809 
trial 
I, the undersigned, have read this protocol and confirm that to the best of my knowledge it 
accurately describes the planned conduct of the trial. 
SIGNATURE 
DATE: 
, MD 
International Coordinating Investigator 
Professor of Neurology, University of Kansas Medical Center 
(KUMC) 
, MD 
International Coordinating Co-Investigator 
Professor in Clinical Neurology 
University College of London  
, MD 
Medical Director 
Orphazyme A/S 


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2. PROTOCOL SUMMARY 
2.1. Synopsis 
PRODUCT 
NAME/NUMBER 
Arimoclomol 
PROTOCOL 
NUMBER 
IBM-OLE 
EUDRACT 
NUMBER 
2019-000749-11 
DEVELOPMENT 
PHASE 
Phase 3b 
PROTOCOL TITLE 
An open-label, non-randomized trial to investigate the efficacy and safety of early versus 
delayed start of arimoclomol in patients with sporadic inclusion body myositis who have 
completed the IBM4809 trial 
INDICATION 
sporadic inclusion body myositis 
OBJECTIVES 
Primary:  
• 
To determine the efficacy (based on the Inclusion Body Myositis Functional 
Rating Scale [IBMFRS]) of early* versus delayed start of arimoclomol 
treatment of IBM up to Month 20 in the open-label extension (OLE) trial.  
Secondary: 
• 
To determine the safety and tolerability of long-term treatment of IBM with 
arimoclomol up to Month 40 in the OLE trial. 
• 
To determine the efficacy (on secondary efficacy endpoints) of early* versus 
delayed start of arimoclomol treatment of IBM up to Month 20 in the OLE 
trial. 
• 
To determine the efficacy (on secondary efficacy endpoints) of early* versus 
delayed start of arimoclomol treatment of IBM up to Month 40 in the OLE 
trial. 
Exploratory:  
• 
 
 
• 
To explore population pharmacokinetics (popPK) and popPK/PD. 
• 
To determine the efficacy (on secondary efficacy endpoints) of early** versus 
delayed start of arimoclomol treatment over periods of 20 months duration.  
*  Including 20 months arimoclomol treatment and 20 months placebo treatment from trial 
IBM4809 for the early and delayed start group, respectively. 
** Including (only) 20 months arimoclomol treatment from trial IBM4809 for the early start 
group. 
RATIONALE  
 
The IBM4809 trial was a double-blind, placebo-controlled trial designed to determine the 
efficacy of 1200 mg/day arimoclomol citrate (400 mg t.i.d.) for 20 months, compared to 
placebo, in patients with IBM. In the present extension trial, patients completing trial 
IBM4809 will be invited to receive open-label arimoclomol at the same daily dosage for 
a further 40 months; those patients who received arimoclomol in the IBM4809 trial will 
be considered the early start group; patients who received placebo in the IBM4809 trial 


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will be considered the delayed treatment group. This design allows the comparison of 
efficacy and safety of arimoclomol between the two groups.  The additional 20 months 
treatment period will permit the evaluation of efficacy and safety over a long-term period 
(40 months) in a greater number of subjects, while affording continued access to 
arimoclomol in the absence of approved effective treatments for IBM. 
TRIAL DESIGN 
This Phase 3b, multicenter, nonrandomized, open-label, uncontrolled clinical extension 
trial is designed to compare the efficacy and safety of early versus delayed start of 
arimoclomol in the treatment of IBM. Up to 150 male and female patients who have 
completed the IBM4809 trial will be available for this trial. Patients must currently be on 
treatment with the investigational medicinal product (IMP) from the blinded IBM4809 
trial (arimoclomol or placebo) and will enroll in this trial at Visit 14/Month 20 of the 
blinded IBM4809 trial.  
Patients who completed the IBM4809 study at a reduced dose of 600 mg/day 
arimoclomol citrate will continue to receive their reduced dose in this open-label 
extension (OLE) study. All other patients will receive 1200 mg/day arimoclomol citrate 
(400 mg t.i.d.). The duration of treatment in this trial is expected to be 40 months. 
The trial is split into two treatment periods, with a more comprehensive data collection 
in the first treatment period (Month 0 – 20) compared to the second treatment period 
(Month 21 – 40). The treatment regime will remain the same throughout the two treatment 
periods.  
Treatment period 1: Patients will be seen in the clinic at baseline and months 1, 5 and 9, 
15 and 20. Visits will be conducted by telephone at month 2, 3, 4, 6, 12 and 18. For the 
telephone visits at month 2, 3, 4 and 6 a clinical safety laboratory assessment is also 
required.  
Efficacy will be assessed by the IBMFRS total score, 6-Minute Walk Test, Modified 
Timed Up and Go (mTUG), Maximal Voluntary Isometric Contraction Testing (MVICT) 
of the quadriceps muscle, hand grip strength testing, 36-Item Short Form Health Survey 
(SF-36), and falls and near falls.
 
.  
Sparse PK samples will be collected for popPK analysis and explorative popPK/PD 
modeling (reported separately).  Additional blood will be drawn for biobanking for future 
potential tests. 
Safety will be assessed by evaluating adverse events (AEs), clinical laboratory test 
results, vital sign measurements, 12-lead electrocardiograms (ECGs), physical 
examination findings, and the Columbia Suicide Severity Rating Scale (C-SSRS). 
Treatment period 2:  
Patients will be seen in the clinic at months 23, 29, 35 and 40. Visits will be conducted 
by telephone at month 26, 32 and 38.  
Efficacy will be assessed by the in-clinic IBMFRS total score and hand grip strength 
testing.  
Safety will be assessed by evaluating AEs, clinical laboratory test results and C-SSRS. 
All AEs observed by the trial personnel or reported by the patient during the trial (from 
the time of visit 1(screening) in IBM-OLE) will be collected. 
If a patient discontinues treatment (or the trial is terminated) an early termination (ET) 
visit will be performed as soon as possible after discontinuation, with a follow-up ET 
phone assessment 2 weeks later. Depending on the timing of discontinuation (before or 
after Month 20) the assessments performed at the ET visit differs according to the relevant 
visit schedule (Treatment period 1 and Treatment period 2). 


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PLANNED NUMBER 
OF PATIENTS 
Up to 150 patients who have completed the IBM4809 trial will be available for this trial. 
TRIAL ENTRY 
CRITERIA 
Inclusion criteria: 
1. Patient is able to comprehend and is willing to provide written informed consent 
and is capable and willing to comply with trial procedures. 
2. Patient has completed the IBM4809 trial on treatment with IMP. 
Exclusion criteria: 
1. Known or suspected allergy or intolerance to arimoclomol or its constituents. 
2. Exposure to any other investigational treatment within 30 days or <5 half-lives 
of the baseline visit or taking part or planning to take part in another 
interventional trial.  
3. Significant protocol deviation in the blinded IBM4809 trial based on the 
investigator’s judgement in discussion with the medical monitor. 
4. Women who are lactating or pregnant, or men or women unwilling to use a 
highly effective method of birth control if not surgically sterile (defined as 
bilateral tubal ligation, bilateral oophorectomy, or hysterectomy for women; 
vasectomy for men) for female participants until 4 weeks after last dose and for 
male participants up to 3 months after last dose. Premenopausal women must 
have a negative pregnancy test prior to dosing with trial medication. Acceptable 
methods of birth control are: 
• 
Hormonal methods associated with inhibition of ovulation such as oral, 
implantable, injectable, or transdermal contraceptives for a minimum 
of 1 full cycle (based on the patient’s usual menstrual cycle period) 
before arimoclomol administration. 
• 
Total abstinence from sexual intercourse since the last menses before 
arimoclomol administration. (The reliability of sexual abstinence needs 
to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the patient. Periodic abstinence 
[calendar, symptothermal, post-ovulation] methods, are not acceptable 
methods of contraception). 
• 
Intrauterine device (IUD) or intrauterine hormone-releasing system 
(IUS). 
5. Any concurrent condition that in the investigator’s opinion will significantly 
interfere with assessment of safety or efficacy.  
6. Inability to comply with the protocol-specified procedures/evaluations and 
scheduled visits as per the investigator. 
TEST PRODUCT 
Name: Arimoclomol citrate will be provided in the form of size “0”, white hard capsules 
of 200 mg for oral administration. 
Dose, route, frequency: Patients who completed the IBM4809 study at a reduced dose of 
arimoclomol will continue to receive their reduced dose of 600 mg/day arimoclomol 
citrate (200 mg t.i.d.) in this OLE study. All other patients will receive 1200 mg/day 
arimoclomol citrate (400 mg t.i.d.) orally. 
CONTROL 
PRODUCT(S) 
Not applicable. 


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TREATMENT 
REGIMENS 
The contents of the hard capsules can be dispersed in 10 to 30 mL (i.e., 1 to 2 tablespoons) 
of water, milk, or juice; or sprinkled on foods such as apple sauce or yogurt to promote 
dose compliance. 
In an aqueous dispersed state, the capsule content can be administered through a gastric 
tube. The tube should be flushed with 5 mL of water. 
If a patient experiences an intolerable AE, dosing may be interrupted, and supportive 
therapy may be administered as required. An interruption of up to 4 weeks (calculated 
from the first day of interruption) prior to resuming arimoclomol is permitted. The 
interruption of the dose should be as short as possible. If the patient experiences the same 
intolerable AE after re-challenge with the full dose of arimoclomol, arimoclomol must 
be discontinued permanently. 
Re-challenge with IMP in cases of increased transaminases should only be done in 
accordance with section 0 of the protocol. 
COORDINATING 
INVESTIGATOR 
, MD, Professor of Neurology 
University of Kansas Medical Center (KUMC) 
PLANNED TRIAL 
SITES 
Approximately 11 trial sites in the United States and 1 trial site in the United Kingdom.  
CRITERIA FOR 
EVALUATION 
• 
Primary efficacy endpoint:  
o 
Change in the IBMFRS total score from IBM4809 baseline to Month 20 in the 
OLE trial. 
• 
Secondary efficacy endpoints:  
o 
Change in 6-Minute Walk Test Distance from IBM4809 baseline to Month 20 
in the OLE trial. 
o 
Change in Modified Timed Up and Go (mTUG) from IBM4809 baseline to 
Month 20 in the OLE trial. 
o 
Change in MVICT of the quadriceps muscle from IBM4809 baseline to Month 
20 in the OLE trial.  
o 
Change in hand grip strength from IBM4809 baseline to Month 20 in the OLE 
trial  
o 
Change in SF-36 from IBM4809 baseline to Month 20 in the OLE trial.  
o 
Number of Falls from IBM4809 baseline to Month 20 in the OLE trial.  
o 
Number of Near Falls from IBM4809 baseline to Month 20 in the OLE trial.  
o 
Change in the IBMFRS total score from IBM4809 baseline to Month 40 in the 
OLE trial.   
o 
Change in hand grip strength from IBM4809 baseline to Month 40 in the OLE 
trial. 
• 
Exploratory endpoints:  
o 
Population pharmacokinetics (popPK) and popPK/PD (reported separately) 
o 
Change from baseline* over 20 months of arimoclomol treatment in IBMFRS 
total score in arimoclomol naïve patients 
o 
Change from baseline* over 20 months of arimoclomol treatment in 6-Minute 
Walk Test Distance in arimoclomol naïve patients 
o 
Change from baseline* over 20 months of arimoclomol treatment in Modified 
Timed Up and Go (mTUG) in arimoclomol naïve patients 
o 
Change from baseline* over 20 months of arimoclomol treatment in MVICT of 
the quadriceps muscle in arimoclomol naïve patients 


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o 
Change from baseline* over 20 months of arimoclomol treatment in hand grip 
strength in arimoclomol naïve patients 
o 
Change from baseline* over 20 months of arimoclomol treatment in SF-36 in 
arimoclomol naïve patients 
• 
Safety endpoints:  
o 
Safety parameters (AEs, SAEs, clinical safety laboratory values, vital signs, C 
SSRS to month 40 
* Baseline is defined at the visit at which the subject receives first administration of arimoclomol 
(corresponding to Month 0 in IBM4809 baseline and Month 0 in the OLE trial for patients randomized to 
arimoclomol and placebo in IBM4809, respectively). 
STATISTICAL 
METHODS 
Analyses will compare efficacy and safety findings between those patients who received 
arimoclomol (early start group) in the IBM4809 trial and those who received placebo 
(delayed start group). Summaries will also present data for the overall group. 
Analysis Populations: 
Safety Population: All patients who receive at least 1 dose or partial dose of arimoclomol 
in the extension trial. Safety analyses will be performed on the Safety Population. 
Modified Intent-to-treat (mITT) Population: All patients receiving at least 1 dose or 
partial dose of arimoclomol in the extension trial, with a baseline value and at least 1 
post-baseline value for IBMFRS. Efficacy analyses will be performed on the mITT 
Population. 
Patient Characteristics and Disposition: 
The distributions of demographic and clinical characteristics will be described for the 
early start and delayed start groups as well as the overall cohort using standard summary 
statistics. 
Efficacy Analysis: 
Differences in change from IBM4809 baseline to Month 20 in the OLE trial in IBMFRS 
between patients randomized to arimoclomol (early start) and placebo (delayed start) in 
IBM4809 will be determined using a modified 2-treatment period/delayed randomization 
analysis (to be detailed in the statistical analysis plan). 
Additional efficacy variables will be explored through descriptive statistics at each 
scheduled visit of the current trial. For statistical analyses 95% confidence intervals will 
be provided for changes from baseline. 
PopPK and popPK/PD Analyses:  
All plasma arimoclomol concentration and dosing data will be merged with the PK 
sampling dates and times and used to create the population PK input file for use in a 
popPK modelling analysis. In addition, the potential relationship between systemic 
exposure of arimoclomol and efficacy/safety measures may be explored using 
appropriate pharmacokinetic/pharmacodynamic models. The population PK and 
popPK/PD analysis plan will be described in a separate protocol and the results reported 
separately.  
Safety Analyses: 
Safety analysis (AEs, clinical safety laboratory values, vital signs, C-SSRS) will be 
descriptive, based on the Safety Population. TEAEs will be summarized by incidence, 
severity and causality. Continuous safety variables (vital signs, clinical safety laboratory 
test results) will be presented using descriptive statistics. For analyses of changes from 
baseline for laboratory values and vital signs parameters, baseline values from the blinded 
IBM4809 trial or from the current trial may be considered. 


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The C-SSRS will be summarized. 
Compliance data will be summarized by treatment group, overall and by visit.  
SAMPLE SIZE 
DETERMINATION 
As this trial is an open-label extension planning to include patients from the previous trial 
(IBM4809), no calculation for sample size was performed. 
TRIAL AND 
TREATMENT 
DURATION 
The overall OLE trial duration from the enrollment of the first patient to the completion 
of the last patient is expected to be approximately 5 years. The maximum participation 
period for an individual subject is 41 months.  
 
2.2. Schedule of Events 
Table 2-1:  
Schedule of Events 
Treatment period 1 (Month 0-20) 
Visit # 
1 
2 
3 
(ph
one 
visit
) 
4 
(ph
one 
visit
) 
5 
(ph
one 
visit
) 
5a 
6  
(ph
one 
visit
) 
7 
8 
(ph
one 
visit
) 
9 
10 
(ph
one 
visit
) 
11 / 
ETa 
Month 
0b 
1 
2 
3 
4 
5 
6  
9 
12 
15 
18 
20 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
 
 
 
 
 
  
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
Xb 
 
 
 
 
 
 
 
 
 
 
 
Vital signs, including weight 
Xb 
X 
 
 
 
X 
 
X 
 
X 
 
X 
Physical Examination 
Xb 
X 
 
 
 
X 
 
X 
 
X 
 
X 
Electrocardiogram 
Xb 
 
 
 
 
 
 
X 
 
 
 
X 
Clinical Safety Lab Tests 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Urine Pregnancy Test 
Xb 
X 
 
 
 
X 
 
X 
 
X 
 
X 
Dispensing of Medication 
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
First dose of open-label 
arimoclomol 
X 
 
 
 
 
 
 
 
 
 
 
 
Return of Medication 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
C-SSRS 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MVICT of the quadriceps muscle 
Xb 
 
 
 
 
 
 
X 
 
 
 
X 
SF-36 
Xb 
 
 
 
 
 
 
X 
 
 
 
X 
Falls diary 
Xb 
X 
 
 
 
X 
 
X 
 
X 
 
X 
Hand Grip Strength 
Xb 
 
 
 
 
 
 
X 
 
 
 
X 
IBMFRS 
Xb 
X 
 
 
 
X 
 
X 
 
X 
 
X 
6MWT 
Xb 
 
 
 
 
X 
 
X 
 
X 
 
X 
mTUG 
Xb 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biobank Samples 
Xb 
 
 
 
 
 
 
X 
 
 
 
X 
PopPK Samples 
 
 
 
 
 
 
 
X 
 
 
 
X 
Concomitant Medications 
Xb,d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
Xb,d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Treatment period 2 (Month 21-40) 
 
Abbreviations: 6MWT = 6-Minute Walk Test; C-SSRS = Columbia Suicide Severity Rating Scale; ET = early termination; 
IBMFRS = Inclusion Body Myositis Functional Rating Scale; 
; mTUG = Modified Timed Up 
and Go; MVICT = Maximal Voluntary Isometric Contraction Testing; PopPK = population pharmacokinetics; SF-36 = 36-Item 
Short Form Health Survey 
Note: Visit windows for all visits are ± 7 days relative to Visit 1. 
a 
If a patient discontinues during treatment period 1 (or the trial is terminated) before Visit 11/Month 20, an ET visit for 
treatment period 1 (month 20) will be performed as soon as possible after discontinuation, with a safety follow up phone visit 
2 weeks later. 
b 
Data from the completion visit of IBM4809 will be transferred to Visit 1 of IBM-OLE if required in the OLE trial, but not 
collected, except for safety labs, which require samples for both studies. If this extension trial has not yet been initiated at the 
site, screen the patient per Section 10.2.1.  
c 
 
 
d 
Ongoing AEs and concomitant medications from IBM4809 should be recorded in the IBM-OLE eCRF. 
e 
Assess and record SAEs occurring since the last evaluation and collect stop dates for already ongoing AEs. 
f  
If a patient discontinues during treatment period 2 (or the trial is terminated) between Visit 11/Month 20 and Visit 18/Month 
40, an ET visit for treatment period 2 (month 40) will be performed as soon as possible after discontinuation, with a safety 
follow up phone visit 2 weeks later. 
 
Visit # 
12 
 
13 
(phone 
visit) 
14 
15 
(phone 
visit) 
16 
17 
(phone 
visit) 
18 / 
ETf 
19 
(Safety 
follow 
up) 
Month 
23 
26 
29 
32 
35 
38 
40 
ET+2 
wks 
Vital signs, including weight 
X 
 
X 
 
X 
 
X 
 
Clinical Safety Lab Tests 
X 
 
X 
 
X 
 
X 
 
Urine Pregnancy Test 
X 
 
X 
 
X 
 
X 
 
Dispensing of Medication 
X 
X 
X 
X 
X 
X 
 
 
Return of Medication 
X 
 
X 
 
X 
 
X 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
 
IBMFRS 
X 
 
X 
 
X 
 
X 
 
Hand Grip Strength 
X 
 
X 
 
X 
 
X 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Xe 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Xe 


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3. TABLE OF CONTENTS 
1. 
APPROVAL SIGNATURES ...................................................................................................2 
2. 
PROTOCOL SUMMARY ........................................................................................................3 
2.1. Synopsis ..........................................................................................................................3 
2.2. Schedule of Events ..........................................................................................................8 
3. 
TABLE OF CONTENTS .......................................................................................................10 
3.1. List of In-Text Tables....................................................................................................13 
4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...........................................14 
5. 
INTRODUCTION ..................................................................................................................16 
5.1. Background and Rationale ............................................................................................16 
5.2. Clinical Experience .......................................................................................................16 
5.3. Summary of Potential Risks and Benefits .....................................................................17 
6. 
OBJECTIVES AND PURPOSE .............................................................................................18 
6.1. Objectives ......................................................................................................................18 
6.1.1 Primary Objective ..............................................................................................18 
6.1.2 Secondary Objectives ........................................................................................18 
6.1.3 Exploratory Objectives ......................................................................................18 
7. 
TRIAL DESIGN .....................................................................................................................19 
7.1. Overall Trial Design and Plan .......................................................................................19 
7.2. Rationale and Discussion of Trial Design .....................................................................20 
7.3. Selection of Doses in the Trial ......................................................................................20 
7.4. Trial Sites ......................................................................................................................20 
7.5. End of Trial Definition ..................................................................................................20 
8. 
PATIENT POPULATION ......................................................................................................21 
8.1. Selection of Trial Population and Diagnosis .................................................................21 
8.2. Trial Entry Criteria ........................................................................................................21 
8.2.1 Inclusion Criteria ...............................................................................................21 
8.2.2 Exclusion Criteria ..............................................................................................21 
8.3. Premature Patient Withdrawal ......................................................................................22 
8.4. Discontinuation of Study Intervention ..........................................................................22 
8.5. Participant Discontinuation/Withdrawal from the Trial ...............................................23 
9. 
TREATMENTS ......................................................................................................................24 
9.1. Identification of Investigational Medicinal Product .....................................................24 
9.1.1 Rescue Medication ............................................................................................24 
9.2. Selection of Timing of Dose for Each Patient ..............................................................24 
9.3. Dose Adjustment Criteria ..............................................................................................24 
9.3.1 Stopping Rules ..................................................................................................24 
9.4. Treatment Compliance ..................................................................................................24 


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9.5. Method of Assigning Patients to Treatment Groups .....................................................24 
9.6. Blinding and Unblinding Treatment Assignment .........................................................24 
9.7. Permitted and Prohibited Therapies ..............................................................................25 
9.7.1 Permitted Therapies ...........................................................................................25 
9.7.2 Prohibited Therapies ..........................................................................................25 
9.7.3 Restrictions ........................................................................................................26 
9.8. Treatment After End of Trial ........................................................................................26 
9.9. Dispensing and Storage .................................................................................................26 
9.10. Drug Accountability ......................................................................................................26 
9.11. Labeling and Packaging ................................................................................................27 
9.11.1 Labeling .............................................................................................................27 
9.11.2 Packaging ..........................................................................................................27 
10. TRIAL PROCEDURES..........................................................................................................28 
10.1. Trial Duration ................................................................................................................28 
10.1.1 Overall Trial Schedule .......................................................................................28 
10.2. Trial Periods and Visits .................................................................................................28 
10.2.1 Baseline .............................................................................................................28 
10.2.2 Treatment Periods: ............................................................................................29 
10.2.2.1 Clinic Visits ...........................................................................................29 
10.2.2.2 Telephone Visits....................................................................................30 
10.2.2.3 Early Termination Visit and Telephone Visit for Patients Who 
Discontinue Prematurely ........................................................................................31 
10.3. Assessments ..................................................................................................................32 
10.3.1 Efficacy Variables .............................................................................................32 
10.3.1.1 IBM Functional Rating Scale ................................................................32 
10.3.1.2 6-Minute Walk Test with 2-Minute Distance Captured ........................32 
10.3.1.3 Modified Timed Up and Go (mTUG) ...................................................32 
10.3.1.4 Quadriceps Muscle Strength Testing ....................................................33 
10.3.1.5 Hand Grip Strength Testing ..................................................................33 
10.3.1.6 SF-36 .....................................................................................................33 
10.3.1.7 Number of Falls and Near Falls ............................................................33 
10.3.2 PK and Biobanking ...........................................................................................33 
10.3.2.1 Population Pharmacokinetics (PopPK) .................................................33 
10.3.2.2 Biobanking ............................................................................................33 
10.3.3 Safety Variables ................................................................................................33 
10.3.3.1 Clinical Safety Laboratory Assessments ...............................................34 
10.3.3.2 Clinical Examinations ...........................................................................36 
10.3.3.3 Adverse Events......................................................................................37 


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11. ADVERSE EVENTS..............................................................................................................38 
11.1. Definitions .....................................................................................................................38 
11.1.1 Adverse Events ..................................................................................................38 
11.1.2 Unexpected Adverse Events ..............................................................................38 
11.1.3 Serious Adverse Events .....................................................................................38 
11.1.4 Treatment-Emergent Adverse Events ...............................................................39 
11.2. Collection of Adverse Events........................................................................................39 
11.2.1 Severity of Adverse Events ...............................................................................40 
11.2.2 Adverse Event Relationship to Investigational Product ....................................40 
11.3. Treatment of Adverse Events ........................................................................................40 
11.4. Reporting of Serious Adverse Events ...........................................................................41 
11.5. Pregnancy ......................................................................................................................42 
12. STATISTICS ..........................................................................................................................43 
12.1. Statistical Analysis ........................................................................................................43 
12.1.1 Analysis Populations .........................................................................................43 
12.1.2 Trial Patients and Demographics ......................................................................43 
12.1.2.1 Disposition and Withdrawals ................................................................43 
12.1.2.2 Protocol Deviations ...............................................................................43 
12.1.2.3 Demographics and Other Baseline Characteristics ...............................44 
12.1.3 Exposure and Compliance .................................................................................44 
12.1.4 Efficacy Analysis ..............................................................................................44 
12.1.4.1 Efficacy Endpoints ................................................................................44 
12.1.4.2 Efficacy Analysis ..................................................................................45 
12.1.4.3 Exploratory, Corroborative, Sensitivity, and Other Analyses...............45 
12.1.5 PopPK and PopPK/PD Analyses .......................................................................45 
12.1.6 Safety and Tolerability Analyses ......................................................................46 
12.1.6.1 Adverse Events......................................................................................46 
12.1.6.2 Clinical Laboratory Evaluations ...........................................................46 
12.1.6.3 Vital Signs .............................................................................................46 
12.1.7 Interim Analysis ................................................................................................46 
12.2. Sample Size Determination ...........................................................................................47 
13. TRIAL CONDUCT ................................................................................................................48 
13.1. Sponsor and Investigator Responsibilities ....................................................................48 
13.1.1 Sponsor Responsibilities ...................................................................................48 
13.1.2 Investigator Responsibilities .............................................................................48 
13.1.3 Confidentiality and Privacy ...............................................................................48 
13.2. Site Initiation .................................................................................................................49 
13.3. Trial Documents ............................................................................................................49 


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13.3.1 Informed Consent ..............................................................................................49 
13.3.2 Investigator’s Regulatory/Good Clinical Practice Documents .........................50 
13.3.3 Case Report Forms ............................................................................................50 
13.3.4 Source Documents .............................................................................................50 
13.4. Data Quality Control .....................................................................................................50 
13.4.1 Monitoring Procedures ......................................................................................50 
13.4.2 Data Management ..............................................................................................51 
13.4.3 Quality Assurance/Audit ...................................................................................51 
13.5. Study Leadership ...........................................................................................................52 
13.6. Trial Termination ..........................................................................................................52 
13.6.1 Regular Trial Termination .................................................................................52 
13.7. Trial Site Closure ..........................................................................................................52 
13.7.1 Record Retention ...............................................................................................52 
13.7.2 Sample Retention ..............................................................................................53 
13.8. Changes to the Protocol ................................................................................................53 
13.9. Use of Information and Publication ..............................................................................53 
14. FINAL CLINICAL STUDY REPORT ..................................................................................55 
15. ETHICAL AND LEGAL CONSIDERATIONS ....................................................................56 
15.1. Declaration of Helsinki and Good Clinical Practice .....................................................56 
15.2. Patient Information and Informed Consent and/or Assent ............................................56 
15.3. Approval by Institutional Review Boards and Independent Ethics Committees ..........56 
15.4. Finance and Insurance ...................................................................................................56 
16. REFERENCES .......................................................................................................................57 
17. ATTACHMENTS ...................................................................................................................58 
17.1. Investigator’s Agreement ..............................................................................................58 
APPENDICES ...............................................................................................................................59 
A. 
Trial-Specific Requirements .........................................................................................60 
17.1.1 Coronavirus (COVID) operational changes ......................................................60 
APPENDIX 1: IBM FUNCTIONAL RATING SCALE ...............................................................61 
APPENDIX 2: 
 SUB-STUDY ................................................................................................62 
B. 
Regulations and Good Clinical Practice Guidelines .....................................................73 
 
3.1. List of In-Text Tables 
Table 2-1:  
Schedule of Events ..............................................................................................8 
 
 


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4. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ABBREVIATION 
EXPLANATION 
AE 
adverse event 
ALS 
amyotrophic lateral sclerosis 
ALT 
alanine aminotransferase (SGPT) 
AST 
aspartate aminotransferase (SGOT) 
BBB 
blood-brain barrier 
BMI 
body mass index 
CRA 
clinical research associate 
CRF 
case report form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DILI 
DMC 
Drug-induced liver injury 
Data Monitoring Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ET 
Early termination 
GCP 
Good Clinical Practice 
GD 
Gaucher’s disease 
HSP 
heat shock protein 
IB 
investigator brochure 
IBM 
inclusion body myositis 
IBMFRS 
Inclusion Body Myositis Functional Rating Scale 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IMPD 
INR 
IRB 
investigational medicinal product dossier 
International Normalised Ratio 
institutional review board 
ITT 
intent-to-treat 
IVIg 
intravenous immunoglobulin 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
mTUG 
Modified Timed Up and Go 
MVICT 
Maximal Voluntary Isometric Contraction Testing 
NASH 
Non-Alcoholic Steatohepatitis 


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ABBREVIATION 
EXPLANATION 
NPC 
Niemann-Pick Type C 
OLE 
open-label extension 
PK 
pharmacokinetics 
Pop-PK 
population pharmacokinetics 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SF-36 
36-Item Short Form Health Survey 
t.i.d. 
3 times a day (ter in die) 
TMF 
trial master file 
ULN 
upper limit of normal 
WHO-DD 
World Health Organization Drug Dictionary 


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5. INTRODUCTION 
5.1. Background and Rationale 
In the US, the prevalence of sporadic inclusion body myositis (IBM) is unknown, but is 
conservatively estimated to be 24 cases per million and the upper prevalence estimate is 45 per 
million (Callan et al., 2017). Because biopsies of IBM muscle contain lymphocytic inflammatory 
cells and show up-regulation of major histocompatibility complex class I molecules (MHC-I), IBM 
was originally grouped with the idiopathic inflammatory myopathies: polymyositis and 
dermatomyositis. However, pathologic trials during the past 25 years have clearly defined it as a 
unique pathogenic entity. Sporadic inclusion body myositis causes both proximal and distal muscle 
weakness, characteristically most prominent in the quadriceps and finger flexors. Over time it can 
lead to severe disability, including falls due to quadriceps muscle weakness and foot drop, 
dysphagia, and eventually respiratory muscle weakness. Sporadic inclusion body myositis seldom 
affects patients under 40 and is much more common over the age of 50. Men are affected more 
frequently than women. Causes of death in patients with IBM are often ascribed to dysphagia, 
weakness of respiratory muscles, malnutrition, cachexia, aspiration, respiratory infection, or even 
respiratory failure (Price et al., 2016). There are no effective treatments for IBM. Therefore, there 
is a significant unmet need for these patients. Patients are often given steroids or intravenous 
immunoglobulin treatment, but the evidence for these treatments is lacking. Supportive measures 
include physical therapy and mild to moderate intensity exercise, and the use of devices and aids 
to mobility including motorized wheelchairs. 
Arimoclomol is an orally available small molecule that readily crosses the blood-brain barrier 
(BBB) to stimulate an increased production of heat shock proteins (HSPs), in particular HSP70, 
which are natural defenses against protein misfolding under cellular stress. Arimoclomol may 
therefore be used to treat conditions that involve misfolded proteins, including lysosomal storage 
diseases such as Niemann-Pick Type C (NPC) and Gaucher’s disease (GD), and protein 
aggregation disorders such as amyotrophic lateral sclerosis (ALS) and IBM. Arimoclomol is being 
developed for the indications NPC, GD, ALS, and IBM. Clinical trials have been or are currently 
conducted in healthy subjects, patients with NPC, GD, ALS, and IBM. Arimoclomol has also been 
evaluated in investigator-led trials in patients with ALS and IBM.  
5.2. Clinical Experience 
A total of 14 clinical trials with arimoclomol relevant for the indications NPC, GD, ALS, and IBM 
have been completed or are ongoing. These include 8 Phase 1 trials in healthy subjects for 
evaluation of a single dose, multiple doses, food effects, absorption, distribution, metabolism and 
elimination, as well as renal safety. In the Phase 1 trials, 112 healthy subjects were exposed to 
arimoclomol and 24 received placebo. Daily doses in healthy subjects ranged from 50 to 1800 mg. 
In NPC, 1 trial is ongoing: a Phase 2/3 trial to evaluate the efficacy and safety of arimoclomol 
compared to placebo (trial CT-ORZY-NPC-002), including 50 patients treated with arimoclomol 
(300 mg/day) or placebo. In ALS, a Phase 2 trial (trial AALS-001) has been conducted assessing 
safety and tolerability and pharmacokinetics (PK) in serum and cerebrospinal fluid. In an extension 
to this trial (trial AALS 001-OL), the safety and exploratory efficacy of longer term (6 months) 
open-label arimoclomol treatment was evaluated. In trial AALS-001, 62 patients with ALS 
received arimoclomol (75 to 300 mg/day) and 22 patients received placebo. In trial AALS-001-
OL, 69 patients received arimoclomol (300 mg/day). Results from these trials suggest that 
arimoclomol crosses the BBB. The ALS functional rating scale-revised (ALSFRS-R) progression 


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rates in the 6-month open-label part of the trial showed slowing of functional loss compared to a 
historical control group. Arimoclomol was safe and well-tolerated in these trials. In addition, an 
investigator-initiated trial in rapidly progressive SOD1-ALS has been conducted where 17 patients 
received arimoclomol (300 to 600 mg/day) and 19 patients received placebo (trial 20100758). An 
investigator-initiated clinical trial with arimoclomol in which 16 patients with inclusion body 
myositis (IBM) received arimoclomol (300 mg/day) and 8 received placebo has been completed 
(trial 10656).  
5.3. Summary of Potential Risks and 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 patients 
with IBM. There was a trend in favor of arimoclomol in secondary endpoints of muscle function 
and functional IBM scales (Ahmed et al., 2016). If arimoclomol was found to be beneficial for the 
treatment of IBM, this would represent the only effective treatment for this otherwise progressive 
disease. 
Data from the completed trials 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 and serum cystatin C, suggesting an inhibitory effect of arimoclomol on tubular 
secretion of creatinine. The increase in serum creatinine may be explained by an interaction of 
arimoclomol with the organic cation transporter 2 (OCT2) and the multidrug and toxin extrusion 
(MATE) transporters. One elderly patient with IBM experienced severe tubulointerstitial nephritis 
with acute tubular injury and acute tubular necrosis approximately 1 month after initiation of 
arimoclomol. Although the patient had autoimmune disease (Sjogren’s syndrome) and was treated 
with omeprazole, both of which may have contributed to the event, it cannot be ruled out that the 
event was caused by treatment with arimoclomol. A summary of the pharmaceutical properties 
and known potential risks of arimoclomol is provided in the current version of the investigator’s 
brochure (IB). The investigator must become familiar with all sections of the arimoclomol IB 
before the start of the trial. 
 


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6. OBJECTIVES AND PURPOSE 
6.1. Objectives 
6.1.1 Primary Objective  
The primary objective is to determine the efficacy (based on the Inclusion Body Myositis 
Functional Rating Scale [IBMFRS]) of early* versus delayed start of arimoclomol treatment of 
IBM up to Month 20 in the OLE trial.  
6.1.2 Secondary Objectives  
Secondary objectives include the following: 
• To determine the safety and tolerability of long-term treatment of IBM with arimoclomol 
up to Month 40 in the OLE trial. 
• To determine the efficacy (on secondary efficacy endpoints) of early* versus delayed start 
of arimoclomol treatment of IBM up to Month 20 in the OLE trial. 
• To determine the efficacy (on secondary efficacy endpoints) of early* versus delayed start 
of arimoclomol treatment of IBM up to Month 40 in the OLE trial. 
6.1.3 Exploratory Objectives  
Exploratory objectives include the following: 
• 
 
. 
• To explore population pharmacokinetics (popPK) and popPK/PD. 
• To determine the efficacy (on secondary efficacy endpoints) of early** versus delayed 
start of arimoclomol treatment over periods of 20 months duration.  
 
*  Including 20 months arimoclomol treatment and 20 months placebo treatment from trial 
IBM4809 for the early and delayed start group, respectively. 
** Including (only) 20 months arimoclomol treatment from trial IBM4809 for the early start 
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7. TRIAL DESIGN 
7.1. Overall Trial Design and Plan 
This Phase 3b, multicenter, nonrandomized, open-labelled, uncontrolled clinical extension trial is 
designed to compare the efficacy and safety of early versus delayed start of arimoclomol in the 
treatment of IBM and to explore long-term safety and tolerability of arimoclomol. Up to 150 male 
and female patients who have completed the IBM4809 trial will be available for this trial. Patients 
must currently be on treatment with the investigational medicinal product (IMP) from the blinded 
IBM4809 trial (arimoclomol or placebo) and will enroll in this trial at Visit 14/Month 20 of the 
blinded IBM4809 trial.  
Patients who completed the IBM4809 study at a reduced dose of arimoclomol will continue to 
receive their reduced dose of 600 mg/day arimoclomol citrate (200 mg t.i.d.) in this open-label 
extension (OLE) study. All other patients will receive 1200 mg/day arimoclomol citrate (400 mg 
t.i.d.).  
The OLE trial is a 40 months open-labelled extension of the blinded IBM4809 trial. Combined 
with the IBM4809 data from treatment period 1 the patients in the active group of IBM4809 will 
provide long-term (up to 60 months) efficacy, safety and tolerability data. For the placebo group 
in IBM4809 the OLE trial will provide additional safety and tolerability data over 40 months and 
information about the impact of delayed treatment initiation on efficacy.  
The OLE trial consist of 2 treatment period. The only difference between the 2 treatment periods 
is the assessments performed and the visit schedule. Both treatment periods are described below.   
 
Treatment period 1 (Month 0 – 20)  
Patients will be seen in the clinic at baseline and month 1, 5 and 9, 15 and 20. Visits will be 
conducted by telephone at month 2, 3, 4, 6, 12 and 18. For the telephone visits at month 2, 3, 4 and 
6 a clinical safety laboratory assessment is also required.  
Efficacy will be assessed by the IBMFRS total score, 6-Minute Walk Test, Modified Timed Up 
and Go (mTUG), Maximal Voluntary Isometric Contraction Testing (MVICT) of the quadriceps 
muscle, hand grip strength testing, 36-Item Short Form Health Survey (SF-36), and falls and near 
falls. 
 
Sparse PK samples will be collected for popPK analysis and explorative popPK/PD modeling. 
Additional blood will be drawn for biobanking for future potential tests. 
Safety and tolerability will be assessed by evaluating adverse events (AEs), clinical laboratory test 
results, vital sign measurements, 12-lead electrocardiograms (ECGs), physical examination 
findings, and the Columbia Suicide Severity Rating Scale (C-SSRS). 
All AEs observed by the trial personnel or reported by the patient during the trial will be 
documented. 
Analyses will compare efficacy and safety findings between those patients who received 
arimoclomol (early start group) in the IBM4809 trial and those who received placebo (delayed 
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Treatment period 2 (Month 21-40) 
Patients will be seen in the clinic at month 23, 29, 35 and 40. Visits will be conducted by telephone 
at month 26, 32 and 38.  
Efficacy will be assessed by the IBMFRS total score and hand grip strength testing. 
Safety and tolerability will be assessed by evaluating AEs, clinical laboratory test results, vital sign 
measurements and C-SSRS. 
Treatment period 2 will provide efficacy and safety data for up to an additional 20 months.  
For the early start group, treatment period 2 provides data from a period which represents the 41st  
to 60th month of active treatment across both clinical trials. For the delayed start group, treatment 
period 2 provides data from a period which represents the 21st to 40th month of active treatment 
across both clinical trials. 
 
7.2. Rationale and Discussion of Trial Design 
The IBM4809 trial is a double-blind, placebo-controlled trial designed to determine the efficacy 
and safety of 1200 mg/day arimoclomol citrate (400 mg t.i.d.) for 20 months, compared to placebo, 
in patients with IBM. In the present extension trial, patients completing trial IBM4809 will be 
invited to receive open-label arimoclomol at the same daily dosage for a further 20 months; those 
patients who received arimoclomol in the IBM4809 trial will be considered the early start group; 
patients who received placebo in the IBM4809 trial will be considered the delayed treatment group. 
The 40 months extension will together with the IBM4809 trial data provide additional information 
on the safety and tolerability of arimoclomol for a total of 60 months for the patients who were 
randomized to arimoclomol in the IBM4809 trial.    
This extension trial allows for additional comparison of efficacy and safety of arimoclomol 
between the two groups, while affording continued access to arimoclomol in the absence of 
approved pharmaceutical treatment for IBM.  
 
7.3. Selection of Doses in the Trial 
Patients who completed the IBM4809 study at a reduced dose of 600 mg/day arimoclomol citrate 
will continue to receive their reduced dose in this OLE study. All other patients in this open-label 
extension trial will be assigned to receive 1200 mg/day arimoclomol citrate (400 mg t.i.d.). 
7.4. Trial Sites 
The trial will take place at approximately 11 sites in the US and 1 site in the UK.  
7.5. End of Trial Definition 
The clinical trial will be considered completed when the last patient’s last trial visit has occurred.  
 


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8. PATIENT POPULATION 
8.1. Selection of Trial Population and Diagnosis 
There is no indication from the available data that age, sex, or race can potentially affect the safety 
or the efficacy of arimoclomol. Thus, male and female patients may be included in the trial. 
Patients who do not satisfy all of the eligibility criteria will not be enrolled. 
8.2. Trial Entry Criteria 
8.2.1 Inclusion Criteria 
A patient will be eligible for trial participation if he or she meets all of the following criteria: 
1. Patient is able to comprehend and is willing to provide written informed consent and is 
capable and willing to comply with trial procedures. 
2. Patient has completed the IBM4809 trial on treatment with IMP. 
8.2.2 Exclusion Criteria 
A patient will be excluded from the trial if he or she meets any of the following criteria: 
1. Known or suspected allergy or intolerance to arimoclomol or its constituents.  
2. Exposure to any other investigational treatment within 30 days or <5 half-lives of the 
baseline visit or taking part or planning to take part in another interventional trial.  
3. Significant protocol deviation in the blinded IBM4809 trial based on the investigator’s 
judgement in discussion with the medical monitor. 
4. 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 (estrogen 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 
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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.  
5. Any concurrent condition that in the investigator’s opinion will significantly interfere with 
assessment of safety or efficacy. 
6. Inability to comply with the protocol-specified procedures/evaluations and scheduled visits 
as per the investigator. 
8.3. Premature Patient Withdrawal 
All patients will be advised that they are free to withdraw from participation in this trial at any 
time, for any reason, and without prejudice. The investigator should make every reasonable 
attempt to keep patients in the trial; however, patients must be withdrawn from the trial if they 
withdraw consent to participate. Investigators must attempt to contact patients who fail to attend 
scheduled visits by telephone or other means to exclude the possibility of an AE being the cause 
of withdrawal. Should this be the cause, the AE must be documented, reported, and followed as 
described in Section 11.2. 
The sponsor reserves the right to request the withdrawal of a patient due to protocol deviations or 
other reasons. 
The investigator also has the right to withdraw patients from the trial at any time for lack of 
therapeutic effect that is intolerable or otherwise unacceptable to the patient, for intolerable or 
unacceptable AEs, intercurrent illness, noncompliance with trial procedures, administrative 
reasons, or in the investigator’s opinion, to protect the patient’s best interest. 
If a patient is withdrawn before completing the trial, the reason for withdrawal and the date of 
discontinuation will be recorded on the appropriate page of the electronic case report form (eCRF). 
Whenever possible and reasonable, the evaluations that were to be conducted at the completion of 
the trial should be performed at the time of premature discontinuation. Discontinuation of Study 
Intervention 
 
8.4. Discontinuation of Study Intervention  
Discontinuation from arimoclomol means discontinuation from the trial, and a final visit and 
2-week follow-up call should be completed as scheduled.  
According to the FDA Guidance for Industry on Drug-Induced Liver Injury (DILI) (4), 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) 
• 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%) 
 


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Re-challenge in case of increased transaminases:  
If in the Investigator’s judgement, a temporary halt in IMP is instituted because of elevated 
transaminases, medical monitor should be consulted. 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. 
 
8.5. Participant Discontinuation/Withdrawal from the Trial 
The patient will be advised in the informed consent form (ICF) that they have the right to withdraw 
from the trial at any time without prejudice and may be withdrawn at the investigator’s or sponsor’s 
discretion at any time. In addition, early withdrawal may occur for any of the following reasons: 
• 
Patient request 
• 
Investigator decides that it is in the patient’s interest 
• 
A serious adverse event (SAE) that is probably or definitely related to arimoclomol  
• 
Significant protocol violation 
• 
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), intravenous immunoglobulin (IVIg), or other immunosuppressants 
• 
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9. TREATMENTS 
9.1. Identification of Investigational Medicinal Product 
Arimoclomol citrate will be provided in the form of size “0”, white hard capsules of 200 mg for 
oral administration.  
9.1.1 Rescue Medication 
Currently there are no rescue medications, treatments, or procedures to treat IBM. 
9.2. Selection of Timing of Dose for Each Patient 
Patients who completed the IBM4809 study at a reduced dose of 600 mg/day arimoclomol citrate 
will continue to receive their reduced dose in this OLE study. For all other patients, including all 
patients who were randomized to placebo in the IBM4809 study, the dose will be 1200 mg/day 
(400 mg t.i.d).  
The contents of the hard capsules can be dispersed in 10 to 30 mL (i.e., 1 to 2 tablespoons) of 
water, milk, or juice; or sprinkled on foods such as apple sauce or yogurt to promote dose 
compliance. 
In an aqueous dispersed state, the capsule content can be administered through a gastric tube. The 
tube should be flushed with 5 mL of water. 
9.3. Dose Adjustment Criteria 
If a patient experiences an intolerable AE, dosing may be interrupted (not reduced) and supportive 
therapy may be administered as required. An interruption of up to 4 weeks (calculated from the 
first day of interruption) prior to resuming arimoclomol is permitted. The interruption of the dose 
should be as short as possible. If the patient experiences the same intolerable AE after re-challenge 
with the full dose of arimoclomol, arimoclomol must be discontinued permanently.  
9.3.1 Stopping Rules 
 According to the FDA Guidance for Industry on Drug-Induced Liver Injury (DILI) (4), IMP must 
be permanently discontinued under circumstances related to elevated transaminases (see Section 
0). IMP must also be discontinued for subjects with elevated transaminases where close 
observation (repeated laboratory tests) is not possible, see Section 0. 
9.4. Treatment Compliance 
Patients will use a medication log and will be instructed to return all unused arimoclomol at each 
clinic visit. Compliance will be assessed by review of the medication log at each visit and by 
documentation of unused arimoclomol. A patient who is not adherent (taking less than 80% of 
assigned capsules) will be counseled at each visit on the importance of taking arimoclomol as 
instructed. 
9.5. Method of Assigning Patients to Treatment Groups 
In this open-label, single-treatment trial, all patients will receive the same treatment. 
9.6. Blinding and Unblinding Treatment Assignment 
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9.7. Permitted and Prohibited Therapies 
All concomitant medications used (including over-the-counter medications and herbal 
supplements) will be recorded in the source document and on the appropriate eCRF. 
9.7.1 Permitted Therapies 
There may be soreness from the strength and functional tests that the patients must undergo. They 
may take normal prophylactic medications or undergo treatments or procedures to ease the 
soreness. Other concomitant medications are also allowed except as prohibited below. 
9.7.2 Prohibited Therapies 
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 MATE1 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 which are MATE1 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, trimetroprim, verapamil, levofloxacin, ciprofloxacin, moxifloxacin, pyrimethamine, 
ondansetron and quinidine. 
Based on in vitro studies, drug interactions related to cytochrome P450 (CYP) enzymes are not 
expected. Even though CYP2D6 inhibition was observed in vitro, the mechanistic static model 
predicts that it will not be clinically relevant. Consequently, concomitant use of drugs that are 
CYP2D6 substrate is not considered to be of concern. 
Animal studies have indicated a possible pharmacodynamic interaction with furosemide increased 
urinary volume and increased urinary creatinine, potassium, sodium, phosphorus and calcium; 
(additive effect) at high doses. Consequently, concomitant treatment with furosemide should be 
done with caution.  
 
The following medications are prohibited during the trial: 
• Use of testosterone except for physiologic replacement doses in case of androgen 
deficiency. Participants must have documented proof of the androgen deficiency 
• Cannabis except for treatment of IBM symptoms (where legal) 
• Prednisone, IVIg, or other immunosuppressants. 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 
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• Participation in other interventional trials, treatment with other investigational medicinal 
products or advanced therapeutic medical products (stem cells, gene therapy etc.), or 
treatment with investigational devices is not allowed. 
If a new precautionary or prohibited medication, treatment, or procedure is identified during the 
trial, all patients will be notified immediately and Institutional Review Boards (IRBs)/ Independent 
Ethics Committees (IECs) will be notified as soon as possible. 
9.7.3 Restrictions 
No other restrictions are specified. 
9.8. Treatment After End of Trial 
Subjects completing this trial may be offered to continue arimoclomol treatment via Early Access 
Programs as per applicable local regulations until arimoclomol is commercially available. Early 
Access Programs may vary depending on location and include Compassionate Use, Named 
Patient, Expanded Access, and Managed Access Programs. 
9.9. Dispensing and Storage 
The study drug (arimoclomol) supplied by Orphazyme A/S is to be used exclusively in the clinical 
trial according to the instructions of this protocol. The investigator is responsible for dispensing 
the study drug according to the dosage scheme and for ensuring its proper storage. 
The investigator must confirm the receipt of the study drug with his or her signature. A copy of 
this receipt must be kept by the investigator and another copy will be stored at Orphazyme A/S 
and/or Premier Research. Until the study drug is dispensed to the patients, it must be stored in a 
securely locked area that is not generally accessible. Based on the available stability data, the study 
drug capsules are recommended to be stored at USP controlled room temperature, i.e., at 15º to 
25ºC (59º to 77ºF) with excursions permitted between 2º and 30ºC (36º to 86ºF). 
The key to the storage area is to be kept by the investigator or designee responsible for the study 
drug. The storage area will be accessible only to those persons authorized by the investigator to 
dispense the study drug. 
9.10. Drug Accountability 
The investigator must maintain adequate records showing the receipt, dispensing, return, or other 
disposition of the study drug, including the date, quantity, batch or code number, and identification 
of patients (patient number) who received the study drug. The investigator will not supply the 
study drug to any person except those named as sub-investigators on the Form FDA 1572, 
designated trial personnel, and patients in this trial. The investigator will not dispense the study 
drug from any trial sites other than those listed on the Form FDA 1572. The study drug may not 
be relabeled or reassigned for use by other patients. Any study drug not dispensed; lost, stolen, 
spilled, or unusable; or received in a damaged container must be documented and reported to the 
sponsor and appropriate regulatory agencies, as required. 
Patients will receive trial medication at visits at baseline and at Months 1, 5, 9, 15, 20, 23, 26, 29, 
32, 35 and 38. Patients will use a medication log and will be instructed to return all unused trial 
medication at each clinic visit.  


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Upon completion of the trial, the study drug (partly used, unused, and empty bottles) must be left 
in the original packaging and returned to the sponsor or designee for destruction. 
9.11. Labeling and Packaging 
Labeling and packaging of the study drug will be performed according to the IMPD. 
9.11.1 Labeling 
Each bottle will have a label affixed that meets the applicable regulatory requirements in the 
countries where the trial is to be conducted. 
Save all empty packaging or packaging containing unused capsules for final disposition by the 
sponsor or contract pharmacy. 
9.11.2 Packaging 
The study drug will be packaged in high density polyethylene (HDPE) bottles, each containing 84 
capsules, and closed with a child-resistant screw cap. 


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10. TRIAL PROCEDURES 
Patients must provide written informed consent before any trial-related procedures are initiated, 
including the cessation of prohibited concomitant therapy. 
For the timing of assessments and procedures throughout the trial, refer to the schedule of events 
(Section 2.2). Throughout the trial, every reasonable effort should be made by trial personnel to 
follow the timing of assessments and procedures in the schedule of events for each patient. If a 
patient misses a trial visit for any reason, the visit should be rescheduled as soon as possible. 
10.1. Trial Duration 
10.1.1 Overall Trial Schedule 
The overall open-label extension trial duration from the enrollment of the first patient to the 
completion of the last patient is expected to be approximately 5 years. The maximum participation 
period for an individual subject adhering to the planned visit schedule is 41 months, including the 
planned safety follow-up visit two weeks after the scheduled ET visit at Month 40.  
10.2. Trial Periods and Visits 
See Section 10.3 for details on conducting the study assessments listed below. 
10.2.1 Baseline 
Patients must currently be on treatment with the IMP from the blinded IBM4809 trial (arimoclomol 
or placebo). The following procedures performed at Visit 14/Month 20 of the blinded IBM4809 
trial will serve as the baseline evaluations for this trial: 
1. Measure vital signs, including weight. 
2. Perform a physical examination.  
3. Perform a 12-lead ECG. 
4. Perform a urine pregnancy test for female patients of childbearing potential. 
5. Record concomitant medications and concomitant therapies. 
6. Assess and record AEs occurring since the last evaluation. 
7. Complete the IBMFRS, MVICT of quadriceps muscle, mTUG, hand grip strength testing, 
6-minute walk test, and SF-36. 
8. Complete the C-SSRS (“since last visit” assessment). 
9. Collect and review the falls diary. 
(NOTE: If this extension trial has not yet been initiated at a patient’s clinical site or if the 
patient are not able to perform in-clinic visits due to COVID-19 when the patient completes 
Visit 14, that patient may enroll in this trial up to 12 weeks after Visit 14/Month 20 of the 
blinded IBM4809 trial. Such patients will need to undergo the full set of baseline assessments, 
and the investigator must confirm eligibility. This possibility will only be available if the 
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The following procedures will be performed at baseline for this OLE trial: 
1. Obtain written informed consent (and/or assent if applicable). 
2. Record demographics. 
3. Record medical history. 
4. Assess inclusion/exclusion criteria. 
5. Collect blood for safety laboratory tests and biobanking. 
6. When all baseline procedures are completed and the site investigator confirms that the 
patient is eligible, enroll the patient. 
7. Administer the first dose of open-label arimoclomol and observe for 1 hour after dosing.  
8. Dispense arimoclomol for the initial 1-month period and give the patient instructions 
regarding dosing schedule and trial requirements. 
9. Give the patient a new falls diary. 
10.2.2 Treatment Periods: 
Treatment period 1: The treatment period begins at the baseline visit and continues until the ET 
visit at month 20.  
Treatment period 2: The treatment period begins after completing treatment period 1 and until the 
ET visit at month 40.  
For a detailed overview of the 2 treatment periods, see Section 2.2.  
 
10.2.2.1 Clinic Visits  
Treatment period 1: (Months 1, 5, 9, 15, and 20) 
The following procedures will be performed at the clinic visits: 
1. Measure vital signs, including weight. 
2. Perform a physical examination.  
3. Perform a 12-lead ECG (Months 9 and 20 only). 
4. Collect blood for clinical safety laboratory tests (all visits) and for biobanking (Months 9 
and 20 only; pre-dose). 
5. Collect blood for PK, at Months 9 and 20 only, at the following timepoints: 
• Month 9: pre-dose and 0.5 hours (+ 60 min) post-dose  
• Month 20: pre-dose and 1.5 hours (+ 60 min) post-dose  
6. Perform a urine pregnancy test for female patients of childbearing potential. 
7. Record concomitant medications and concomitant therapies. 
8. Assess and record AEs occurring since the last evaluation. 


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9. Complete the IBMFRS.  
10. Complete the 6-minute walk test, and mTUG (Months5, 9, 15, and 20 only). 
11. Complete the MVICT of quadriceps muscle, hand grip strength testing, and SF-36 (all at 
Months 9 and 20 only). 
12. Complete the C-SSRS (“since last visit” assessment). 
13. Collect and review the falls diary. 
14. Collect empty arimoclomol packaging and unused arimoclomol, and (at all but final visit) 
dispense additional arimoclomol. 
 
Treatment period 2: (Months 23, 29, 35 and 40) 
The following procedures will be performed at the clinic visits: 
1. Measure vital signs, including weight. 
2. Collect blood for clinical safety laboratory tests (all visits) 
3. Perform a urine pregnancy test for female patients of childbearing potential. 
4. Collect empty arimoclomol packaging and unused arimoclomol, and (at all but final visit) 
dispense additional arimoclomol. 
5. Complete the C-SSRS (“since last visit” assessment). 
6. Complete the IBMFRS.  
7. Complete the hand grip strength testing 
8. Record concomitant medications and concomitant therapies. 
9. Assess and record AEs occurring since the last evaluation. 
10.2.2.2 Telephone Visits  
Treatment period 1: (Months 2, 3, 4, 6, 12, and 18)  
The following procedures will be performed at the telephone visits: 
1. Record concomitant medications and concomitant therapies. 
2. Assess and record AEs occurring since the last evaluation. 
3. Complete the C-SSRS (“since last visit” assessment). 
4. Ensure the patient has sufficient arimoclomol and arrange for additional arimoclomol 
supplies if needed. 
5. Clinical Safety Laboratory assessments must be obtained at month 2, 3, 4 and 6 (preferably 
using Home Health Care or alternatively Local Laboratory)  


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Treatment period 2: (Months 26, 32 and 38)  
The following procedures will be performed at the telephone visits: 
1. Complete the C-SSRS (“since last visit” assessment). 
2. Record concomitant medications and concomitant therapies. 
3. Assess and record AEs occurring since the last evaluation. 
10.2.2.3 Early Termination Visit and Telephone Visit for Patients Who Discontinue 
Prematurely 
Treatment period 1:  
If a patient discontinues treatment (or the trial is terminated) before Visit 11/Month 20, an ET visit 
(see visit 11 in visit schedule) will be performed as soon as possible after discontinuation, and a 
follow-up phone assessment will be done 2 weeks later (see visit 19 in visit schedule for treatment 
period 2) .  
The following procedures will be performed at the ET visit: 
1. Measure vital signs, including weight. 
2. Perform a physical examination.  
3. Perform a 12-lead ECG. 
4. Collect blood for clinical safety laboratory tests, biobanking, and PK. 
5. Perform a urine pregnancy test for female patients of childbearing potential. 
6. Record concomitant medications and concomitant therapies. 
7. Assess and record AEs occurring since the last evaluation. 
8. Complete the IBMFRS, 6-minute walk test, and mTUG. 
9. Complete the MVICT of quadriceps muscle, hand grip strength testing, and SF-36. 
10. Complete the C-SSRS (“since last visit” assessment). 
11. Collect and review the falls diary. 
12. Collect empty arimoclomol packaging and unused arimoclomol. 
The following procedures will be performed at the ET phone visit: 
1. Record concomitant medications and concomitant therapies. 
2. Assess and record SAEs occurring since the last evaluation and collect stop dates for 
already ongoing AEs. 
 
Treatment period 2:  
If a patient discontinues treatment (or the trial is terminated) after Visit 11/Month 20 and before 
visit 18/month 40, an ET visit (see visit 18 in visit schedule) will be performed as soon as possible 


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after discontinuation, and a follow-up phone assessment will be done 2 weeks later (see visit 19 in 
visit schedule for treatment period 2).  
The following procedures will be performed at the ET visit: 
1. Measure vital signs, including weight. 
2. Collect blood for clinical safety laboratory tests (all visits) 
3. Perform a urine pregnancy test for female patients of childbearing potential. 
4. Collect empty arimoclomol packaging and unused arimoclomol. 
5. Complete the C-SSRS (“since last visit” assessment). 
6. Complete the IBMFRS.  
7. Complete the hand grip strength testing 
8. Record concomitant medications and concomitant therapies. 
9. Assess and record AEs occurring since the last evaluation. 
10.3. Assessments 
Trial assessments will be performed at the time points listed in the Schedule of Events 
(Section 2.2). 
10.3.1 Efficacy Variables 
10.3.1.1 IBM Functional Rating Scale 
The IBMFRS is a quickly administered (10 minutes) ordinal rating scale used to determine 
patients’ 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. The 
IBMFRS is provided in Appendix 1. 
10.3.1.2 6-Minute Walk Test with 2-Minute Distance Captured 
Patients 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. Patients 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 devices during the test will be 
recorded. 
10.3.1.3  Modified Timed Up and Go (mTUG) 
The mTUG measures the patient’s ability to get up from a chair (allowing patients to use their 
arms), walk 3 meters, turn around, walk back to the chair, and sit down. The use of nearby walls 
or assistance from a caregiver is not allowed. This test will be performed twice and both results 
will be recorded. 


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10.3.1.4 Quadriceps Muscle Strength Testing 
Maximal voluntary isometric contraction testing (MVICT) of the patient’s quadriceps muscle will 
be performed using the MicroFET hand myometer. This is a hand-held device that allows the 
examiner to push against a muscle while the patient resists. The patient will be encouraged by the 
clinical evaluator (CE) to exert maximal effort. Each test will be performed twice on each side and 
both sets of results will be recorded. The CE should strive to perform each test consistently 
between the 2 trials (see the Clinical Evaluator’s Manual). 
10.3.1.5 Hand Grip Strength Testing 
Hand grip strength will be assessed using a Jamar Dynamometer. The test will be performed twice 
on each hand and both sets of results will be recorded (see the Clinical Evaluator’s Manual).  
10.3.1.6 SF-36 
The 36-Item Short Form Health Survey is a 36-item, patient-reported survey of health status. 
10.3.1.7 Number of Falls and Near Falls 
Falls are common for patients with IBM. Patients will record the number of falls and near falls in 
a falls diary. 
10.3.2 PK and Biobanking 
10.3.2.1 Population Pharmacokinetics (PopPK) 
Arimoclomol plasma concentrations will be assayed. Approximately 1 mL of blood will be drawn 
for each sample. Samples of blood will be drawn as specified in the laboratory manual at Month 9 
(Visit 7) pre-dose and 0.5 hours (+ 60 min) post-dose, and at Month 20 (Visit 11) pre-dose and 1.5 
hours (+ 60 min) post-dose. A total of 4 samples per patient will be drawn; 2 samples at Month 9 
and 2 samples at Month 20. Patients will be asked to confirm the mode of administration (as per 
Section 9.2) of the last dose taken at home before the PopPK blood draw.  
10.3.2.2 Biobanking 
Blood will be drawn for biobanking for future potential tests. Blood samples of approximately 
9 mL per time point will be obtained, stored, and shipped as detailed in the Central Laboratory 
Manual.   
10.3.3 Safety Variables 
Safety assessments will include the evaluation of adverse events (AEs), clinical safety laboratory 
test results, vital signs, 12-lead electrocardiograms (ECGs), physical examinations, and the 
C-SSRS, depending on the treatment period (see Table 2-1). 


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10.3.3.1 Clinical Safety Laboratory Assessments 
10.3.3.1.1 Clinical Safety Laboratory Tests to be Performed 
Samples for the following clinical safety laboratory tests will be collected at the time points 
specified in the schedule of events (Section 2.2). 
Hematology: 
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) 
Serum Chemistry: 
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 
Urine pregnancy test: 
for women of childbearing potential only 
 
Blood samples for safety testing will be sent to a central laboratory for analysis. Urine pregnancy 
tests will be conducted at the trial sites. 
If the subject cannot attend the trial site for close observation in relation to elevated transaminases, 
the analyses may be conducted at a local laboratory. For guidance on follow-up of specific 
laboratory abnormalities, see section 10.3.3.1.2. 
10.3.3.1.2 Follow-up for specific laboratory abnormalities 
10.3.3.1.2.1 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. 
10.3.3.1.2.2 Increased transaminases 
Transaminases (AST, ALT) > 3 x ULN must be further investigated in line with the FDA Guidance 
on Drug-Induced Liver Injury (4). 
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: 


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• 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 
stabilised or the baseline level of the patient has been reestablished. 
• 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 discontinued (see section 0) 
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. 
 
10.3.3.1.3 Specimen Handling Requirements 
The transmission of infectious agents may occur through contact with contaminated needles and 
blood or blood products. Consequently, appropriate blood and body fluid precautions should be 
employed by all trial personnel involved in the collection of blood and handling of specimens in 
both the clinic and laboratory settings. Refer to current recommendations of the appropriate 
authorities. 
In addition to appropriate handling of patient samples, specific regulations exist regarding the 
shipment of biologic/etiologic samples. Procedures and regulations for the packaging and shipping 
of infectious samples are outlined in the trial laboratory manual. The investigator is responsible 


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for ensuring that all trial samples that are to be transported to another location are packed and 
shipped appropriately according to the applicable regulations.  
10.3.3.1.4 Evaluation of Clinical Safety Laboratory Values 
The normal ranges of values for the clinical laboratory assessments in this trial will be provided 
by the responsible laboratory and submitted to Orphazyme A/S prior to the beginning of the trial. 
They will be regarded as the reference ranges on which decisions will be made. 
If a laboratory value is out of the reference range, it is not necessarily clinically relevant. The 
investigator must evaluate the out-of-range values and record his or her assessment of the clinical 
relevance in the appropriate CRF/eCRF. 
All clinical laboratory values that in the investigator’s opinion show clinically relevant or 
pathological changes during or after termination of treatment must be reported as AEs and 
followed, as described in Section 11.2. 
All measurements described in this section are recognized standard methods. 
 
10.3.3.2 Clinical Examinations 
10.3.3.2.1 Vital Signs 
Vital signs, including weight, heart rate, respiratory rate, and sitting blood pressure will be 
measured after the patient has been in a sitting position for 5 minutes. Temperature will also be 
measured. Any clinical significant abnormality must be reported as an AE.  
10.3.3.2.2 Twelve-lead Electrocardiogram 
A standard 12-lead ECG will be performed after the patient has been lying down for at least 
5 minutes. All ECG recordings will be identified with the patient number, date, and time of the 
recording. The ECG interpretation will be recorded in the patient’s eCRF. Any clinically 
significant abnormality must be reported as an AE. 
10.3.3.2.3 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. Any clinically significant 
abnormality must be reported as an AE.  
10.3.3.2.4 Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS will be administered to the patient by trial personnel using the “since last visit” 
version of the scale at all visits, including telephone visits.  


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10.3.3.3 Adverse Events 
The definitions and management of AEs, and any special considerations for AEs, are provided in 
Section 11. 
 


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11. ADVERSE EVENTS 
11.1. Definitions 
11.1.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not related to the medicinal product. 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality, of the disease or condition. Worsening of a 
pre-existing condition is considered an AE. 
11.1.2 Unexpected Adverse Events 
An unexpected adverse event is one for which the nature or severity is not consistent with the 
applicable product information (e.g., current version of the arimoclomol IB). Orphazyme will 
assess expectedness for any SAEs reported in the trial. 
For example, hepatic necrosis would be unexpected (greater severity) if the IB only listed elevated 
hepatic enzymes or hepatitis. Likewise, cerebral thromboembolism and cerebral vasculitis would 
be unexpected (greater specificity) if the IB only listed cerebral vascular accidents. 
Furthermore, reports that add significant information on specificity or severity of a known, already 
documented adverse reaction constitute unexpected events. Examples would be (a) acute renal 
failure as an expected adverse reaction with a subsequent new occurrence of interstitial nephritis 
(interstitial nephritis would be unexpected) and (b) hepatitis with a first occurrence of fulminant 
hepatitis (fulminant hepatitis would be unexpected.) 
11.1.3 Serious Adverse Events 
An SAE is any untoward medical occurrence that at any dose: 
• results in death 
• is life-threatening 
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it was more severe. 
• requires inpatient hospitalization or prolongation of existing hospitalization 
NOTE: Inpatient hospitalization is defined as 24 hours in a hospital or an overnight stay. 
An elective hospital admission to treat a condition present before exposure to the study 
drug, or a hospital admission for a diagnostic evaluation of an AE, does not qualify the 
condition or event as an SAE. Further, an overnight stay in the hospital that is only due to 
transportation, organization, or accommodation problems and without medical background 
does not need to be considered an SAE. 
• results in persistent or significant disability/incapacity 


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• is a congenital anomaly 
NOTE: A congenital anomaly in an infant born to a mother who was exposed to the study 
drug during pregnancy is an SAE. However, a newly diagnosed pregnancy in a patient that 
has received study drug is not considered an SAE unless it is suspected that the study 
drug(s) interacted with a contraceptive method and led to the pregnancy.  
• is an important medical event 
NOTE: Medical and scientific judgment should be exercised in deciding whether it is 
appropriate to consider other situations serious, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may jeopardize 
the patient or may require intervention to prevent one of the other outcomes listed in the 
definition above. 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, development of drug dependency, or drug abuse. The occurrence of 
malignant tumors is also to be considered serious.  
11.1.4 Treatment-Emergent Adverse Events 
An AE is defined as treatment-emergent if the first onset or worsening is after the first 
administration of arimoclomol in the current trial. 
11.2. Collection of Adverse Events 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE described previously. At each visit, the patient will be allowed 
time to spontaneously report any issues since the last visit or evaluation. The investigator will then 
monitor and/or ask about or evaluate AEs using nonleading questions, such as 
• “How are you feeling?” 
• “Have you experienced any issues since your last visit?” 
• “Have you taken any new medications since your last visit?” 
Any clinically relevant observations made during the visit will also be considered AEs. 
AEs will be collected from the Visit 1 and until the end of trial visit. Any SAEs reported to the 
investigator after the end of trial shall be reported if they are considered at least possibly related to 
arimoclomol.   
All AEs will be followed to resolution or the last visit, whichever comes first. SAEs will be 
followed up until a final outcome has been established. For SAEs which have stabilised and for 
which the patient cannot be expected to recover during the trial, for example chronic illnesses, the 
final outcome should be considered ‘recovered with sequalae’ or ‘not recovered’ and a statement 
that the SAE has stabilised should be added to the narrative in the SAE form.  
Information to be collected includes event description, duration, clinician’s assessment of severity, 
causality, seriousness, concomitant therapy given (or other action taken), action taken with respect 
to arimoclomol, and outcome. All AEs occurring while in study must be documented appropriately 
regardless of relationship. 


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All new AEs or worsening of any ongoing events from the completion of IBM4809 will be 
recorded on the AE pages of the CRF (ongoing AEs from IBM4809 should also be recorded on 
AE page of the CRF). 
If the AE is serious, this must be indicated on the Adverse Event Form. Furthermore, the 
investigator must fill out a Serious Adverse Event Form and report the SAE to the safety vendor 
immediately (within 24 hours) after becoming aware of it (see Section 11.4). 
11.2.1 Severity of Adverse Events 
The clinical severity of an AE will be classified as: 
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]).  
It is important to distinguish between severe AEs and SAEs. Severity is a classification of intensity 
whereas an SAE is an AE that meets serious criteria, as described in Section 11.1.3. 
11.2.2 Adverse Event Relationship to Investigational Product 
The investigator must make an assessment of each AE’s relationship to arimoclomol. The 
categories for classifying the investigator’s opinion of the relationship are as follows: 
Probably Related  AEs that are temporally linked and for which the trial product is more 
likely to be the explanation than other causes, which may improve when 
not using trial product  
Possibly Related  AEs that could equally well be explained by trial product or other causes, 
which are usually temporally linked and may improve when not using trial 
product but do not reappear when using trial 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  
 An AE is considered related to arimoclomol if it is at least possibly related. 
11.3. Treatment of Adverse Events 
Adverse events that occur during the trial will be treated, if necessary, by established standard of 
care. If such treatment constitutes a deviation from the protocol, the patient’s participation in the 
trial should be evaluated. The decision about whether the patient may continue in the trial will be 
made by the sponsor after consultation with the investigator and/or medical monitor and 
documented in the eCRF. 
If a patient experiences AEs that are not tolerable, the investigator must decide whether to stop the 
patient’s involvement in the study and/or treat the patient.  


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11.4. Reporting of Serious Adverse Events 
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: 
 
Trial 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 trial 
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.  
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. 
Follow-up information should also be provided within 24 hours of the investigator becoming aware 
of it.  
It is necessary only to provide the new information, together with the following minimal 
information (initial report, adverse event, date of occurrence, patient identification (ID), trial ID, 
study drug name [arimoclomol], 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 data clarification form. 
Investigators or other site personnel should only send relevant or requested anonymized supporting 
documentation (e.g. ECG, laboratory results, autopsy report) to the safety vendor.  
Follow-up reports (as many as required) should be completed and submitted following the same 
procedure above.  
Reporting to Competent Authorities and IRBs/IEC 
The investigator is responsible for reporting SAEs to the institutional review board (IRB)/ 
independent ethics committee (IEC) as required by current applicable legislation for the concerned 
country.  
Orphazyme is responsible for assessing whether or not an SAE is expected. The reference safety 
information for this clinical trial is the current version of the Investigator’s Brochure. 
Orphazyme is responsible for reporting all SAEs that are assessed as causally related to the IMP 
by either the investigator or Orphazyme, and that are unexpected (suspected, unexpected serious 


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adverse reactions [SUSARs]) in an expedited manner to regulatory authorities according to the 
current applicable legislation in the concerned countries. Investigators will be notified of such 
SUSARs and the evolving safety profile on an ongoing basis. 
Orphazyme is also responsible for reporting to the IRBs/IECs that require unblinded reporting. 
11.5. 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 11.4. A pregnant patient should discontinue trial treatment.  
All pregnancies must be followed up until delivery or termination of the pregnancy and final outcome 
must be reported on the Pregnancy Follow-Up Form within 24 hours of first knowledge and sent to 
the safety vendor using the contact details in Section 11.4. 


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12. STATISTICS 
12.1. Statistical Analysis 
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, all testing of statistical significance will be two-sided, and a difference 
resulting in a P value of ≤ 0.05 will be considered statistically significant.  
For analyses involving trial site, if the number of patients per site is small, sites may be pooled for 
analysis or omitted from statistical models. The final determination will be made prior to database 
lock.  
Summary statistics will be provided for the variables described below. For continuous variables, 
these statistics will typically include the number of patients, mean, standard deviation (SD), 
median, minimum, and maximum. For categorical variables, these statistics will typically include 
the number and percentage of patients in each category. 
Analyses will compare efficacy and safety findings between those patients who received 
arimoclomol and placebo, respectively, in the IBM4809 trial, reflecting the original randomisation. 
This facilitates an analysis of the effect of early versus delayed treatment start of arimoclomol. 
Summaries will also present data for the overall group. 
12.1.1 Analysis Populations 
Safety Population: All patients who receive at least 1 dose or partial dose of arimoclomol in the 
extension trial. Safety analyses will be performed on the Safety Population. 
Modified Intent-to-treat (mITT) Population: All patients receiving at least 1 dose or partial dose 
of arimoclomol in the extension trial, with a baseline value and at least 1 post-baseline value for 
IBMFRS. Efficacy analyses will be performed on the mITT Population. 
Inclusion in the analysis populations will be determined prior to database lock. 
12.1.2 Trial Patients and Demographics 
12.1.2.1 Disposition and Withdrawals 
The numbers of patients enrolled, completing, and withdrawing, along with reasons for 
withdrawal, will be tabulated overall and by IBM4809 treatment groups. The number of patients 
in each analysis population will be reported. 
12.1.2.2 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol or ICH GCP 
requirements. The noncompliance may be either on the part of the participant, the investigator, or 
the trial site staff. As a result of deviations, corrective actions are to be developed by the site and 
implemented promptly.  
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
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days of the scheduled protocol-required activity. All deviations must be addressed in trial source 
documents and reported to Premier Research. Protocol deviations must be sent to the reviewing 
Institutional Review Board (IRB) per their policies. The site investigator is responsible for 
knowing and adhering to the reviewing IRB requirements. Further details about the handling of 
protocol deviations will be included in the protocol deviation guidance plan. Deviations assessed 
as important will be addressed in the study report. 
12.1.2.3 Demographics and Other Baseline Characteristics 
The distributions of demographic and clinical characteristics will be described for the early start 
and delayed start groups as well as the overall cohort using standard summary statistics. 
Prior and concomitant medications will be summarized overall and by treatment group, by the 
number and percentage of patients taking each medication, classified using World Health 
Organization Drug Dictionary (WHO-DD) Anatomical Therapeutic Chemical (ATC) classes and 
preferred terms. 
12.1.3 Exposure and Compliance 
Investigational product administration will be summarized in terms of each patient’s duration of 
exposure. Descriptive statistics, including the mean, median, SD, minimum, maximum, and 
quartiles, will be provided overall and by treatment group.  
12.1.4 Efficacy Analysis 
Efficacy variables will be summarized and analysed using the mITT population. 
12.1.4.1 Efficacy Endpoints 
• Primary efficacy endpoint:  
o Change in the IBMFRS total score from IBM4809 baseline to Month 20 in the OLE trial. 
• Secondary efficacy endpoints:  
o Change in 6-Minute Walk Test Distance from IBM4809 baseline to Month 20 in the OLE 
trial. 
o Change in Modified Timed Up and Go (mTUG) from IBM4809 baseline to Month 20 in 
the OLE trial. 
o Change in MVICT of the quadriceps muscle from IBM4809 baseline to Month 20 in the 
OLE trial.  
o Change in hand grip strength from IBM4809 baseline to Month 20 in the OLE trial  
o Change in SF-36 from IBM4809 baseline to Month 20 in the OLE trial. 
 
o Number of Falls from IBM4809 baseline to Month 20 in the OLE trial.  
o Number of Near Falls from IBM4809 baseline to Month 20 in the OLE trial.  
o Change in the IBMFRS total score from IBM4809 baseline to Month 40 in the OLE trial.   
o Change in hand grip strength from IBM4809 baseline to Month 40 in the OLE trial. 
 


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• Exploratory endpoints:  
o Population pharmacokinetics (popPK) and popPK/PD (reported separately) 
o Change from baseline* over 20 months of arimoclomol treatment in IBMFRS total score 
in arimoclomol naïve patients 
o Change from baseline* over 20 months of arimoclomol treatment in 6-Minute Walk Test 
Distance in arimoclomol naïve patients 
o Change from baseline* over 20 months of arimoclomol treatment in Modified Timed Up 
and Go (mTUG) in arimoclomol naïve patients 
o Change from baseline* over 20 months of arimoclomol treatment in MVICT of the 
quadriceps muscle in arimoclomol naïve patients 
o Change from baseline* over 20 months of arimoclomol treatment in hand grip strength in 
arimoclomol naïve patients 
o Change from baseline* over 20 months of arimoclomol treatment in SF-36  in 
arimoclomol naïve patients 
• Safety endpoints:  
o Safety parameters (AEs, SAEs, clinical safety laboratory values, vital signs, C SSRS to 
month 40 
* Baseline is defined at the visit at which the subject receives first administration of arimoclomol (corresponding to 
IBM4809 baseline and IBMOLE baseline for patients randomized to arimoclomol and placebo in IBM4809, 
respectively) 
12.1.4.2 Efficacy Analysis 
Differences in change from IBM4809 baseline to Month 20in the OLE trial in IBMFRS between 
patients randomized to arimoclomol (early start) and placebo (delayed start) in IBM4809 will be 
determined using a modified 2-treatment period/delayed randomization analysis (to be detailed in 
the statistical analysis plan [SAP]). 
Additional efficacy variables will be explored through descriptive statistics at each scheduled visit 
of the current trial. For statistical analyses, 95% confidence intervals will be provided for changes 
from baseline. 
12.1.4.3 Exploratory, Corroborative, Sensitivity, and Other Analyses 
Additional exploratory analyses as well as sensitivity analyses for the primary efficacy endpoint 
will be described in the SAP as appropriate. 
12.1.5 PopPK and PopPK/PD Analyses 
All plasma arimoclomol concentration and dosing data will be merged with the PK sampling dates 
and times and used to create the population PK input file for use in a popPK modelling analysis. 
In addition, the potential relationship between systemic exposure of arimoclomol and 
efficacy/safety measures may be explored using appropriate pharmacokinetic/pharmacodynamic 
models. The population PK and popPK/PD analysis plan will be described in a separate protocol 
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12.1.6 Safety and Tolerability Analyses 
Safety analysis, based on AEs, SAEs, clinical safety laboratory values, vital signs, and C-SSRS, 
will be descriptive, based on the Safety Population.  
Continuous safety variables (vital signs, laboratory test results) will be presented using descriptive 
statistics. For analyses of changes from baseline for laboratory values and vital signs parameters, 
baseline values from the blinded IBM4809 trial or from the current trial may be considered.  
The C-SSRS will be summarized. 
12.1.6.1 Adverse Events 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
Version 21.0 or higher.  
An AE is defined as treatment-emergent if the first onset or worsening is after the first 
administration of arimoclomol in the current trial. 
The number and percentage of patients with AEs will be displayed overall and for each treatment 
group by system organ class (SOC) and preferred term (PT). Summaries of AEs by severity and 
relationship to arimoclomol will also be provided. Serious adverse events and AEs resulting in 
discontinuation of arimoclomol will be summarized separately in a similar manner. Patient listings 
of AEs, SAEs, and AEs causing discontinuation of arimoclomol will be produced.  
12.1.6.2 Clinical Laboratory Evaluations 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual (absolute) values 
and changes from baseline values will be presented for clinical laboratory values overall and for 
each treatment group at each time point. 
The number of patients with clinical laboratory values categorized as below, within, or above 
normal ranges will be tabulated showing change from baseline (shift tables) for each clinical 
laboratory analyte overall and by treatment group and by trial visit. 
Laboratory values that are outside the normal range will also be flagged in the data listings and 
presented with the corresponding normal ranges. Any out-of-range values that are identified by 
the investigator as being clinically significant will also be shown in a data listing. 
12.1.6.3 Vital Signs 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from baseline will be calculated for systolic blood pressure (SBP), diastolic blood pressure 
(DBP), heart rate (HR), and respiratory rate (RR.) 
The number of patients with vital signs values categorized as below, within, or above normal 
ranges will be tabulated showing change from baseline (shift tables) for each parameter overall 
and by treatment group and by trial visit. Pre- and post-treatment values may also be presented 
with an analysis of mean changes from baseline. 
12.1.7 Interim Analysis 
No interim analyses are planned.  


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12.2. Sample Size Determination 
As this trial is an open-label extension planning to include patients from the previous trial, no 
calculation for sample size was performed.   


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13. TRIAL CONDUCT 
Steps to ensure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate trial sites, review of protocol procedures with the investigator and associated 
personnel before the trial, periodic monitoring visits, and meticulous data management. 
13.1. Sponsor and Investigator Responsibilities 
13.1.1 Sponsor Responsibilities 
The sponsor is obligated to conduct the trial in accordance with strict ethical principles 
(Section 15). The sponsor reserves the right to withdraw a patient from the trial (Section 8.3), to 
terminate participation of a trial site at any time (Section 13.7), and/or to discontinue the trial 
(Section 13.6). 
Orphazyme A/S agrees to provide the investigator with sufficient material and support to permit 
the investigator to conduct the trial according to the trial protocol. 
13.1.2 Investigator Responsibilities 
By signing the Investigator’s Agreement (Section 17.1), the investigator indicates that he or she 
has read the protocol carefully, fully understands the requirements, and agrees to conduct the trial 
in accordance with the procedures and requirements described in this protocol.  
The trial will be conducted in accordance with ICH GCP and applicable United States (US) Code 
of Federal Regulations (CFR). The principal investigator will assure that no deviation from, or 
changes to, the protocol will take place without prior agreement from the Investigational New 
Drug (IND) sponsor, funding agency and documented approval from the Institutional Review 
Board (IRB), except where necessary to eliminate an immediate hazard(s) to the trial participants. 
All personnel involved in the conduct of this trial have completed Human Subjects Protection and 
ICH GCP training. 
Investigators should ensure that all persons who are delegated trial-related responsibilities are 
adequately qualified and informed about the protocol, the study drug, and their specific duties 
within the context of the trial. Investigators are responsible for providing Orphazyme A/S with 
documentation of the qualifications, GCP training, and research experience for themselves and 
their staff as required by the sponsor and the relevant governing authorities. 
To ensure compliance with the guidelines, the trial may be audited by an independent person. The 
investigator agrees, by written consent to this protocol, to cooperate fully with compliance checks 
by allowing access to all trial documentation by authorized individuals. 
13.1.3 Confidentiality and Privacy 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor, and their interventions. This confidentiality is extended to cover testing 
of biological samples and genetic tests in addition to the clinical information relating to 
participants. Therefore, the trial protocol, documentation, data, and all other information generated 
will be held in strict confidence. No information concerning the trial 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. 


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The trial monitor, other authorized representatives of the sponsor, representatives of the IRB, 
regulatory agencies, or pharmaceutical company supplying trial 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 trial. The 
clinical trial site will permit access to such records. 
The trial participant’s contact information will be securely stored at each clinical site for internal 
use during the trial. At the end of the trial, 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. 
13.2. Site Initiation 
Trial personnel may not screen or enroll patients into the trial until after receiving notification from 
the sponsor or its designee that the trial can be initiated at the trial site. The trial site will not be 
authorized for trial initiation until: 
1. The trial site has received the appropriate IRB/IEC approval for the protocol and the 
appropriate ICF. 
2. All regulatory/GCP documents have been submitted to and approved by the sponsor or its 
designee. 
3. The trial site has a Clinical Trial Agreement in place. 
4. Trial site personnel, including the investigator, have participated in a trial initiation 
meeting. 
13.3. Trial Documents 
All documentation and material provided by Orphazyme A/S for this trial are to be retained in a 
secure location and treated as confidential material. 
13.3.1 Informed Consent 
Consent forms describing in detail the trial intervention, trial procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering trial intervention.  
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
trial and continues throughout the individual’s trial participation. Consent forms will be 
IRB-approved and the participant will be asked to read and review the document. The investigator 
will explain the research trial to the participant and answer any questions that may arise. A verbal 
explanation will be provided in terms suited to the participant’s comprehension of the purposes, 
procedures, and potential risks of the trial and of their rights as research participants. Participants 
will have the opportunity to carefully review the written consent form and ask questions prior to 
signing. The participants should have the opportunity to discuss the trial with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document prior to any procedures being done specifically for the trial. Participants must 
be informed that participation is voluntary and that they may withdraw from the trial at any time, 
without prejudice. A copy of the informed consent document will be given to the participants for 
their records. The informed consent process will be conducted and documented in the source 
document (including the date) and the form signed before the participant undergoes any 


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trial-specific procedures. The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this trial. 
13.3.2 Investigator’s Regulatory/Good Clinical Practice Documents 
The regulatory/GCP documents listed in the trial plan and must be received from the investigator 
and reviewed and approved by Orphazyme A/S or its designee before the trial site can initiate the 
trial and before Orphazyme A/S will authorize shipment of study drug to the trial site. Copies of 
the investigator’s regulatory/GCP documents must be retained at the trial site in a secure location. 
Additional documents, including a copy of the protocol and applicable amendment(s), the 
arimoclomol IB, eCRF completion guidelines, copies of regulatory references, copies of IRB/IEC 
correspondence, and study drug accountability records should also be retained as part of the 
investigator’s regulatory/GCP documents. It is the investigator’s responsibility to ensure that 
copies of all required regulatory/GCP documents are organized, current, and available for 
inspection. 
13.3.3 Case Report Forms 
By signing the Investigator’s Agreement (Section 17.1), the investigator agrees to maintain 
accurate eCRFs and source documentation as part of the case histories for all patients who sign an 
ICF. 
Case report forms are considered confidential documents and should be handled and stored 
accordingly. The sponsor or its designee will provide the necessary training on the use of the 
specific eCRFs used during the trial to ensure that the trial information is captured accurately and 
appropriately. 
To ensure data accuracy, eCRF data for individual patient visits should be completed as soon as 
possible after the visit. All requested information must be entered in the electronic data capture 
(EDC) system according to the completion guidelines provided by the sponsor or its designee. 
The eCRFs must be signed by the investigator or a sub-investigator. These signatures serve to 
attest that the information contained in the eCRFs is accurate and true. 
13.3.4 Source Documents 
Information recorded in the EDC system should be supported by corresponding source 
documentation. Examples of acceptable source documentation include, but are not limited to, 
hospital records, clinic and office charts, laboratory notes, and recorded data from automated 
instruments, memoranda, and pharmacy dispensing records. 
13.4. Data Quality Control 
Orphazyme A/S and its designees will perform quality control checks on this clinical trial. 
13.4.1 Monitoring Procedures 
Orphazyme A/S and/or its designee 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) (CRA[s]) will visit the investigator and trial site at periodic intervals 
and maintain periodic communication. The investigator agrees to allow the CRA(s) and other 
authorized Orphazyme A/S personnel access. The CRA(s) will maintain current personal 


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knowledge of the trial through observation, review of trial records and source documentation, and 
discussion of the conduct of the trial with the investigator and staff. While on site, the CRA(s) will 
review 
• regulatory documents, directly comparing entries in the EDC system with the source 
documents 
• consenting procedures 
• AE procedures 
• storage and accountability of study drug and trial materials 
The CRA will ask for clarification and/or correction of any noted inconsistencies. Procedures for 
correcting eCRFs are described in the trial plan. As representatives of the sponsor, CRAs are 
responsible for notifying project management of any noted protocol deviations. 
By signing the Investigator’s Agreement (Section 17.1), the investigator agrees to meet with the 
CRA(s) during trial site visits; to ensure that trial staff is available to the CRA(s) as needed; to 
provide the CRA(s) access to all trial documentation, to the clinical supplies dispensing and storage 
area; and to assist the monitors in their activities, if requested. Further, the investigator agrees to 
allow Orphazyme A/S or designee auditors or inspectors from regulatory agencies to review 
records and to assist the inspectors in their duties, if requested.  
For additional information, please refer to the clinical monitoring plan (CMP). 
13.4.2 Data Management 
Orphazyme A/S or designee will be responsible for activities associated with the data management 
of this trial. The standard procedures for handling and processing records will be followed per 
GCP and Premier Research’s standard operating procedures. A comprehensive data management 
plan (DMP) will be developed, including a data management overview, description of database 
contents, annotated CRF, pre-entry review list, self-evident correction conventions, query 
contacts, and consistency checks. 
Trial site personnel will be responsible for providing resolutions to all data queries. The 
investigator will be required to document electronic data review to ensure the accuracy of the 
corrected and/or clarified data. Procedures for soliciting and documenting resolution to data 
queries are described in the trial plan. 
13.4.3 Quality Assurance/Audit 
This trial will be subject to audit by Orphazyme A/S or its designee. Audits may be performed to 
check compliance with GCP guidelines and can include: 
• site audits 
• Trial Master File (TMF) audits 
• database audits 
• document audits (e.g., protocol and/or CSR) 
Orphazyme A/S or its designee may conduct additional audits on a selection of trial sites, requiring 
access to patient notes, trial documentation, and facilities or laboratories used for the trial. 


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The trial site, facilities, all data (including source data), and documentation will be made available 
for audit by quality assurance auditors and for IRB/IEC or regulatory authorities according to GCP 
guidelines. The investigator agrees to cooperate with the auditor during the visit and will be 
available to supply the auditor with CRFs or other files necessary to conduct that audit. Any 
findings will be strictly confidential. 
If a regulatory authority informs the investigator that it intends to conduct an inspection, the 
investigator shall notify Orphazyme A/S immediately. 
13.5. Study Leadership 
A Scientific Steering Committee will govern the conduct of the study and provide scientific 
direction. The Steering Committee composition is composed of 
 (Chair), 
, 
, 
, 
, and an Orphazyme 
representative. The Steering Committee will meet and act according to the Steering Committee 
Charter. 
13.6. Trial Termination 
The trial may be terminated at Orphazyme A/S’s discretion at any time and for any reason. 
13.6.1 Regular Trial Termination 
The end of this trial is defined as the date of the last visit of the last patient (last patient out or last 
patient last visit) participating in the trial. Within 90 days of the end of the clinical trial, Orphazyme 
A/S or designee will notify the IECs and regulatory authorities about the regular termination of 
the trial as required according to national laws and regulations. 
13.7. Trial Site Closure 
At the end of the trial, all trial sites will be closed. Orphazyme A/S may terminate participation of 
a trial site at any time. Examples of conditions that may require premature termination of a trial 
site include, but are not limited to, the following: 
• Noncompliance with the protocol and/or applicable regulations and guidelines 
• Inadequate patient enrolment 
13.7.1 Record Retention 
The investigator shall retain and preserve 1 copy of all data generated in the course of the trial, 
specifically including, but not limited to, those defined by GCP as essential until: 
• At least 5 years after the last marketing authorization for arimoclomol has been approved 
or the sponsor has discontinued its research with arimoclomol, or 
• At least 5 years have elapsed since the formal discontinuation of clinical development of 
arimoclomol. 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or if needed by the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her intent to 
destroy all such material. The sponsor has 30 days to respond to the investigator’s notice, and the 
sponsor has further opportunity to retain such materials at the sponsor’s expense. 


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13.7.2 Sample Retention 
Samples may be used for purposes related to this research. The samples will be stored until the 
sponsor has determined that specimens are no longer needed, and the decision has been made that 
none of the samples needs to be reanalysed. In addition, identifiable samples can be destroyed at 
any time at the request of the patient. 
De-identified biological samples will be stored as detailed in the Central Laboratory Manual 
During the conduct of the trial, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
bio sample storage may not be possible after the trial is completed.  
13.8. Changes to the Protocol 
This protocol cannot be altered or changed except through a formal protocol amendment, which 
requires the written approval of Orphazyme A/S. The protocol amendment must be signed by the 
investigator and approved by the IRB or IEC before it may be implemented. Protocol amendments 
will be filed with the appropriate regulatory agencies having jurisdiction over the conduct of the 
trial. 
13.9. Use of Information and Publication 
The study will be registered at www.clinicaltrials.gov. By signing the study protocol, the 
investigator agrees with the use of results of the trial for the purposes of national and international 
registration, publication and information for medical and pharmaceutical professionals. 
As the trial is a multi-center trial, any publication based on the results obtained at the trial site shall 
not be made before the first multi-center publication describing the primary results of the OLE has 
been published. If a publication concerns the analyses of subsets of data from the trial, the 
publication shall make reference to the relevant multi-center publication(s). Upon completion of 
the trial, and any prior publication of multi-center data, or when the trial data are adequate (in 
Orphazyme’s discrete and reasonable judgement), the trial site may prepare the data deriving from 
the trial for publication. The publishing investigator(s) will not make any publication or other 
public disclosure, whether oral or written, that includes any trial data or describes any work carried 
out using the study drug unless a draft of such proposed publication or other public disclosure has 
been provided to UCL (
 and 
), KUMC (
 and 
), other members of the Scientific Steering Committee who will also perform 
the review for the Muscle Study Group, and to Orphazyme A/S for review at least 45 days prior to 
any such submission for publication or public disclosure. During such 45-day period, Orphazyme 
A/S may require that any publication or other public disclosure is delayed for up to 4 months to 
permit adequate steps to be taken to secure patent or other protection of the subject matter referred 
to therein and/or to require the deletion of any confidential information that would be disclosed by 
such publication or public disclosure. After Orphazyme has secured that intellectual property 
protection of the subject matter and Orphazyme has released the manuscript for publication, the 
publishing investigator(s) may submit the proposed publication to outside reviewers or 
publications for review. 
In any publication or public disclosure, whether oral or written, that mentions the trial, the 
publishing investigator(s) will acknowledge Orphazyme A/S. 


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Orphazyme A/S may use all such publications and public disclosures at its own discretion, 
including the use for regulatory submissions. 
 


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14. FINAL CLINICAL STUDY REPORT 
Orphazyme A/S will retain ownership of the data. 
The final CSR will be written within 1 year of completion of the clinical part of the trial and 
submitted to regulatory authorities if appropriate or required. This report will include a summary 
of the trial results based on a statistical evaluation and clinical assessment of the protocol-defined 
endpoints. 
  


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15. ETHICAL AND LEGAL CONSIDERATIONS 
15.1. Declaration of Helsinki and Good Clinical Practice 
This trial will be conducted in compliance with the April 1996 ICH Guidance for Industry GCP 
E6 (including archiving of essential trial documents), the Integrated Addendum to ICH E6 (R2) of 
November 2016, the Declaration of Helsinki, the applicable regulations of the country(ies) in 
which the trial is conducted, and with the Commission Directives 2001/20/EC and 2005/28/EC. 
See Appendix C for regulation and guidelines. 
15.2. Patient Information and Informed Consent and/or Assent 
A properly constituted, valid IRB or IEC must review and approve the protocol, the investigator’s 
ICF, and related patient information and recruitment materials before the start of the trial. 
It is the responsibility of the investigator to ensure that written informed consent and/or assent is 
obtained from the patient before any activity or procedure is undertaken that is not part of routine 
care.  
15.3. Approval by Institutional Review Boards and Independent Ethics Committees 
A valid IRB/IEC must review and approve this protocol before trial initiation. Written notification 
of approval is to be provided by the investigator to the sponsor or designee before shipment of 
investigational drug supplies and will include the date of the committee’s approval and the 
chairperson’s signature.  
Until written approval by the IRB/IEC has been received by the investigator, no patient may 
undergo any procedure not part of routine care for the patient’s condition. 
Protocol amendments must also be reviewed and approved by the IRB/IEC. Written approval from 
the IRB/IEC, or a designee, must be received by Orphazyme A/S before implementation. 
15.4. Finance and Insurance 
Details on finance and insurance will be provided in a separate agreement between the investigator 
and the sponsor. 


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16. REFERENCES 
1. Callan A, Capkun G, Vasanthaprasad V, Freitas R, Needham M. A systematic review and 
meta-analysis of prevalence trials of sporadic inclusion body myositis. J Neuromuscul Dis. 
2017;4(2):127-137.  
2. 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. 
3. Ahmed M, Machado PM, Miller A, et al. Targeting protein homeostasis in sporadic 
inclusion body myositis. Sci Transl Med. 2016;8(331):331ra41. 
4. FDA Guidance for Industry on Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation, July 2009 
 


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17. ATTACHMENTS 
17.1. Investigator’s Agreement 
PROTOCOL 
NUMBER: 
IBM-OLE (version 5.0)  
PROTOCOL TITLE: 
An open-label, non-randomized trial to investigate the efficacy and 
safety of early versus delayed start of arimoclomol in patients with 
inclusion body myositis who have completed the IBM4809 trial 
FINAL PROTOCOL: 
18-Jan-2021 
The undersigned acknowledges possession of and has read the Investigator’s Brochure on 
arimoclomol and has discussed these data with the trial monitor. Having considered fully all the 
available information, the undersigned considers that it is ethically justifiable to give the study 
drug to selected patients in his/her care, according to the trial protocol. 
He or she agrees to use the trial material, arimoclomol, only as specified in the protocol. He or she 
understands that changes cannot be made to the protocol without prior written approval of 
Orphazyme A/S. 
He or she understands that any deviation from the protocol may lead to early termination of the 
trial. 
He or she agrees to report to Orphazyme A/S within time any clinical AE or abnormal laboratory 
value that is serious, whether or not considered related to the administration of arimoclomol. 
He or she agrees to comply with Orphazyme A/S and regulatory requirements for the monitoring 
and auditing of this trial. 
In addition, he or she agrees that the trial will be carried out in accordance ICH, the Declaration of 
Helsinki, and the local laws and regulations relevant to the use of new therapeutic agents. 
I, the undersigned, have carefully read this protocol and agree that it contains all the necessary 
information required to conduct the trial. 
Principal Investigator: 
 
 
Printed Name: 
 
 
 
 
Signature: 
 
 
 
 
Date: 
 
 
 
Investigator’s name and address (stamp): 


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APPENDICES 
A. Trial-Specific Requirements 
B. Regulations and Good Clinical Practice Guidelines 
C. Address List 
 
 


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A. Trial-Specific Requirements 
 
17.1.1 Coronavirus (COVID) operational changes  
The document (COVID-19) Addendum 1.0 dated 06-Aug-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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APPENDIX 1: 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 


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APPENDIX 2: 
 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.


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B. Regulations and Good Clinical Practice Guidelines
1. Regulations
Refer to the following United States Code of Federal Regulations (CFR):
•
FDA Regulations 21 CFR, Parts 50.20 – 50.27
Subpart B – Informed Consent of Human Subjects
•
FDA Regulations 21 CFR, Parts 56.107 – 56.115
Part 56 – Institutional Review Boards
Subpart B – Organization and Personnel
Subpart C – IRB Functions and Operations
Subpart D – Records and Reports
•
FDA Regulations 21 CFR, Parts 312.50 – 312.70
Subpart D – Responsibilities of Sponsors and Investigators
Refer to the following European Directives (and applicable regulations/guidance’s): 
•
European Directive 2001/20/EC and related guidance documents
•
European Directive 2005/28/EC and related guidance documents>
2. Good Clinical Practice Guidelines
ICH GCP guidelines can be found at the following URLs:
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_G
uideline.pdf 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__
Step_4.pdf 

SAP_001.pdf: 
Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
 Page 1 of 37 
Sponsor: 
Orphazyme A/S 
Protocol Title: 
An open-label, non-randomized trial to investigate the efficacy and 
safety of early versus delayed start of arimoclomol in patients with 
sporadic inclusion body myositis who have completed the 
IBM4809 trial 
Protocol Number: 
IBM-OLE 
Premier Research PCN: 
ORPA208736 
Document Version: 
FINAL Version 1.0 
Document Date: 
20 October 2021 
Approvals 
Role 
Signatures 
Date 
Biostatistician 
Print Name: 
 
Sign Name: 
Peer Reviewer 
Print Name: 
 
Sign Name: 
CONFIDENTIAL
Clinicaltrials.gov ID 
NCT04049097 
This document contains information which is the property of Zevra 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 
Zevra Denmark A/S. 


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
 Page 2 of 37 
Role 
Signatures 
Date 
Orphazyme A/S 
Print Name: 
 
Sign Name: 
Document History 
Not applicable 
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
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Table of Contents 
Approvals ........................................................................................................................................ 1 
Document History ........................................................................................................................... 2 
Table of Contents ............................................................................................................................ 3 
List of Tables .................................................................................................................................. 5 
List of Figures ................................................................................................................................. 5 
1.
Trial Objectives and Endpoints ........................................................................................... 6 
1.1. 
Trial Objectives ............................................................................................................. 6 
1.1.1. Primary Objectives........................................................................................................ 6 
1.1.2. Secondary Objectives.................................................................................................... 6 
1.1.3. Exploratory Objectives ................................................................................................. 6 
1.2. 
Trial Endpoints.............................................................................................................. 7 
1.2.1. Efficacy Endpoints ........................................................................................................ 7 
1.2.2. Safety Endpoints ........................................................................................................... 7 
1.2.3. Exploratory Endpoints .................................................................................................. 7 
1.2.4. Pharmacokinetic/Pharmacodynamic Variable(s) .......................................................... 7 
2.
Overview ............................................................................................................................. 8 
3.
Overall Trial Design and Plan............................................................................................. 9 
3.1. 
Overall Design .............................................................................................................. 9 
3.2. 
Sample Size and Power ............................................................................................... 10 
3.3. 
Trial Population .......................................................................................................... 10 
3.4. 
Treatments Administered and Method of Assigning Patients to Treatment 
Groups ......................................................................................................................... 10 
3.5. 
Blinding and Unblinding............................................................................................. 11 
3.6. 
Schedule of Events ...................................................................................................... 11 
4.
Statistical Analysis and Reporting .................................................................................... 14 
4.1. 
Introduction ................................................................................................................. 14 
5.
Analysis Populations & Treatment Durations .................................................................. 15 
5.1. 
Analysis Populations ................................................................................................... 15 
5.2. 
Observation Period...................................................................................................... 15 
6.
Statistical Analysis ............................................................................................................ 16 
6.1. 
Baseline ....................................................................................................................... 16 
6.2. 
Analysis Visit Windows ............................................................................................. 17 
6.3. 
Multiple Comparisons ................................................................................................. 20 
6.4. 
Efficacy Endpoints ...................................................................................................... 20 
6.4.1. Analyses of Primary Endpoint .................................................................................... 20 
6.5. 
Analyses of Secondary Endpoints .............................................................................. 20 
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
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6.5.1. Six Minutes Walking distance test; distance at 6 minutes (6MWD) .......................... 20 
6.5.2. Modified Timed Up and Go (mTUG) ......................................................................... 21 
6.5.3. Grip strength using the Jamar device .......................................................................... 21 
6.5.4. Quadriceps Muscle Strength Testing .......................................................................... 21 
6.5.5. Falls and Near Falls .................................................................................................... 22 
6.5.6. SF-36 Results .............................................................................................................. 22 
6.6. 
Derived Variables ....................................................................................................... 22 
6.7. 
Data Adjustments/Handling/Conventions .................................................................. 22 
7.
Trial Patients and Demographics ...................................................................................... 24 
7.1. 
Disposition of Patients and Withdrawals .................................................................... 24 
7.2. 
Protocol Violations and Deviations ............................................................................ 24 
7.3. 
Demographics and Other Baseline Characteristics ..................................................... 24 
7.4. 
Exposure and Compliance .......................................................................................... 25 
7.4.1. Exposure ..................................................................................................................... 25 
7.4.2. Calculation of capsules taken...................................................................................... 25 
7.4.3. Dose interruption and patient discontinuation ............................................................ 25 
7.4.4. Compliance ................................................................................................................. 26 
7.4.5. Average daily exposure............................................................................................... 26 
7.5. 
Baseline Columbia Suicide Severity Rating Scale (C-SSRS) .................................... 26 
8.
Safety and Tolerability Analysis ....................................................................................... 27 
8.1. 
Adverse Events ........................................................................................................... 27 
8.2. 
Adverse Events Leading to Withdrawal ..................................................................... 28 
8.3. 
Serious Adverse Events and Deaths ........................................................................... 28 
8.4. 
Clinical Laboratory Evaluations ................................................................................. 28 
8.5. 
Vital Signs ................................................................................................................... 29 
8.6. 
Electrocardiograms ..................................................................................................... 29 
8.7. 
Physical examination results ....................................................................................... 30 
8.8. 
Columbia Suicide Severity Rating Scale (C-SSRS) ................................................... 30 
8.9. 
Concomitant Medication ............................................................................................. 30 
9.
Changes from Planned Analysis and clarifications .......................................................... 31 
10.
Other Planned Analysis..................................................................................................... 32 
10.1. Pharmacokinetic Analysis ........................................................................................... 32 
11.
References ......................................................................................................................... 33 
12.
Tables, Listings, and Figures ............................................................................................ 34 
Appendix 1: Abbreviations List .................................................................................................... 35 
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
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List of Tables 
Table 1: Schedule of Events - Treatment period 1 (Month 0-20) ................................................. 12 
Table 2: Schedule of Events – Treatment period 2 (Month 21-40) .............................................. 13 
Table 3: Window bounds for scheduled IBMFRS , Vital signs assessments and Urine Pregnancy 
Test (visits 1, 2, 5a, 7, 9, 11, 12, 14, 16 and 18) ................................................................... 17 
Table 4: Window bounds for ECG and SF-36 scheduled assessments (visits 1, 7 and 11).......... 18 
Table 5: Window bounds for Hand Grip Strength scheduled assessments (visits 1, 7, 11, 12, 14, 
16 and 18) ............................................................................................................................. 18 
Table 6: Window bounds for 6MWD and MTUG scheduled assessments pattern at (visits 1, 5a, 
7, 9 and 11 ............................................................................................................................. 18 
Table 7: Window bounds for C-SSRS scheduled assessments visits (1, 2, 3, 4, 5, 5a, 6, 7, 8, 9, 
10, 11, 12, 13, 14, 15, 16, 18) ............................................................................................... 19 
Table 8: Window bounds for Lab scheduled assessments visits (1, 2, 3, 4, 5, 5a, 6, 7, 9, 11, 12, 
14, 16 and 18) ....................................................................................................................... 19 
List of Figures 
N/A. 
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
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1.
Trial Objectives and Endpoints
1.1. Trial Objectives 
This is an extension study of the IBM4809 study, which recently reported results, and showed 
that the treatment was not effective in treating IBM. It would have been unethical to continue 
with the OLE study, as patients would not be expected to benefit from it. 
Following the early termination of the study by the Sponsor, this statistical analysis plan (SAP) is 
focused on safety analysis. All assessments supposed to be used in the efficacy part will be 
summarized in tables by using descriptive statistics and presented in the listing, but no specific 
efficacy analysis will be performed. 
Consequently, this SAP is designed to outline the methods to be used in the analysis of study 
data to answer the safety objectives. 
1.1.1.  Primary Objectives 
Before termination of study the primary objective was to determine the efficacy (based on the 
Inclusion Body Myositis Functional Rating Scale [IBMFRS]) of early* versus delayed start of 
arimoclomol treatment of IBM up to Month 20 in the OLE trial.  
1.1.2.  Secondary Objectives 
Before termination of study the secondary objectives were to determine the efficacy (on 
secondary efficacy endpoints) of early* versus delayed start of arimoclomol treatment of IBM up 
to Month 20 and up to Month 40  in the OLE trial. Another secondary objective was to determine 
the safety and tolerability of long-term treatment of IBM with arimoclomol up to Month 40 in 
the OLE trial. 
1.1.3. Exploratory Objectives 
Before termination of study the exploratory objectives were 
 
 to explore 
population pharmacokinetics (popPK) and popPK/PD and to determine the efficacy (on 
secondary efficacy endpoints) of early** versus delayed start of arimoclomol treatment over 
periods of 20 months duration. 
* Including 20 months arimoclomol treatment and 20 months placebo treatment from trial IBM4809 for the early and delayed
start group, respectively.
** Including (only) 20 months arimoclomol treatment from trial IBM4809 for the early start group 
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
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1.2. Trial Endpoints 
1.2.1. Efficacy Endpoints 
Due to early termination of study by Sponsor the efficacy endpoints were revised, and most of 
them will not be analysed, since the focus were moved to the safety evaluations. 
1.2.1.1. Primary and Secondary Efficacy Endpoint 
Before termination of study the primary efficacy endpoint of this trial was change in the 
IBMFRS total score from IBM4809 baseline to Month 20 in the OLE trial.  
Before termination of  study by Sponsor the secondary efficacy endpoints were change in 6-
Minute Walk Test Distance, change in Modified Timed Up and Go (mTUG), change in MVICT 
of the quadriceps muscle, change in hand grip strength, change in SF-36 from IBM4809 baseline 
to Month 20 in the OLE trial, change in the IBMFRS total score from IBM4809 baseline to 
Month 40 in the OLE trial, and change in hand grip strength from IBM4809 baseline to Month 
40 in the OLE trial, and number of Falls and Near Falls from IBM4809 baseline to Month 20 in 
the OLE trial.  
1.2.2. Safety Endpoints 
The safety endpoints will be on the main focus of this trial and will include the following (to 40 
months): 

Adverse events (AEs), SAEs

Clinical safety laboratory tests

Vital signs

ECGs

Columbia Suicide Severity Rating Scale (C-SSRS)
1.2.3. Exploratory Endpoints 
Due to early termination of study by Sponsor the exploratory endpoints will not be analysed. 
Before termination of  study the exploratory endpoints included the following: population 
pharmacokinetics (popPK) and popPK/PD,  change from baseline* over 20 months of 
arimoclomol treatment in IBMFRS total score, 6-Minute Walk Test Distance, Modified Timed 
Up and Go (mTUG), MVICT of the quadriceps muscle, hand grip strength, and SF-36  in 
arimoclomol naïve patients  
* Baseline is defined at the visit at which the subject receives first administration of arimoclomol (corresponding to IBM4809
baseline and IBMOLE baseline for patients randomized to arimoclomol and placebo in IBM4809, respectively)
1.2.4. Pharmacokinetic/Pharmacodynamic Variable(s) 
Due to early termination of study by Sponsor the PK/PD endpoints will not be analysed. 
Before termination of  study the pharmacokinetic (PK) endpoints of the trial were to constitute 
arimoclomol plasma concentrations The calculation of parameters for population PK analysis 
was planned to be described in a separate PK analysis plan (PKAP), but won`t be performed. 
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
 Page 8 of 37 
2.
Overview
This statistical analysis plan (SAP) describes the planned analysis and reporting for Orphazyme 
A/S protocol number IBM-OLE (An open-label, non-randomized trial to investigate the efficacy 
and safety of early versus delayed start of arimoclomol in patients with sporadic inclusion body 
myositis who have completed the IBM4809 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.  
Since the study was terminated by the Sponsor, study objectives and endpoints were revised, 
hence the actual analysis will differ from what was defined in the Study Protocol. In case of 
differences between SAP and protocol, this SAP takes precedence. 
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 descriptive analysis of the data pertaining to the IBM-OLE 
trial. 
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
 Page 9 of 37 
3.
Overall Trial Design and Plan
3.1. Overall Design 
This Phase 3b, multicenter, nonrandomized, open-label, uncontrolled clinical extension trial is 
designed to compare the efficacy and safety of early versus delayed start of arimoclomol in the 
treatment of IBM.  
Up to 150 male and female patients who have completed the IBM4809 trial will be available for 
this trial. Patients must currently be on treatment with the investigational medicinal product 
(IMP) from the blinded IBM4809 trial (arimoclomol or placebo) and will enroll in this trial at 
Visit 14/Month 20 of the blinded IBM4809 trial. In this trial there will be two treatment groups: 

Early group (patients who received arimoclomol in the blinded IBM4809 trial)

Delayed group (patients who received placebo in the blinded IBM4809 trial)
11 trial sites in the United States and 1 trial site in the United Kingdom. 
Patients who completed the IBM4809 study at a reduced dose of 600 mg/day arimoclomol citrate 
(200 mg t.i.d.) will continue to receive their reduced dose in this open-label extension (OLE) 
study. All other patients will receive 1200 mg/day arimoclomol citrate (400 mg t.i.d.).  
The duration of treatment in this trial was supposed to be 40 months, but the study was early 
terminated by the Sponsor.  
The trial was expected to be split into two treatment periods with remaining the same throughout 
the two treatment periods. 
Treatment period 1: 
Patients will be seen in the clinic at baseline and months 1, 5 and 9, 15 and 20. Visits will be 
conducted by telephone at month 2, 3, 4, 6, 12 and 18. For the telephone visits at month 2, 3, 4 
and 6 a clinical safety laboratory assessment is also required.  
Efficacy part will be revised and assessed by the descriptive summary of IBMFRS total score, 6-
Minute Walk Test, Modified Timed Up and Go (mTUG), Maximal Voluntary Isometric 
Contraction Testing (MVICT) of the quadriceps muscle, hand grip strength testing, 36-Item 
Short Form Health Survey (SF-36), and falls and near falls.  
 
 Sparse PK samples were supposed to be  
collected for popPK analysis and explorative popPK/PD modeling (reported separately). 
Additional blood was expected to be drawn for biobanking for future potential tests. But due to 
early termination of study, 
 PK/PD analysis won`t be performed.  
Safety will be assessed by evaluating adverse events (AEs), clinical safety laboratory test results, 
vital sign measurements, 12-lead electrocardiograms (ECGs), and the Columbia Suicide Severity 
Rating Scale (C-SSRS).  
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
 Page 10 of 37 
Treatment period 2: 
Patients supposed to be seen in the clinic at months 23, 29, 35 and 40. Visits supposed to be 
conducted by telephone at month 26, 32 and 38.  
Efficacy were planned to be assessed by the in-clinic IBMFRS total score and hand grip strength 
testing. Safety will be assessed by evaluating AEs, clinical laboratory test results and C-SSRS. 
All AEs observed by the trial personnel or reported by the patient during the trial (from the time 
of visit 1(screening) in IBM-OLE) will be collected.  
If a patient discontinues treatment (or the trial is terminated) an early termination (ET) visit will 
be performed as soon as possible after discontinuation, with a follow-up ET phone assessment 2 
weeks later. Depending on the timing of discontinuation (before or after Month 20) the 
assessments performed at the ET visit differs according to the relevant visit schedule (Treatment 
period 1 and Treatment period 2). 
 
 
 
 
 
 
3.2. Sample Size and Power 
As this trial is an open-label extension planning to include patients from the previous trial 
(IBM4809), no calculation for sample size was performed. 
3.3. Trial Population 
Patients with sporadic IBM according to the protocol/meeting the eligibility criteria, who have 
completed the IBM4809 trial. 
3.4. Treatments Administered and Method of Assigning Patients to Treatment 
Groups 
In this open-label, single-treatment trial, all patients will receive the same treatment 
(arimoclomol citrate). 
Patients who completed the IBM4809 study at a reduced dose of 600 mg/day arimoclomol citrate 
or reduced placebo dose will continue on reduced dose arimoclomol citrate in this OLE study. 
All other patients in this open-label extension trial will be assigned to receive 1200 mg/day 
arimoclomol citrate (400 mg t.i.d.). 
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
 Page 11 of 37 
3.5. Blinding and Unblinding 
During the OLE trial, patients must remain blinded as to their treatment assignment in IBM4809. 
3.6. Schedule of Events 
A detailed schedule of events planned for the trial is provided in Table 1 (Treatment period 1) 
and Table 2 (Treatment period 2) below. 
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
 Page 12 of 37 
Table 1: Schedule of Events - Treatment period 1 (Month 0-20) 
Visit # 
1 
2 
3 
(phone 
visit) 
4 
(phone 
visit) 
5 
(phone 
visit) 
5a 
6 
(phone 
visit) 
7 
8 
(phone 
visit) 
9 
10 
(phone 
visit) 
11/ 
ETa
Month 
0b 
1 
2 
3 
4 
5 
6 
9 
12 
15 
18 
20 
Consent 
X 
Eligibility 
X 
Demographics 
X 
Medical History 
Xb 
Vital signs, including 
weight 
Xb 
X 
X 
X 
X 
X 
Physical Examination 
Xb 
X 
X 
X 
X 
X 
Electrocardiogram 
Xb 
X 
X 
Clinical Safety Lab Tests 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Test 
Xb 
X 
X 
X 
X 
X 
Dispensing of Medication 
X 
X 
X 
X 
X 
X 
First dose of open-label 
arimoclomol 
X 
Return of Medication 
X 
X 
X 
X 
X 
C-SSRS
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MVICT of the quadriceps 
muscle 
Xb 
X 
X 
SF-36 
Xb 
X 
X 
Falls diary 
Xb 
X 
X 
X 
X 
X 
Hand Grip Strength 
Xb 
X 
X 
IBMFRS 
Xb 
X 
X 
X 
X 
X 
6MWT 
Xb 
X 
X 
X 
X 
mTUG 
Xb 
X 
X 
X 
X 
 
 
 
 
Biobank Samples 
Xb 
X 
X 
PopPK Samples 
X 
X 
Concomitant Medication 
Xb,d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
Xb,d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
 Page 13 of 37 
Table 2: Schedule of Events – Treatment period 2 (Month 21-40) 
Visit # 
12 
13 (phone 
visit) 
14 
15 (phone 
visit) 
16 
17 (phone 
visit) 
18/ 
ETf
19 (Safety 
follow up) 
Month 
23 
26 
29 
32 
35 
38 
40 
ET +2 wks 
Vital signs, including weight 
X 
X 
X 
X 
Clinical Safety Lab Tests 
X 
X 
X 
X 
Urine Pregnancy Test 
X 
X 
X 
X 
Dispensing of Medication 
X 
X 
X 
X 
X 
X 
Return of Medication 
X 
X 
X 
X 
C-SSRS
X 
X 
X 
X 
X 
X 
X 
IBMFRS 
X 
X 
X 
X 
Hand Grip Strength 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
Xe
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Xe
Phone visits are shaded gray. 
Abbreviations: 6MWT = 6-Minute Walk Test; C-SSRS = Columbia Suicide Severity Rating Scale; ET = early termination; 
IBMFRS = Inclusion Body Myositis Functional Rating Scale; 
; mTUG = Modified Timed Up 
and Go; MVICT = Maximal Voluntary Isometric Contraction Testing; PopPK = population pharmacokinetics; SF-36 = 36-Item 
Short Form Health Survey. 
Note: Visit windows for all visits are ± 7 days relative to Visit 1. 
a.
If a patient discontinues during treatment period 1 (or the trial is terminated) before Visit 11/Month 20, an ET visit for
treatment period 1 (month 20) will be performed as soon as possible after discontinuation, with a safety follow up
phone visit 2 weeks later.
b.
Data from the completion visit of IBM4809 will be transferred to Visit 1 of IBM-OLE if required in the OLE trial, but
not collected, except for safety labs, which require samples for both studies.
c.
d.
Ongoing AEs and concomitant medications from IBM4809 should be recorded in the IBM-OLE eCRF.
e.
Assess and record SAEs occurring since the last evaluation and collect stop dates for already ongoing AEs.
f.
If a patient discontinues during treatment period 2 (or the trial is terminated) between Visit 11/Month 20 and Visit
18/Month 40, an ET visit for treatment period 2 (month 40) will be performed as soon as possible after discontinuation,
with a safety follow up phone visit 2 weeks later.
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
 Page 14 of 37 
4.
Statistical Analysis and Reporting
4.1. Introduction 
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations 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. 
Section 6.2 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 data points will be 
highlighted in the lists. 
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
 Page 15 of 37 
5.
Analysis Populations & Treatment Durations
5.1. Analysis Populations 
The following analysis populations are planned for this trial: 

Safety Population: All patients who receive at least 1 dose or partial dose of
arimoclomol in the extension trial. Safety analyses will be performed on the Safety
Population.

Modified Intent-to-treat (mITT) Population: All patients receiving at least 1 dose or
partial dose of arimoclomol in the extension trial, with a baseline value and at least 1
post-baseline value for IBMFRS. Efficacy analyses will be performed on the mITT
Population.
Inclusion in the analysis populations will be determined prior to database lock 
5.2. Observation Period 
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 (mITT, SAF or All
screened patients)

Secondly, data points from the selected patients from the first step will be selected.
Since the study was terminated by the Sponsor, exploratory endpoints, that include comparison 
with the baseline of main IBM4809 study, will not be analysed.  
All by-visit statistics will summarize the data at each scheduled visit and change from OLE 
baseline.  
Baseline will be the assessment performed at the month 0 of this OLE study, if applicable. 
If not applicable, then the baseline will be the last assessment transferred from the main Visit 
14/Month 20 of IBM4809 study.  
Only scheduled visits will be tabulated, with exception of including unscheduled visits to outlier 
tables (laboratory abnormality etc.). All visits (scheduled and unscheduled) will be included in 
the listings. 
Medical history data (from OLE study as well as transferred from IBM4809) will be listed and 
tabulated. 
Adverse events that start or continue inside the OLE timeline only will be summarized and listed 
(the overview table will summarize both AEs and TEAEs, but the subsequent tables will be 
performed for TEAEs only). AEs that started and finished before 1st dose in the OLE study 
won`t be presented. 
Medications starting or continuing beyond the first dose in OLE study will be considered as 
concomitant regardless they were before the last dose of IMP or after. Medications started and 
finished before 1st dose in the OLE will be treated as prior. 
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
 Page 16 of 37 
6.
Statistical Analysis
6.1. Baseline 
In this open-label extension trial baseline will be the last observation recorded prior to the first 
dose in the OLE study.  
Baseline will be the assessment performed at the month 0 of this OLE study, if applicable. If not 
applicable, then the baseline will be the last assessment transferred from the main Visit 
14/Month 20 of IBM4809 study.  
Patients must currently be on treatment with the IMP from the blinded IBM4809 trial 
(arimoclomol or placebo), and some assessments performed at Visit 14/Month 20 of the blinded 
IBM4809 trial will serve as a baseline, while others will be collected at baseline of this OLE 
study.  
The following procedures performed at Visit 14/Month 20 of the blinded IBM4809 trial will 
serve as the baseline evaluations for this trial: 
1. Measure vital signs, including weight.
2. Perform a physical examination.
3. Perform a 12-lead ECG.
4. Perform a urine pregnancy test for female patients of childbearing potential.
5. Record concomitant medications and concomitant therapies.
6. Assess and record AEs occurring since the last evaluation.
7. Complete the IBMFRS, MVICT of quadriceps muscle, mTUG, hand grip strength testing,
6-minute walk test, and SF-36.
8. Complete the C-SSRS (“since last visit” assessment).
9. Collect and review the falls diary.
(NOTE: If this extension trial has not yet been initiated at a patient’s clinical site or if the patient
are not able to perform in-clinic visits due to COVID-19 when the patient completes Visit 14,
that patient may enroll in this trial up to 12 weeks after Visit 14/Month 20 of the blinded
IBM4809 trial. Such patients will need to undergo the full set of baseline assessments, and the
investigator must confirm eligibility. This possibility will only be available if the patient is able
to perform visit 14 in the IBM4809 trial before 01-Feb-2021).
The following procedures will be performed at baseline for this OLE trial: 
1. Obtain written informed consent (and/or assent if applicable).
2. Record demographics.
3. Record medical history.
4. Assess inclusion/exclusion criteria.
5. Collect blood for safety laboratory tests and biobanking.
6. When all baseline procedures are completed and the site investigator confirms that the patient
is eligible, enroll the patient.
7. Administer the first dose of open-label arimoclomol and observe for 1 hour after dosing.
8. Dispense arimoclomol for the initial 1-month period and give the patient instructions
regarding dosing schedule and trial requirements.
9. Give the patient a new falls diary
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021   |    AD109.01  Effective date 26-Jun-2017 
 Page 17 of 37 
6.2. 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 3 to Table 8 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 summary statistics. 
Unscheduled visits will be mapped to the appropriate visit depending on which visit window 
they fall within.  
The final in-person visit is normally scheduled for month 40, 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".  
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. 
Table 3: Window bounds for scheduled IBMFRS , Vital signs assessments and Urine 
Pregnancy Test (visits 1, 2, 5a, 7, 9, 11, 12, 14, 16 and 18) 
 Visit 
Month 
Nominal time 
(Analysis Relative 
Day) 
Lower bound 
(Analysis Relative 
Day) 
Upper bound 
(Analysis Relative Day) 
V1 
0 
1 
NA 
1 
V2 
1 
31 
2 
91 
V5a 
5 
151 
92 
211 
V7 
9 
271 
212 
331 
V9 
15 
451 
392 
511 
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021   |    AD109.01  Effective date 26-Jun-2017 
 Page 18 of 37 
V11 
20 
601 
541 
646 
V12 
23 
691 
647 
751 
V14 
29 
871 
812 
931 
V16 
35 
1051 
992 
1111 
V18 
40 
1201 
1142 
1261 
Table 4: Window bounds for ECG and SF-36 scheduled assessments (visits 1, 7 and 11) 
Visit 
Month 
Nominal time 
(Analysis Relative 
Day) 
Lower bound 
(Analysis Relative 
Day) 
Upper bound 
(Analysis Relative Day) 
V1 
0 
1 
NA 
1 
V7 
9 
271 
211 
331 
V11 
20 
601 
541 
661 
Table 5: Window bounds for Hand Grip Strength scheduled assessments (visits 1, 7, 11, 12, 
14, 16 and 18) 
Visit 
Month 
Nominal time 
(Analysis Relative 
Day) 
Lower bound 
(Analysis Relative 
Day) 
Upper bound 
(Analysis Relative Day) 
V1 
0 
1 
NA 
1 
V7 
9 
271 
211 
331 
V11 
20 
601 
541 
646 
V12 
23 
691 
647 
751 
V14 
29 
871 
811 
931 
V16 
35 
1051 
991 
1111 
V18 
40 
1201 
1141 
1261 
Table 6: Window bounds for 6MWD and MTUG scheduled assessments pattern at (visits 1, 
5a, 7, 9 and 11 
Visit 
Month 
Nominal time 
(Analysis Relative 
Day) 
Lower bound 
(Analysis Relative 
Day) 
Upper bound 
(Analysis Relative Day) 
V1 
0 
1 
NA 
1 
V5a 
5 
151 
91 
211 
V7 
9 
271 
212 
331 
V9 
15 
451 
391 
511 
V11 
20 
601 
541 
661 
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021   |    AD109.01  Effective date 26-Jun-2017 
 Page 19 of 37 
Table 7: Window bounds for C-SSRS scheduled assessments visits (1, 2, 3, 4, 5, 5a, 6, 7, 8, 
9, 10, 11, 12, 13, 14, 15, 16, 18) 
 Visit 
Month 
Nominal time 
(Analysis Relative 
Day) 
Lower bound 
(Analysis Relative 
Day) 
Upper bound 
(Analysis Relative Day) 
V1 
0 
1 
NA 
1 
V2 
1 
31 
2 
46 
V3 
2 
61 
47 
76 
V4 
3 
91 
77 
106 
V5 
4 
121 
107 
136 
V5a 
5 
151 
137 
166 
V6 
6 
181 
167 
226 
V7 
9 
271 
227 
316 
V8 
12 
361 
317 
406 
V9 
15 
451 
407 
496 
V10 
18 
541 
497 
571 
V11 
20 
601 
572 
646 
V12 
23 
691 
647 
736 
V13 
26 
781 
737 
826 
V14 
29 
871 
827 
916 
V15 
32 
961 
917 
1006 
V16 
35 
1051 
1007 
1126 
V18 
40 
1201 
1141 
1261 
Table 8: Window bounds for Lab scheduled assessments visits (1, 2, 3, 4, 5, 5a, 6, 7, 9, 11, 
12, 14, 16 and 18) 
 Visit 
Month 
Nominal time 
(Analysis Relative 
Day) 
Lower bound 
(Analysis Relative 
Day) 
Upper bound 
(Analysis Relative Day) 
V1 
0 
1 
NA 
1 
V2 
1 
31 
2 
46 
V3 
2 
61 
47 
76 
V4 
3 
91 
77 
106 
V5 
4 
121 
107 
136 
V5a 
5 
151 
137 
166 
V6 
6 
181 
167 
226 
V7 
9 
271 
227 
331 
V9 
15 
451 
392 
511 
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
 Page 20 of 37 
V11 
20 
601 
542 
646 
V12 
23 
691 
647 
751 
V14 
29 
871 
811 
931 
V16 
35 
1051 
992 
1111 
V18 
40 
1201 
1141 
1261 
6.3. Multiple Comparisons 
Not applicable for this OLE study. No efficacy testing will be performed. 
6.4. Efficacy Endpoints 
Since the study was terminated by Sponsor, the efficacy analysis was simplified from what was 
planned in the Study Protocol: no hypothesis testing for the effectiveness between the early-start 
group and delayed-group will be performed.  
6.4.1. Analyses of Primary Endpoint 
The descriptive statistics for IBMFRS total score at each visit and change from baseline will be 
presented: the number of non-missing values at each visit, mean, median, standard deviation, 
minimum, maximum, 1st, and 3rd quartiles will be tabulated. No summarization will be 
performed for sub-domains. 
The baseline value for the IBMFRS assessment will be copied from the completion visit of 
IBM4809 and will be transferred to this OLE study. 
All IBMFRS data will be presented in listing. 
Missing data will not be imputed. 
6.5. Analyses of Secondary Endpoints 
Since the study was terminated by Sponsor, the efficacy analysis was simplified from what was 
planned in the Study Protocol: no hypothesis testing for the effectiveness in secondary endpoints 
between the early-start group and delayed-group will be performed.  
Missing data will not be imputed. 
6.5.1. Six Minutes Walking distance test; distance at 6 minutes (6MWD) 
The descriptive statistics for 6 Minute Walk Test Distance at each visit and change from baseline 
will be summarized using descriptive statistics. 
The OLE baseline value for the 6 Minute Walk Test assessment will be the assessment 
transferred from the completion visit of IBM4809. 
All 6MWD data will be presented in listing. 
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
 Page 21 of 37 
6.5.2.  Modified Timed Up and Go (mTUG) 
When summarizing 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. 
The descriptive statistics for Modified Timed Up and Go Test at each visit and change from 
baseline will be presented: the number of non-missing values at each visit, mean, median, 
standard deviation, minimum, maximum, 1st, and 3rd quartiles will be tabulated  
The OLE baseline value for the Modified Timed Up and Go Test assessment will be the 
assessment transferred from the completion visit of IBM4809. 
All mTUG data will be presented in the listing. 
6.5.3. Grip strength using the Jamar device  
Grip strength is assessed for both the right and the left hand. 
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 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 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. 
The number of non-missing values at each visit as well as change from the baseline will be 
tabulated using mean, median, standard deviation, minimum, maximum, 1st, and 3rd quartiles. 
All hand grip results will be listed. 
6.5.4. Quadriceps Muscle Strength Testing 
Maximal voluntary isometric contraction testing (MVICT) of the patient’s quadriceps muscle 
will be performed using the MicroFET hand myometer. This is a hand-held device that allows 
the examiner to push against a muscle while the patient resists. The patient will be encouraged 
by the clinical evaluator (CE) to exert maximal effort. Each test will be performed twice on each 
side and both sets of results will be recorded.  
The descriptive statistics for MVICT at each visit and change from baseline will be presented: 
the number of non-missing values at each visit, mean, median, standard deviation, minimum, 
maximum, 1st, and 3rd quartiles will be tabulated  
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
 Page 22 of 37 
The OLE baseline value for the MVICT assessment will be the assessment transferred from the 
completion visit of IBM4809. 
All MVICT results will be listed. 
6.5.5. Falls and Near Falls 
All falls and near falls data will be listed, no tabulation will be done. 
6.5.6. SF-36 Results 
The raw values of the SF-36 results will be presented in the listing. No derived scores will be 
calculated. 
6.6. Derived Variables 
Entity 
Definition 
Change from baseline 
Value at current timepoint – value at baseline 
BMI 
Weight in kilograms / (Height in meters) ^2 
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 after the first dose 
of IMP until last dose of IMP + 14 days 
6.7. 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. 
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 in this OLE study, then
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
 Page 23 of 37 
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
of the treatment period, 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 treatment period, in which case either the month of the treatment period
is used if that results in a date within the treatment period, or otherwise the previous
month

If both month and day are missing and the year is the same as the end of the treatment
period, then the date is assigned as the end of the treatment  period. If the year is not the
same as the end of the 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.
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
 Page 24 of 37 
7.
Trial Patients and Demographics
7.1. Disposition of Patients and Withdrawals 
The number of patients screened and who failed the screening will be summarized. 
Disposition will also include tabulations of the number of patients who initiated the trial, 
initiated the trial on 400 mg TID dosage or 200 mg TID respectively, withdrew from trial drug 
and discontinued the study early (for all reasons and due to impact of COVID-19), 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 the 
treatment group and overall for the SAF. 
The number and percentage of patients in each analysis set (SAF and mITT) for each study 
center (UK, USA) and overall will also be summarized. 
7.2. Protocol Violations and Deviations 
Protocol deviations will be recorded in external spreadsheets maintained by the Clinical 
Operations group which will being viewed on an ongoing basis and finalized prior to database 
lock. 
Incidences of protocol deviations (important, non-important, and all) will be summarized in the 
external spreadsheets by protocol deviation category. The number of patients with any protocol 
deviations as well as deviation related to COVID-19 will be summarized by counts and 
percentages. 
All protocol deviations will be listed. 
7.3. Demographics and Other Baseline Characteristics 
Summary statistics for age, gender, race, age at diagnosis, ethnicity, height, weight, and BMI 
will be presented by treatment group and overall. Patients will be also summarized by age groups 
(>65 years and >75 years). 
For the continuous variables, the number of non-missing values and the mean, standard 
deviation, minimum, median, maximum, 1st and 3rd quartiles will be tabulated.  
For the categorical variables, the counts and proportions of each value will be tabulated.   
These analyses for demographics and baseline characteristics will be conducted for the SAF 
population.  
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. Medical history will include data from in OLE study as well 
as transferred from IBM4809 study. 
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
 Page 25 of 37 
All demographics, baseline characteristics and medical history data will be listed. 
7.4. Exposure and Compliance 
7.4.1. Exposure 
The duration of exposure to IMP will be calculated as follows: from the date of last dosing minus 
the first day of dosing in OLE study + 1. The exposure calculation will not take therapy 
interruptions into account.  
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. 
7.4.2. 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 clinic 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 (Best Case): 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 (Worst Case): 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).  
7.4.3. Dose interruption and patient discontinuation 
At any time during the trial, the protocol permits that the IMP may be temporarily interrupted for 
up to 4 weeks for an intolerable AE with supportive therapy (if needed). The interruption of the 
dose should be as short as possible. If the patient experiences the same intolerable AE after re-
challenge with the full dose of arimoclomol, arimoclomol must be discontinued permanently. 
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
 Page 26 of 37 
Sites record start and stop dates of an interruption, then the sites record if patient discontinued 
permanently (in case of the same intolerable AE). It will be assumed the date of discontinuation 
is the day after stop date of the interruption. 
In addition to calculating overall exposure (see above), for patients that discontinued 
permanently due to the same intolerable AE after re-challenge with the full dose of arimoclomol, 
number of days exposed will be calculated as follows: from day prior to discontinuation due to 
repeated intolerable AE minus the first day of dosing +1. 
Length of interruption (including all reasons, and COVID-19 related reason as well) will be 
summarized using descriptive statistics. 
7.4.4. 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, if patient came from IBM4809 study
with 1200 mg/day (400 mg t.i.d.) dosage;
-
3 times the number of days in the relevant period, if patient came from IBM4809 study
with 600 mg/day (200 mg t.i.d.) dosage.
Trial drug administration data will be listed. 
The number of capsules dispensed (assuming the worst case and best case separately), returned 
and used (assuming the worst case and best case separately), as well as treatment compliance 
will be summarized by treatment group, overall and by visit, for the SAF population.  
7.4.5. Average daily exposure 
Average daily exposure (mg) will be calculated as follows. 
Average daily exposure (mg) = Average daily exposure (caps) x amount of free base (mg), where 
average daily exposure (caps) = sum of total exposure doses (caps) during the treatment divided 
by the duration of exposure. 
Average daily exposure will be summarized using descriptive statistics. 
7.5. Baseline Columbia Suicide Severity Rating Scale (C-SSRS) 
Baseline characteristics will be tabulated for Suicidal Ideation and Suicidal Behavior separately. 
Assessment performed at Visit 14/Month 20 of the blinded IBM 4809 trial will be served as the 
baseline evaluation for this OLE study. 
All results from the C-SSRS will be listed. 
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
 Page 27 of 37 
8.
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, and C-SSRS. 
All safety analyses will be performed on the SAF population unless otherwise specified. 
8.1. Adverse Events 
Adverse events (AEs) will be coded using the MedDRA version 20.1 dictionary. 
AEs after the first dose of IMP until the last dose of IMP +14 days will be considered treatment-
emergent adverse events (TEAEs).   
Adverse events that start or continue inside the OLE timeline only will be summarized and listed. 
AEs that started and finished before 1st dose in the OLE study, but were transferred from main 
4809 study  won`t be presented. 
The overall table of the incidence of AEs will summarize number and percentage of patients, 
number of AEs and TEAEs as well as rate in following categories: with any adverse event; mild, 
moderate and severe AEs and TEAEs; AEs and TEAEs related to study drug, serious AEs and 
TEAEs; serious AEs and TEAEs related to study drug; AEs and TEAEs leading to temporary 
interruption of IMP and AEs as well as TEAEs leading to treatment discontinuation by treatment 
groups and overall. Number of patients as well as observation time (years) will be tabulated.  
The table with 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. 
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 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 treatment-emergent 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) and be tabulated. In the listings the raw (non-imputed) values of severity or 
relationship will be presented.  
Any abnormal clinical significant physical examination findings will be recorded as AEs, 
according to Investigator`s request. 
No inferential statistical tests will be performed. 
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
 Page 28 of 37 
8.2. 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. 
8.3. Serious Adverse Events and Deaths 
Serious treatment emergent AEs as well as death will be listed. 
Serious treatment emergent AEs  will also be tabulated by SOC and PT and presented by 
treatment for the SAF population. The summary for deaths will be also presented. 
8.4. 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).

Clinical chemistry: 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.
Descriptive statistics of the observed values and change from baseline (continuous data) will be 
presented by treatment group and visit for each haematology, clinical chemistry parameter and 
cystatin C as well. 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.  
Local laboratory results will be used for the analysis in case subject cannot attend the trial site 
for close observation in relation to elevated transaminases. All local laboratory results will be 
flagged in the data listings. 
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. 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: 
•
Post baseline sCr value ≥ 1.5x baseline value
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
 Page 29 of 37 
•
Post-baseline sCr value ≥ 2x baseline value
•
Post-baseline sCr value ≥ 3x baseline value
The incidence of patients fulfilling the below criteria will be summarized:
•
ALT ≥ 3 × ULN
•
ALT ≥ 5 × ULN
•
ALT ≥ 8 × ULN
•
ALT ≥ 20 × ULN
•
AST ≥ 3 × ULN
•
AST ≥ 5 × ULN
•
AST ≥ 8 × ULN
•
AST ≥ 20 × ULN
•
ALT or AST ≥ 3.0x ULN
•
ALT or AST ≥ 5.0x ULN
•
ALT or AST ≥ 8x ULN
•
ALT or AST ≥ 20 × ULN
•
Total Bilirubin≥ 2x ULN
•
ALP ≥ 2 x ULN
•
ALP ≥ 3 × ULN
•
(ALT or AST ≥ 3.0x ULN) and Total Bilirubin≥ 2x ULN and ALP ≤ 1.5x ULN
•
ALT ≥ 3 × ULN & Total Bilirubin ≥ 2 × ULN & ALP ≤ 1.5 × ULN
•
AST ≥ 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.
Number (%) of patients that have potentially clinically significant laboratory values overall and 
by visit will be presented. 
Plots of all mean ALT, AST, ALP, LDH, GGT, total bilirubin, creatinine, creatine kinase, and 
Cystatin C Results with error bars, that represent +/- 1 x standard error of the mean will be 
presented over the time, separately by treatment group. 
8.5. 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 using the 
SAF population.  
Vital signs will be listed. 
8.6. 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 using the SAF population.  
ECG results (normal/abnormal) will be listed. Clinically significant abnormalities will be 
flagged. 
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
 Page 30 of 37 
8.7. Physical examination results 
No physical examination data will be presented. The investigators have been asked to record 
abnormal clinical significant results as AEs. 
8.8. 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. 
Baseline characteristics will further be tabulated for Suicidal Ideation and Suicidal Behavior 
separately. 
All results from the C-SSRS will be listed. 
8.9. Concomitant Medication 
Prior medications will be presented separately from concomitant medications. 
Medications that started prior to the start of the trial drug in this OLE study 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 in this OLE study will be 
considered to be concomitant, regardless they were before the last dose of IMP or after. 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. Medications will be coded using WHODD v. B2 Sep2017. 
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
 Page 31 of 37 
9.
Changes from Planned Analysis and clarifications
The analyses presented in the SAP were accustomed to the study requirements due to early 
termination of the study. The changes are the following: 

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.


Due to early study termination by the Sponsor the planned analysis was revised: no testing of
efficacy hypothesis to be performed in this OLE study, but the data supposed to be used for
efficacy will be summarized at each visit and change from baseline using descriptive
statistics. The focus of the analyses was moved to safety endpoints. All exploratory
endpoints, as well as any PK assessments, won`t be analyzed
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
 Page 32 of 37 
10.
Other Planned Analysis
10.1. Pharmacokinetic Analysis 
No PK/PD data will be summarized or listed due to early termination of study by the Sponsor 
and revised study objectives and endpoints. 
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
 Page 33 of 37 
11.
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).
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
 Page 34 of 37 
12.
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. 
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
 Page 35 of 37 
Appendix 1: Abbreviations List 
Abbreviation 
Definition 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase (SGPT) 
AST 
Aspartate Aminotransferase (SGOT) 
BMI 
Body Mass Index 
CRF 
Case Report Form 
CS 
Clinically Significant 
CTR 
Clinical Trial Report 
C-SSRS
Columbia Suicide Severity Rating Scale 
DBL 
Database Lock 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ET 
Early Termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
HR 
Heart Rate 
IBM 
Inclusion Body Myositis 
IBMFRS 
Inclusion Body Myositis Functional Rating Scale 
ICH 
International Council for Harmonization 
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
 Page 36 of 37 
Abbreviation 
Definition 
ID 
Identification 
IMP 
Investigational Medicinal Product 
mITT 
Modified Intent-To-Treat 
KUMC 
University of Kansas Medical Center 
LDH 
Lactate Dehydrogenase 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
mTUG 
Modified Timed Up and Go 
MVICT 
Maximal Voluntary Isometric Contraction Testing 
N 
Number 
OLE 
Open-label 
PD 
Pharmacodynamics 
PK 
Pharmacokinetic 
PKAP 
Pharmacokinetic Analysis Plan 
RBC 
Red Blood Cells 
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 
CONFIDENTIAL


Statistical Analysis Plan,  
Orphazyme A/S  
Protocol Number IBM-OLE 
PCN Number ORPA208736
AD-ST-33.05  Effective date: 22-Jan-2018 
FINAL Version 1.0 | 20 October 2021     |    AD109.01  Effective date 26-Jun-2017 
 Page 37 of 37 
Abbreviation 
Definition 
SD 
Standard Deviation 
SF-36 
36-Item Short Form Health Survey
SOC 
System Organ Class 
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 
CONFIDENTIAL