A Phase 3, Randomised, Placebo-Controlled Trial of Arimoclomol in Amyotropic Lateral Sclerosis
Phase: PHASE3
Conditions: Amyotrophic Lateral Sclerosis
Sponsor: ZevraDenmark

Protocol number: ORARIALS-01 
Date: 08-Jun-2020 
Version: Final 7.0 
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CLINICAL TRIAL PROTOCOL 
A Phase 3, Randomised, Placebo-Controlled Trial of 
Arimoclomol in Amyotrophic Lateral Sclerosis
Sponsor: Orphazyme A/S, Ole Maaløes Vej 3, DK-2200 Copenhagen N, Denmark 
Coordinating investigator: 
, MD PhD 
Protocol number: ORARIALS-01 
EudraCT No.: 2018-000137-13 
ClinicalTrials.gov Identifier: NCT03491462
Trial product name: Arimoclomol Capsules 
Date of Amendment: 08-Jun-2020 
Strengths of arimoclomol are presented throughout this document by weight of the citrate 
salt. 
The trial will be conducted according to the protocol and in compliance with Good Clinical Practice (GCP), 
with the Declaration of Helsinki and with other applicable regulatory requirements 
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.

 
 
 
 
 
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Approval Statement, Orphazyme A/S 
This trial protocol was subjected to critical review. The information it contains is consistent 
with current knowledge of the risks and benefits of the investigational product, as well as 
with the moral, ethical and scientific principles governing clinical research as set out in the 
Declaration of Helsinki (1) and the guidelines on Good Clinical Practice (GCP) (2). 
 
 
_____________________________________ 
_____________________ 
, MD 
 
 
 
Date 
Medical Director, Orphazyme A/S 
 
Phone: 
 
  
 
 
_____________________________________ 
_____________________ 
, PhD 
 
 
 
 
Date 
Biostatistician, President ProSoft Clinical 
 
Phone: 
 
 

 
 
 
 
 
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Approval Statement International Coordinating Investigator 
This trial protocol was subjected to critical review and has been approved by Orphazyme 
A/S. The information it contains is consistent with the current risk/benefit evaluation of the 
investigational product as well as with the moral, ethical and scientific principles governing 
clinical research as set out in the Declaration of Helsinki (1) and the guidelines on Good 
Clinical Practice (GCP) (2). 
 
 
 
_____________________________________ 
_____________________ 
 MD, PhD  
 
 
Date 
Professor of Neurology 
Walter Bradley Chair in ALS Research  
Chief, Neuromuscular Division 
University of Miami 
1120 NW 14th St CRB1318 
Miami FL 33136 
USA 
 
Phone: 
 
 

 
 
 
 
 
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Acknowledgement Statement Investigators 
Each participating investigator must agree to the approved clinical trial protocol and 
consolidated clinical trial protocol(s) (including any protocol amendments) by signing a 
clinical trial protocol acknowledgement form. 
The investigator must be familiar with the applicable country-specific requirements as 
described in section 10.4.    

 
 
 
 
 
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Protocol Amendment 
This document is a Consolidated Clinical Trial Protocol, which includes protocol 
amendment. 
The details of the amendments below are presented in a separate Summary of Changes Made 
to Protocol Content as Part of Protocol Amendments: 
• Clinical Trial Protocol version 1.0 dated 12th March 2018 (applicable globally) 
• Clinical Trial Protocol version 2.0 dated 26th June 2018 (applicable only to Canada) 
• Clinical Trial Protocol version 3.0 dated 1st August 2018 (applicable globally) 
• Clinical Trial Protocol version 4.0 dated 3rd February 2019 (applicable globally) 
• Clinical Trial Protocol version 4.1 dated 01st April 2019 (applicable only to France) 
• Clinical Trial Protocol version 5.0 dated 16th July 2019 (applicable globally) 
• Clinical Trial Protocol version 6.0 dated 25th October 2019 (applicable globally) 
• Clinical Trial Protocol version 7.0 dated 08th June 2020 (applicable globally) 
 
The sponsor confirms that the changes introduced in version 7.0 qualify for classification as 
substantial amendments. Country specific information are contained in Section 10.4. 

 
 
 
 
 
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Table of Contents 
APPROVAL STATEMENT, ORPHAZYME A/S.......................................................... 2 
APPROVAL STATEMENT INTERNATIONAL COORDINATING 
INVESTIGATOR .............................................................................................................. 3 
ACKNOWLEDGEMENT STATEMENT INVESTIGATORS .................................... 4 
TABLE OF CONTENTS .................................................................................................. 6 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................. 11 
1. 
SCHEDULE OF TRIAL PROCEDURES ............................................. 14 
2. 
INTRODUCTION AND RATIONALE ................................................. 19 
2.1 
Amyotrophic Lateral Sclerosis ................................................................... 19 
2.2 
Arimoclomol .............................................................................................. 20 
2.3 
Experience with Arimoclomol ................................................................... 21 
2.3.1 
Non-clinical Experience....................................................................... 21 
2.3.2 
Clinical Experience .............................................................................. 21 
2.4 
Trial Rationale ............................................................................................ 23 
2.4.1 
Justification for the Trial ...................................................................... 23 
2.4.2 
Justification for Selected Dose............................................................. 23 
2.4.3 
Justification for Placebo ....................................................................... 25 
2.4.4 
Justification for Endpoints ................................................................... 25 
2.4.4.1 Permanently Assisted Ventilation (PAV)- and Tracheostomy-Free 
Survival .......................................................................................... 25 
2.4.4.2 Disease Progression, as Measured by Change from Baseline on the 
ALSFRS-R ..................................................................................... 26 
2.4.4.3 Decline of Respiratory Function, as Quantified by Change From 
Baseline on the Slow Vital Capacity (SVC) as % of Predicted.... 26 
2.5 
Risk-Benefit Assessment ........................................................................... 26 
2.6 
Ethical Considerations ............................................................................... 27 
3. 
OBJECTIVES AND ENDPOINTS ........................................................ 28 
4. 
TRIAL DESIGN ....................................................................................... 30 
4.1 
Overall Trial Design ................................................................................... 30 
4.2 
Number of Subjects .................................................................................... 33 
4.3 
End of Trial Definition ............................................................................... 33 
5. 
TRIAL POPULATION AND WITHDRAWAL ................................... 34 
5.1 
Subject Eligibility ...................................................................................... 34 
5.2 
Inclusion Criteria ........................................................................................ 34 
5.3 
Exclusion Criteria....................................................................................... 35 

 
 
 
 
 
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5.4 
Screening, Screening Failures and Randomisation Procedure ................... 36 
5.5 
Discontinuation .......................................................................................... 37 
5.5.1 
Discontinuation from Treatment .......................................................... 37 
5.5.2 
Discontinuation from the Trial ............................................................. 37 
5.6 
Missed Visits and Lost to Follow-Up ........................................................ 38 
6. 
TREATMENTS ........................................................................................ 39 
6.1 
Trial Products ............................................................................................. 39 
6.2 
Administration of Investigational Medicinal Products .............................. 40 
6.3 
Interactive Web Response System ............................................................. 41 
6.4 
Treatment Assignment ............................................................................... 41 
6.4.1 
Randomisation ..................................................................................... 41 
6.4.2 
Blinding................................................................................................ 41 
6.4.3 
Emergency Unblinding of Individual Subject Treatment .................... 41 
6.5 
Dose Modification and IMP Discontinuation ............................................ 42 
6.5.1 
Permanent Discontinuation of IMP ..................................................... 42 
6.5.2 
Temporary Halt of IMP and Dose Modification.................................. 43 
6.6 
Treatment logistics and accountability....................................................... 44 
6.6.1 
Labelling and packaging of IMPs ........................................................ 44 
6.6.2 
Storage of IMPs ................................................................................... 44 
6.6.3 
Drug Distribution and Dispensation .................................................... 44 
6.6.4 
Drug Accountability and Destruction .................................................. 45 
6.6.5 
Treatment Compliance ......................................................................... 46 
6.7 
Mode of Administration ............................................................................. 46 
6.8 
Concomitant Medication and Procedures .................................................. 46 
6.9 
Prohibited Medication and Procedures ...................................................... 48 
6.10 
Provision for Subject Care Following Trial Completion ........................... 49 
7. 
TRIAL ASSESSMENTS AND PROCEDURES ................................... 50 
7.1 
General Principles ...................................................................................... 50 
7.1.1 
Investigator’s or Delegate’s Responsibilities....................................... 50 
7.1.2 
Nomination of Primary Caregiver and Legal Representative .............. 50 
7.1.3 
Rater Training and Certification .......................................................... 51 
7.1.4 
Subject Instruction ............................................................................... 52 
7.1.4.1 Investigational Medical Product ........................................................ 52 
7.1.4.2 Subject Diary ...................................................................................... 52 
7.1.4.3 Patient Reported Outcomes (PROs) .................................................. 52 
7.1.5 
Sequence of Assessments .................................................................... 52 
7.1.6 
Visit Scheduling ................................................................................... 53 
7.1.7 
Subject Assessment when Unable to Travel to the Trial Site .............. 53 
7.2 
Baseline Characteristics ............................................................................. 54 
7.2.1 Demographics ............................................................................................ 54 
7.2.2   General Medical History ............................................................................. 55 
7.2.3 
ALS Characterisation ........................................................................... 55 
7.2.4 
El Escorial Diagnostic Criteria for ALS .............................................. 55 

 
 
 
 
 
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7.2.5 
Respiratory Rate................................................................................... 56 
7.2.6 
Body Height ......................................................................................... 56 
7.2.7 
Use of Tobacco and Nicotine-Containing Products............................. 56 
7.3 
Efficacy Assessments ................................................................................. 56 
7.3.1 
Survival (PAV/Tracheostomy/Death) .................................................. 56 
7.3.2 
ALS Functional Rating Scale – Revised (ALSFRS-R) ....................... 57 
7.3.3 
Slow Vital Capacity (SVC) .................................................................. 57 
7.3.4 
Edinburgh Cognitive and Behavioural ALS Screen (ECAS) .............. 58 
7.4 
Health-Related Quality of Life Assessment ............................................... 59 
7.4.1 
EuroQol, Five-Dimensional, Five-Level Descriptive System (EQ-5D-
5L) ........................................................................................................ 59 
7.4.2 
Schedule for the Evaluation of Individual Quality of Life-Direct 
Weighting (SEIQoL-DW) .................................................................... 60 
7.5 
Safety Assessments .................................................................................... 61 
7.5.1 
Physical Examination........................................................................... 61 
7.5.2    Neurological Examination ......................................................................... 61 
7.5.3 
Vital Signs ............................................................................................ 61 
7.5.4 
Body Weight ........................................................................................ 62 
7.5.5 
Electrocardiogram – 12 lead ................................................................ 62 
7.5.6 
Columbia Suicide Severity Rating Scale (C-SSRS) ............................ 63 
7.5.7 
Adverse Events .................................................................................... 63 
7.5.7.1     Definitions of Adverse Events and Serious Adverse Events .......... 63 
7.5.7.2 Collection of adverse events ............................................................... 64 
7.5.7.3 Disease Progression ........................................................................... 67 
7.5.7.4 Death ................................................................................................... 67 
7.5.7.5 Follow-Up for Final Outcome of Adverse Events ............................. 67 
7.5.7.6 Reporting of Serious Adverse Events ................................................ 67 
7.5.7.7 Pregnancies ........................................................................................ 68 
7.5.7.8 Overdose ............................................................................................. 69 
7.5.7.9 Handling of an Urgent Safety Measure ............................................ 69 
7.5.8 
Pregnancy Test ..................................................................................... 69 
7.5.9 
Clinical Safety Laboratory Assessments ............................................. 70 
7.5.9.1 Central Laboratory ............................................................................. 70 
7.5.9.2 Local Laboratory ................................................................................ 72 
7.5.10 
Follow-up for Specific Laboratory Abnormalities .............................. 72 
7.5.10.1 
Increased Serum Creatinine ......................................................... 72 
7.5.10.2 
Increased Transaminases ............................................................. 72 
7.6 
Biological Sample Assessments ................................................................. 73 
7.6.1 
Genomic Assessments ......................................................................... 73 
7.6.2 
Pharmacokinetics Assessments ............................................................ 74 
7.6.2.1 Blood Samples .................................................................................... 74 
7.6.2.2 Cerebrospinal Fluid (CSF) Samples ................................................. 74 
7.6.3 
Biomarker Assessments ....................................................................... 75 
7.6.4 
Biorepository........................................................................................ 76 
7.6.5 
Estimate of Total Blood Volume and CSF Volume Collected ............ 76 
7.6.6 
Destruction of Biological Material ...................................................... 77 

 
 
 
 
 
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7.7 
Home Visit / Contract Nursing Service ..................................................... 77 
8 
STATISTICAL METHODS ................................................................... 78 
8.1 
Sample Size ................................................................................................ 78 
8.2 
Trial Analysis Sets ..................................................................................... 79 
8.3 
Statistical Analysis ..................................................................................... 79 
8.3.1 
Disposition of Subjects ........................................................................ 79 
8.3.2 
Demographics and Other Baseline Characteristics .............................. 79 
8.3.3 
Exposure and Treatment Compliance .................................................. 80 
8.3.3.1 Exposure ............................................................................................. 80 
8.3.3.2 Treatment Compliance ....................................................................... 80 
8.3.4 
Analysis of Efficacy ............................................................................. 80 
8.3.4.1 Primary Efficacy Analysis ................................................................. 80 
8.3.4.2 Secondary Efficacy Analysis .............................................................. 80 
8.3.5 
Analysis of Safety ................................................................................ 81 
8.3.5.1 Adverse Events .................................................................................... 81 
8.3.5.2 Other Safety Parameters .................................................................... 81 
8.3.6 
Exploratory Analysis ........................................................................... 81 
8.3.6.1 Efficacy ............................................................................................... 81 
8.3.6.2 Health-related Quality of Life ............................................................ 81 
8.3.6.3 Pharmacokinetics ............................................................................... 81 
8.3.6.4 Biomarkers ......................................................................................... 82 
8.3.7 
General Principles ................................................................................ 82 
8.3.8 
Handling of Missing Values ................................................................ 82 
9 
REFERENCE LIST ................................................................................. 83 
10 
APPENDICES .......................................................................................... 87 
10.1 
Protocol summary ...................................................................................... 87 
10.2 
Trial governance considerations ................................................................ 96 
10.2.1 
Regulatory and ethical considerations ................................................. 96 
10.2.2 
Informed consent process .................................................................... 96 
10.2.3 
Subject card .......................................................................................... 97 
10.2.4 
Subject and data confidentiality ........................................................... 98 
10.2.5 
Processing of personal data .................................................................. 98 
10.2.6 
Record keeping, quality control and data handling ............................. 99 
10.2.6.1 
Investigator Logs ........................................................................... 99 
10.2.6.2 
Case report forms .......................................................................... 99 
10.2.6.3 
Principles for data entry ............................................................... 99 
10.2.6.4 
Source data .................................................................................... 99 
10.2.6.5 
Trial monitoring .......................................................................... 100 
10.2.6.6 
Protocol compliance .................................................................... 100 
10.2.6.7 
Sponsor audits, IRB/IEC review and regulatory agency 
inspections ................................................................................... 101 
10.2.6.8 
Data handling .............................................................................. 101 
10.2.6.9 
Archiving of trial documentation ............................................... 103 
10.2.7 
Registration, reporting and publication policy................................... 103 

 
 
 
 
 
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10.2.8 
Insurance ............................................................................................ 104 
10.2.9 
Financial disclosure ........................................................................... 104 
10.2.10 
Data Monitoring Committee .............................................................. 104 
10.2.11 
Trial and site disclosure ..................................................................... 105 
10.2.11.1 Premature termination of trial or trial site ................................ 105 
10.2.11.2 Completion of trial ...................................................................... 105 
10.2.12 
Responsibilities .................................................................................. 106 
10.2.13 
Neurological examination criteria ...................................................... 106 
10.3 
Contact list ............................................................................................... 108 
10.3.1 
International coordinating investigator .............................................. 108 
10.3.2 
National coordinating investigator ..................................................... 108 
10.3.3 
Investigators ....................................................................................... 108 
10.3.4 
Data Monitoring Committee .............................................................. 108 
10.3.5 
Sponsor .............................................................................................. 108 
10.3.6 
Service Providers ............................................................................... 109 
10.3.6.1 
Contract Research Organisations .............................................. 109 
10.3.6.2 
Contract Manufacturing Organisations .................................... 109 
10.3.6.3 
Contract Laboratory Services ..................................................... 110 
10.4 
Country-Specific Requirements ............................................................... 111 
10.4.1 
Canada................................................................................................ 111 
10.4.2 
France ................................................................................................. 111 
10.5 
Coronavirus (COVID) operational changes ............................................. 112 
 
Tables in Text 
Table 1 
Schedule of trial procedures .............................................................................. 14 
Table 2 
Estimated Safety Margin Based on Exposure at NOAEL in 52-week Toxicity 
Study in Dog and Steady State Exposure in Healthy Subjects at 400 mg t.i.d. (Study 
AALS-005) .................................................................................................................. 24 
Table 3 
Objectives and Endpoints .................................................................................. 28 
Table 4: Description of investigational medicinal products ............................................ 39 
Table 5: Quantities of ingredients in trial product .......................................................... 40 
Table 6 
Clinical Assessments when an In-Person Visit is Conducted at the Subject’s 
Home / Residency ....................................................................................................... 54 
Table 7 
Clinical Safety Laboratory Parameters ............................................................. 71 
Table 8 
Biomarker Sampling ......................................................................................... 76 
Table 9 
Sample Size Calculation ................................................................................... 79 
Table 10 Parameters for neurological examination ........................................................ 107 
 
Figures in Text 
Figure 1: Trial Design ....................................................................................................... 32 
 

 
 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADME 
Absorption, distribution, metabolism and elimination  
AE 
Adverse event 
ALAT 
Alanine aminotransferase 
ASAT 
Aspartate aminotransferase 
ALS 
Amyotrophic lateral sclerosis 
ALSFRS-R 
ALS Functional Rating Scale-Revised 
ANCOVA 
Analysis of covariance 
ATMP 
Advanced therapy medicinal product 
AUC 
Area under the curve 
BMI 
Body mass index 
BUN 
Blood urea nitrogen  
CAFS 
Combined Assessment of Function and Survival 
CI 
Confidence interval 
CNS 
Central nervous system 
CONSORT 
Consolidated Standards of Reporting Trials 
CMAP 
Compound muscle action potential 
Cmax 
Maximum concentration 
CMO 
Contract Manufacturing Organisation 
CRA 
Clinical research associate 
CRO 
Contract Research Organisation 
CSF 
Cerebrospinal fluid 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTR 
Clinical trial report 
CTIMP 
Clinical Trial of an Investigational Medicinal Product 
DILI 
Drug-induced liver injury 
DtP 
Direct to patient 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic acid 
eCRF 
Electronic case report form 
ECAS 
Edinburgh Cognitive and Behavioural Screen 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
EMG 
Electromyography 
EQ-5D-5L 
EuroQol Five-Dimensional, Five-Level Descriptive System 
EQ VAS 
EQ Visual Analogue Scale  

 
 
 
 
 
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EU 
European Union 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FEV6 
Forced expiratory volume in 6 seconds  
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma-Glutamyl Transferase 
GMP 
Good Manufacturing Process 
hCG 
Human chorionic gonadotropin  
HDPE 
High density polyethylene 
HIV 
Human immunodeficiency virus 
HPMC 
Hydroxypropyl methyl cellulose 
HRQoL 
Health-related quality of life 
HSP70 
Heat shock protein-70 
ICH 
International Council for Harmonisation 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
INR 
International Normalised Ratio 
IRB 
Institutional review board 
ITT 
Intent-to-treat 
IRT 
Interactive response technology 
LOCF 
Last observation carried forward  
MedDRA 
Medical Dictionary for Regulatory Activities 
MUNE 
Motor unit number estimate 
MRC 
Medical research council 
NASH 
Non-Alcoholic Steatohepatitis 
NOAEL 
No observed adverse event level 
Nfl 
Neurofilament light chain 
p75ECD 
p75 neurotrophin receptor extracellular domain  
Ph. Eur. 
European Pharmacopeia 
PAV 
Permanent assisted ventilation  
PIL 
Patient Information Leaflet 
PK 
Pharmacokinetics 
PP 
Per protocol 
PRO 
Patient reported outcome 
PRO-ACT 
Pooled Resource Open-Access ALS Clinical Trials  

 
 
 
 
 
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QoL 
Quality of life  
QP 
Qualified Person 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SEIQoL-DW Schedule of the Evaluation of Individual QoL (direct weighting)  
SmPC 
Summary of Product Characteristics  
SOD1 
Super oxide dismutase 1 
SUSAR 
Serious unexpected suspected adverse reaction 
SVC 
Slow vital capacity 
TAR 
Transactive response 
TBL 
Total Bilirubin 
TDP-43 
TAR DNA binding protein 43 
TEAE 
Treatment-emergent adverse event 
t.i.d. 
Three times daily 
ULN 
Upper limit of normal 
USP-NF 
United States Pharmacopeia-National Formulary 
VC 
Vital capacity 

 
 
 
 
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ALSFRS-R, AE, Concomitant Medication and survival. Clinical safety laboratory tests may be required if there are any clinically significant parameters 
out of range due to an AE possibly or probably related to the IMP; samples should be collected until resolution. 
d. Demographics include age, sex, race and ethnicity. 
e. General medical history, as well as the history of any diagnostic testing such as electromyography and nerve conduction studies; imaging; muscle 
biopsy; and antibodies. 
f. Assessment to be completed only when possible. 
g. The diary consists of logs to record: IMP compliance, mode of administration, concomitant medication and non-invasive ventilation support. 
h. The ALSFRS-R will be performed over the telephone for remote visits. If the scale is administered over the telephone and the patient is unable to 
respond because of significant bulbar impairment the caregiver should relay the questions and responses. 
i. If a visit is missed, every effort should be made to ensure that as much information as practically possible is collected at a telephone contact as close to 
the scheduled visit date as possible. If the missed visit was expected to be in person, the assessments and procedures scheduled for remote visits should 
be followed.   
j. At any time during the trial, the IMP may be temporarily halted for up to 4 weeks for an intolerable AE. Following re-challenge at the intended dose, de-
escalation from 1200 mg/day (400 mg t.i.d.) to 600 mg/day (200 mg t.i.d.) may be considered. The subject will remain on this decreased dose for the 
remainder of the trial. Re-challenge with IMP in cases of elevation of transaminases should only be done in accordance with section 6.5 Dose 
Modification and IMP Discontinuation. 
k. Examinations will only be conducted in those subjects able to attend the trial site. 
l. Vital signs include blood pressure (supine; seated if supine is not possible) pulse and body temperature.  
m. The C-SSRS “Screening/Baseline” assessment will be used at the Screening visit and the “since the last visit” version at all other visits. 
n. Signs and symptoms occurring during the screening period will be collected and entered on the AE form  
o. Only stop dates for ongoing AEs and new SAEs will be collected. 
p. Women of childbearing potential only. Serum test at Screening and urine test on all other occasions. 
q. Clinical safety laboratory tests include haematology, chemistry (including Cystatin C) and urinalysis. 
r. Profiling for common genes associated with ALS. 
s. Biomarker assessments for HSP70, NfL and chitotriosidase. 
t. Biomarker assessments for HSP70 and NfL. 
u. Biomarker assessments in urine for p75ECD. 
v. At Week 20, PK samples will be collected pre-dose and at 0.5 hours post-dose. At Week 52 PK samples will be collected pre-dose and at 1.5 hours post-
dose. The time of the dose prior to the visit should be recorded in the subject diary and transcribed to the eCRF. 
w. ALSFRS-R and SVC are assessed at Screening and Baseline. The assessment at the Screening visit is used for determination of subject eligibility. The 
assessment at the Baseline visit is used for analysis purposes and the value will not exclude the subject. 
x. Visit to be conducted in case of a) premature IMP discontinuation or b) subject completing trial, but not continuing into open label extension trial 

 
 
 
 
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y. At screening a blood sample will be sent to the central laboratory for testing of HIV, HBV and HCV status. The result must be available in time for the 
Baseline visit where final eligibility is confirmed. 
z. At the first sign of elevated transaminases (ASAT or ALAT > 3 x ULN), a single serum sample should be taken for use and stored frozen (shipment may 
be ambient) at the central laboratory at the earliest opportunity. 
 
 

 
 
 
 
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2. INTRODUCTION AND RATIONALE 
2.1 Amyotrophic Lateral Sclerosis 
Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig's disease, is a progressive, fatal 
neurodegenerative disorder. The loss of motor neurons causes the muscles under their control 
to weaken and waste away, leading to paralysis and death, usually due to respiratory failure, 
within 3-5 years of symptom onset. Symptoms include loss of motor control in hands, arms 
and legs, tripping and falling and bulbar symptoms with difficulty speaking, swallowing 
and/or breathing, persistent fatigue, and twitching and cramping of the muscles. In addition, 
cognitive and behavioural changes are often seen.  
Several mechanisms have been implicated in the pathogenesis of ALS. These include 
excitotoxicity, oxidative stress, neuro-inflammation, mitochondrial dysfunction, disrupted 
nucleocytoplasmic transport and impaired proteostasis characterised by protein misfolding 
and aggregation. Of these, the latter two are increasingly recognised as general molecular 
hallmarks of ALS (3).  
While rare in prevalence, ALS is considered one of the most common neuromuscular diseases 
worldwide. The incidence of ALS is estimated at between 1-3 per 100,000 individuals per 
year globally. The patient population in Europe and the United States is estimated to be 
approximately 50,000 patients and about 10 percent of ALS cases are inherited. While the 
mean age of onset is between 55 and 65 years, symptoms can begin at any adult age. The 
disease occurs more frequently in men than women, whereas prevalence is roughly the same 
throughout the world (4-5.4 per 100,000 individuals) with no ethnic, racial or socioeconomic 
differences.   
Around 10 percent of patients with ALS have ALS associated with pathogenic mutations 
(commonly referred to as ‘familial ALS’) and the remaining 90 percent are isolated or 
sporadic in nature and are denoted ‘sALS’. 
The focus of medical care is to give symptomatic management of patients with mild to 
moderate disease and easing (palliative) intervention in patients with severe or terminal 
disease. The care of ALS patients is often provided in multidisciplinary clinics, with a team 
comprised by respiratory therapist, physiotherapist, occupational therapist, dietician, speech 
consultant and social worker.  
There is significant unmet medical need for further treatment options as current therapies 
convey only modest treatment benefit. The only approved treatment for ALS in EU, riluzole 
(Rilutek®), has been granted a marketing authorisation in the EU in 1996 to extend life or the 
time to mechanical ventilation for patients with ALS. According to the product’s Summary of 
Product Characteristics (Rilutek® SmPC), clinical trials have demonstrated that Rilutek® 
extends survival for patients with ALS. Survival was defined as patients who were alive, not 
intubated for mechanical ventilation and tracheotomy-free. The mode of action of riluzole is 
not fully understood. It may exert its effect via an inhibitory effect on glutamate release, 
inactivation of voltage-dependent sodium channels, and/or ability to interfere with 
intracellular events that follow transmitter binding at excitatory amino acid receptors. 

 
 
 
 
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Riluzole has since been approved as a 5 mg/mL oral suspension (Teglutik®, Tiglutik®) with a 
recommended dose of 100mg daily (50 mg every 12 hours). 
In May 2017, the Food and Drug Administration (FDA) approved edaravone (Radicava®, 
Radicut®), which is the first approved ALS treatment option for more than 20 years. 
Edaravone is thought to act as a free-radical scavenger which prevents oxidative stress 
damage to neurones. It is an intravenous infusion treatment for ALS and has been shown to 
reduce functional decline as measured by the ALS Functional Rating Scale-Revised 
(ALSFRS-R) by 33%. As the clinical trials were of short duration (6 months), there is no 
information available on the effect on survival. 
2.2 Arimoclomol 
Orphazyme A/S (hereafter referred to as Orphazyme) is developing arimoclomol for treatment 
of ALS.  
Arimoclomol amplifies the heat shock response under conditions of cellular stress (3). The 
heat shock response promotes natural folding of nascent proteins and refolding of damaged or 
mutated proteins via enhanced heat shock protein expression, a mechanism of action that is 
thought to be highly relevant to an essential and early pathophysiological event that leads to 
neurodegeneration in ALS (4,5). 
Notably, in super oxide dismutase 1 (SOD1) mutant mice that model some of the features of 
human SOD1 ALS, arimoclomol amplifies the production of heat shock proteins, rescues 
motor neurons, improves neuromuscular function and extends lifespan, even when treatment 
is initiated after the emergence of clinical and pathological manifestations of disease (6, 7).   
A major hallmark of sporadic and most forms of familial ALS, is the presence of mis-
localised transactive response (TAR) DNA binding protein 43 (TDP-43) in cytoplasmic 
inclusions in affected areas of the central nervous system (CNS) (9). TDP-43 belongs to a 
group of ribonucleic acid (RNA) binding proteins, several of which have been shown to be 
mutated in different forms of ALS (9), and is involved in regulation of RNA splicing and 
modulation of microRNA biogenesis (11). TDP-43 plays an important role in neuronal 
plasticity by regulating protein synthesis in dendrites (12), and mutated and misfolded forms 
are prone to toxic fibrillization in stress granules (11). Importantly, arimoclomol ameliorates 
TDP-43 pathology in a mouse model for multisystem proteinopathy, a disease that is tightly 
linked to ALS on a genetic level (13). Additional evidence of the relevance of heat shock 
response in ALS comes from preclinical data demonstrating that activation of the heat shock 
response leads to clearance of TDP-43 inclusions (14). Thus, augmentation of the heat shock 
response might remedy the mis-localisation and inclusion of TDP-43 and other ALS related 
proteins, and thereby be a promising target for new treatment (summarised in (15)). 
See the current version of the Investigator’s Brochure for further information (19). 
In conclusion, the mode of action of arimoclomol addresses fundamental pathophysiological 
processes of ALS and by doing so, arimoclomol may potentially slow the progression of the 
disease and the associated symptoms with or without riluzole treatment.  

 
 
 
 
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judged this event to be probably related to the IMP and Orphazyme considered the causality 
to be possibly related. 
See the current version of the Investigator’s Brochure (IB) for further information (19). 
Trial AALS-001 was a multicentre, double-blind, placebo-controlled 12-week trial with the 
objective to assess the safety, tolerability, and pharmacokinetics (PK) of arimoclomol in ALS 
(16).  
A total of 62 subjects with ALS received arimoclomol at 75, 150, or 300 mg/day (25, 50, or 
100 mg t.i.d.) and 22 subjects received placebo t.i.d. A total of 9 serious adverse events 
(SAEs) (all on active treatment) were reported, including 3 deaths, none of which were 
assessed as related to the investigational medicinal product (IMP) by the investigator. 
Arimoclomol was safe and well-tolerated. No clinically significant abnormal changes were 
reported in vital signs or electrocardiogram (ECG) assessments with treatment. There were 
small statistically significant changes in mean laboratory tests, including increased serum 
creatinine and decreased creatinine clearance. The mean changes in serum creatinine were 
neither time nor dose-dependent, within the clinically accepted normal range and returned to 
pre-dose levels after completion of the dosing regimen. Arimoclomol resulted in dose-linear 
pharmacologic exposures and the half-life did not change with continued treatment. At steady 
state, the mean CSF-to-serum ratios ranged between 0.4 and 0.6 across dose levels at the 3 
hour post-dose time point and between 0.9 and 1.1 at the 6 hour post-dose time point. 
 
In the open-label extension to this trial (17), the long-term (6 months) safety and exploratory 
efficacy of arimoclomol treatment was evaluated. In total, 69 ALS patients from the AALS 
001 trial were treated with arimoclomol 300 mg/day (100 mg t.i.d.) for up to 6 months. 
Arimoclomol 300 mg/day was safe and well-tolerated. One participant discontinued treatment 
due to an adverse event (AE) (respiratory failure). There were no trial medication-related 
clinically meaningful changes in vital signs, ECGs, or laboratory safety tests. In particular, 
serum creatinine levels did not increase with treatment. Seventeen (17) SAEs were reported in 
14 patients. One SAE, pulmonary embolism, was rated by the site investigator as possibly 
related to the IMP. All other SAEs were assessed as not related or unlikely related to the IMP. 
Exploratory efficacy assessment of the open-label extension part of the trial showed a slower 
reduction in ALSFRS-R compared to a historical placebo control group (approximately 30% 
difference in decline, p=0.034). There was no treatment effect on vital capacity, body weight 
or body mass index (BMI). 
In the investigator-led randomised, double-blinded, placebo-controlled clinical trial, ALS 
patients with pathogenic SOD1 mutations associated with aggressive disease course were 
treated with arimoclomol (17 patients) or placebo t.i.d. (19 patients) for 12 months (18). The 
patients randomised to arimoclomol were initially treated with 300 mg/day (100 mg t.i.d.), 
however this dose regimen was later amended to 600 mg/day (200 mg t.i.d.) following an 
interaction with the FDA. Albeit not powered for efficacy, consistent directional benefit was 
observed across the predefined efficacy endpoints survival function (ALSFRS-R) and 
pulmonary function (forced expiratory volume in 6 seconds, FEV6). Arimoclomol was safe 
and well-tolerated and a consistent directional benefit of arimoclomol over placebo across 
predefined efficacy endpoints was observed. In a post hoc analysis, a clear dose response 

 
 
 
 
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relationship in this trial between 300 mg/day (100 mg t.i.d.) and 600 mg/day (200 mg t.i.d.) 
was not observed, possibly due to the low number of patients. 
In conclusion, given the results from these two Phase 2 trials with preliminary indication of 
effectiveness at doses of 300-600 mg/day (100 to 200 mg t.i.d.) and favourable tolerability, it 
appears justified to further increase the dose to 1200 mg/day (400 mg t.i.d.) to investigate 
whether a higher dose may result in greater efficacy and acceptable tolerability.  
For further information on experience with arimoclomol, see the current edition of the IB 
(19). 
2.4 Trial Rationale 
2.4.1 
Justification for the Trial 
To date, only two drugs (riluzole and edaravone) are approved for the treatment of ALS in the 
US and one drug (riluzole) is approved in the EU. Nuedexta® is used for symptomatic 
treatment of pseudobulbar effect in ALS patients. The high unmet medical need persists 
despite these treatment options and ALS still to date is a rapidly progressive 
neurodegenerative disease that leads to progressive weakness and ultimately to death due to 
respiratory failure. The mode of action of arimoclomol is expected to be relevant across the 
disease spectrum of both familial and sporadic ALS.  
The trial has been designed to conform with the recommendations of the FDA draft guidance 
document for industry (20) and the European Medicines Agency (EMA) guideline on clinical 
investigation of medicinal products for the treatment of ALS (21). 
2.4.2 
Justification for Selected Dose  
Seven clinical pharmacology studies have been performed in healthy volunteers with daily 
doses ranging from 50 mg to 1800 mg. The maximum single dose administered is 800 mg and 
the maximum repeated dose is 1800 mg daily (600 mg t.i.d.) for 5 days (Study AALS-005). 
During these studies the maximum tolerated dose was not reached. In the renal safety study, 
1200 mg/day (400mg t.i.d.) or matching placebo were administered for 28 days (Study 
AALS-010). No tolerability or safety issues were identified.  
Two clinical phase 2 trials have been completed in ALS (AALS-001 and SOD1-ALS). In the 
12-week dose ranging trial (AALS-001), 84 ALS patients were randomised in a 1:1:1:1 ratio 
to placebo, 25 mg, 50 mg or 100 mg t.i.d., respectively. There were no significant increases in 
treatment-related adverse events or serious adverse events as compared to placebo. Sixty-nine 
patients from AALS-01 continued into the open label extension trial of 6 months duration and 
were all administered 300 mg/day (100 mg t.i.d.). Disease progression, as measured by 
ALSFRS-R, was slower in the trial population compared to a historical placebo control group, 
indicating a potential treatment benefit (16). 

 
 
 
 
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a higher dose than that studied in phase 2 clinical trials may be safe, well tolerated and 
efficacious. Therefore, the dose of 1200 mg/day (400 mg t.i.d.) is selected for the present 
phase 3 trial in ALS to maximise chances of the individual subject to receive an efficacious 
treatment. 
2.4.3 
Justification for Placebo 
The use of placebo in confirmatory trials in ALS is supported by the FDA draft guidance 
document for industry (20) and the EMA guideline on clinical investigation of medicinal 
products for the treatment of ALS (21) where background treatments with approved products 
are also favoured. The present trial includes placebo control to demonstrate the benefit of 
arimoclomol in the treatment of ALS. Subjects will be randomly assigned to active or placebo 
treatment in a disproportionate ratio weighted 2:1 towards active therapy. Subjects may also 
be treated with a background stable dose of riluzole. Riluzole use will be a stratification factor 
meaning that there is a chance that subjects without background riluzole therapy may also 
receive placebo. The probability of receiving placebo will be explained clearly in the 
informed consent form. 
2.4.4 
Justification for Endpoints 
The proposed primary endpoint in the present trial is the measurement of Combined 
Assessment of Function and Survival (CAFS) in the arimoclomol treatment arm as compared 
to the placebo after treatment for 18 months. The CAFS is used to compare each trial 
subjects’ outcome to others in the trial in a series of pairwise comparisons, based on function 
and survival (22). For each pairwise comparison, a trial subject is assigned a score and then 
the summed scores are ranked for all participants.  
While historically ALS clinical trials have assessed survival and function as independent 
endpoints, the CAFS combines the endpoints and thereby decreases the confounding effect of 
mortality on analysis of functional outcomes. Thus, the CAFS is a robust statistical tool for 
ALS clinical trials and appropriately accounts for and weights mortality in the analysis of 
function. The individual components of CAFS (function and survival) will also be analysed 
separately as secondary outcome measures. 
The secondary efficacy assessment of arimoclomol in the present trial will be completed by 
the following evaluations: 
2.4.4.1 
Permanently Assisted Ventilation (PAV)- and Tracheostomy-Free Survival 
In accordance with the completed SOD1-ALS Phase 2 trial (18) this endpoint is defined as 
permanently assisted ventilation (PAV)- and tracheostomy-free survival. This endpoint is 
commonly used in ALS clinical trials and, given the rapidly progressing disease course in the 
population to be studied, represents a relevant “hard” endpoint. PAV will be defined as the 
first of 7 consecutive days on which PAV was used for >22 hours/day. 

 
 
 
 
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2.4.4.2 
Disease Progression, as Measured by Change from Baseline on the ALSFRS-R 
The ALSFRS and the revised version that includes respiratory function (ALSFRS-R) is the 
most widely used instrument to measure function in ALS clinical trials.  It is a validated and 
disease specific questionnaire (23,24,25,26) The functional decline averages about 1 point per 
month in untreated patients (27). 
2.4.4.3 
Decline of Respiratory Function, as Quantified by Change From Baseline on 
the Slow Vital Capacity (SVC) as % of Predicted 
Vital capacity (VC) has been most thoroughly studied, and has been shown to decline by 
about 3% per month throughout much of the disease course (28). The rate of decline of VC is 
strongly correlated with survival, as would be expected given the close relationship between 
respiratory function and survival in ALS. VC was used as a primary outcome measure in one 
xaliproden Phase 3 trial in ALS patients (29), and showed a statistically significant positive 
effect in the treated group. This effect was not seen in patients simultaneously taking riluzole, 
however. In many other clinical trials, VC has been employed as a secondary outcome 
measure, without a clear demonstration of difference between active treatment and placebo. 
Patients on topiramate showed a modestly increased rate of progression compared to those on 
placebo, though this difference was not statistically significant, suggesting that vital capacity 
can be impacted by treatments. The SVC is a valid and robust measurement of the pulmonary 
function and is highly correlated with survival. 
2.5 
Risk-Benefit Assessment 
Arimoclomol has shown an acceptable safety profile in ALS patients as well as in healthy 
subjects. Preliminary evidence of benefit has been established in two Phase 2 trials at doses 
up to 600 mg/day (please see Section 2.3.2). The clinical trial in mutant SOD1 ALS patients 
lacked the statistical precision to conclude efficacy, however the consistency of results across 
the range of prespecified efficacy outcome measures suggests a possible therapeutic benefit of 
arimoclomol. Data from the open label extension of the Phase 2 trial in sporadic ALS was 
suggestive of an effect in reducing the decline of ALSFRS-R when comparing to historical 
controls. Therefore, the present trial will be conducted in the general ALS population, i.e. 
including both patients with sporadic and familial ALS and irrespective of genotype. 
Clinical trials in healthy subjects and patients with ALS and NPC indicate that arimoclomol is 
associated with a reversible increase in serum creatinine/decreased in creatinine clearance, 
most likely due to inhibition of OCT-2 and MATEs, without any effects on renal function, 
although. One event of severe tubulointerstitial nephritis with acute tubular injury and acute 
tubular necrosis with arimoclomol have been reported. 
Increases in transaminases (ALAT/ASAT) have been observed in a minority of patients 
treated with blinded IMP in ongoing trials with arimoclomol. The maximum increase has 
been above 20x upper limit of normal (ULN). The values have returned to baseline either 
during treatment or after discontinuation of blinded IMP.  
In conclusion, current risk with arimoclomol can be handled within a clinical trial context and 
appropriate measures have been instituted in this trial to protect subjects from possible risks. 

 
 
 
 
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The current benefit-risk ratio is favourable and supports the administration of arimoclomol for 
the purposes of achieving the objectives of this trial. 
2.6 
Ethical Considerations 
No paediatric patients or other vulnerable subject’s, including individual’s incapable of giving 
informed consent at the time of enrolment, will be included in this clinical trial. Furthermore, 
women who are pregnant, breastfeeding, or trying to become pregnant will not be enrolled in 
this clinical trial. Women of child-bearing potential must agree to use a highly effective 
method of contraception to prevent pregnancy during the clinical trial and until 1 month after 
discontinuation of treatment with the IMP. All female subjects of child-bearing potential will 
have a pregnancy test performed before treatment, during treatment and at End of Trial to 
ensure that no fetuses are exposed to the IMP. 
Since ALS is a rapidly progressing neurological condition, the ability of a trial subject to 
confirm ongoing or provide new consent may be diminished (i.e. the trial subject may decline 
to a legal status of an incapacitated adult). Since there is the possibility of needing to 
reconsent subjects in the clinical trial due to unforeseen circumstances, a legal representative 
will be nominated by the time of the Baseline visit to ensure that this occurs while the subject 
is competent. In this circumstance (and in accordance with local legislation or guidelines) a 
legal representative will ensure the subject’s best interests and legal rights are protected 
throughout the trial should the subject become incompetent. Legal representation certificate 
must be obtained as per applicable country legal requirements and procedures. While the 
subject is competent, informed consent for any research procedure or intervention is sought 
from the subject only. The subject may freely decline consent and the legal representative will 
not be consulted. Based on the selection criteria, this trial will not prompt legislation 
regarding enrolment of incapacitated adults into clinical trials in emergency situations.  
Additionally, this individual will give consent to be contacted during the conduct of the trial 
should contact with the subject become challenged. 
Altogether, the risks associated with participating in this clinical trial are considered 
outweighed by the benefit of a potential future treatment option for ALS.  
In accordance with the current version of the International Council for Harmonisation (ICH) 
Good Clinical Practice (GCP) guidelines, qualified medical personnel will be appointed by 
Orphazyme and will be readily available to advise on trial-related medical questions. Medical 
monitoring will be performed throughout the trial. Safety data will be reviewed regularly by 
Orphazyme, and an independent Data Monitoring Committee (DMC; see Appendix 10.2.10) 
to ensure that prompt action is taken, if needed, to ensure subject safety.  
In conclusion, the trial design chosen for this efficacy and safety trial on arimoclomol is 
regarded as ethically justified and adherent with ethical requirements. 

 
 
 
 
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Objectives 
Endpoints 
Health-Related Quality of Life 
To evaluate the effect of 1200 mg/day 
arimoclomol (400 mg t.i.d.) compared to 
placebo on health-related quality of life  
• 
The SEIQoL-DW for the subject over a treatment period 
of 76 weeks 
• 
The SEIQoL-DW for the caregiver over a treatment 
period of 76 weeks 
• 
EQ-5D-5L over a treatment period of 76 weeks 
 
Pharmacokinetics (will be reported separately from the main Clinical Trial Report) 
To investigate CSF and plasma levels of 
arimoclomol following administration of 
1200 mg/day arimoclomol (400 mg t.i.d.) 
• 
Plasma and CSF concentrations of arimoclomol at weeks 
20 and 52 
 
Biomarkers (will be reported separately from the main Clinical Trial Report ) 
To evaluate the effect of 1200 mg/day 
arimoclomol (400 mg t.i.d.) compared to 
placebo on candidate biomarkers of target 
engagement, disease activity (markers 
reflecting ongoing neurodegeneration), 
and disease progression in blood, urine, 
and CSF compared to placebo. 
 
Absolute values and change from Baseline to Week 20, Week 52, 
and Week 76 for 400 mg t.i.d. arimoclomol compared to placebo 
in blood, urine, and CSF for the following biomarker endpoints: 
• 
HSP70 in CSF and blood 
• 
NfL in CSF and blood 
• 
Urinary p75ECD 
• 
Chitotriosidase in CSF 
 
Abbreviations: ALS: amyotrophic lateral sclerosis; ALSFRS-R: ALS functioning rating scale revised; CAFS: 
Combined Assessment of Function and Survival; CSF: cerebrospinal fluid; C-SSRS: Colombia Suicide 
Severity Rating scale; ECAS: Edinburgh Cognitive and Behavioural Screen; EQ-5D-5L:EuroQol Five-
Dimensional, Five-Level Descriptive System; HSP70: heat shock protein-70; NfL: neurofilament light 
chain; p75ECD: p75 neurotrophin receptor extracellular domain; PAV: permanent assisted ventilation; 
SCV: slow vital capacity; SEIQoL-DW: the schedule for the evaluation of individual quality of life (direct 
weighting); TEAE: treatment-emergent adverse event; t.i.d.. three times daily 

 
 
 
 
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4. 
TRIAL DESIGN 
4.1 
Overall Trial Design 
This is a multicentre, randomised, double-blind, placebo-controlled, parallel group trial to 
evaluate the efficacy and safety of 1200 mg/day arimoclomol (400 mg t.i.d.) over a 76 weeks’ 
treatment period).  
Patients diagnosed with ALS who had first appearance of symptoms (weakness) within the 
previous 18 months will be eligible for screening.  
In accordance with the eligibility criteria (see Sections 5.2 and 5.3), subjects participating in 
the present trial may be on a stable background treatment with riluzole. Additionally, a subset 
of up to 18 subjects on stable (i.e. minimum 6 months’) treatment with edaravone and who 
otherwise fulfil the eligibility criteria are planned for enrolment (see exclusion criterion 5). 
Following confirmation of eligibility during the Screening/Baseline period (Day -28 to Day 
1), subjects will be randomised in a 2:1 ratio to receive either 1200 mg/day arimoclomol 
(400 mg t.i.d.) or placebo orally t.i.d. Randomisation will be stratified by background riluzole 
use. The first post-baseline assessment will take place in-person at the investigator site 4 
weeks after the Baseline visit; subsequent assessments will consist of a combination of in-
person visits and remote visits (telephone calls). 
Subjects will attend the investigator site for an in-person visit on a 4-weekly basis for the 
initial 6 months of treatment (on Weeks 4, 8, 12, 16, 20, 24, 28), followed by an 8-weekly 
basis to 12 months (on Weeks 36, 44 and 52), and then for the following 6 months of 
treatment in-person visits are scheduled on a 12-weekly basis until the Safety Follow Up (on 
Weeks 64 and 76). Assessments will include those for efficacy and safety, as well as sampling 
of biofluids for clinical safety laboratory tests, biomarkers, and PK according to the schedule 
of procedures (Table 1). If a subject is no longer able to attend the site, appropriate trial site 
staff (e.g. nurse, sub-investigator or contract nursing services as required) may assess the 
subject by conducting a home visit. 
On the remaining weeks of the treatment period (Weeks 32, 40, 48, 56, 60, 68 and 72) a 
remote visit will be conducted by the subject receiving a telephone call from the trial site 
staff. Assessments will therefore be limited to efficacy and safety evaluations according to the 
schedule of procedures. 
All visits should be scheduled within the visit window (+/- 7 days) relative to the Baseline 
visit. Every effort should be made to ensure that the in-person visits at Week 52 and Week 76 
are arranged as close as possible to the scheduled time-point. 
An independent DMC will be established to monitor benefit:risk and ensure that subjects are 
not unnecessarily exposed to the IMP in the event that the expected benefit:risk should 
change. The DMC will act in accordance with the DMC charter and may have access to 
unblinded data (see Appendix 10.2.10). 

 
 
 
 
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At any time during the trial, the IMP may be temporarily halted for up to 4 weeks for an 
intolerable AE. Following re-challenge at the intended dose, de-escalation from 1200 mg/day 
(400 mg t.i.d.) to 600 mg/day (200 mg t.i.d.) may be considered. The subject will continue on 
this decreased dose for the remainder of the trial. Re-challenge with IMP in cases of elevation 
of transaminases should only be done as specified in Section 6.5 regarding dose modification 
and IMP discontinuation. Subjects who discontinue treatment will be encouraged to attend all 
planned visits as per protocol after drug discontinuation. Additionally, these subjects will 
have remote visit 2 weeks after the premature IMP discontinuation.  
If a subject reaches a trial survival endpoint (e.g. tracheostomy or PAV), the IMP will be 
permanently discontinued. The subject will be offered to participate in an open-label 
extension trial which will be conducted as a separate trial. 
Subjects who complete 76 weeks of randomised treatment will be offered participation in a 
separate open-label extension which will be conducted as separate clinical trial. 
 
 
 
 
 
 
 
 
 

 
 
 
 
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Figure 1: 
Trial Design 

 
 
 
 
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4.2 
Number of Subjects 
The anticipated disposition of subjects is as follows; 
Number of subjects planned to be screened: Approximately 298 
Estimated screen failure rate: 25% 
Number of subjects planned to be randomised: Approximately 231  
Estimated trial discontinuation rate: 40% 
Number of subjects expected to complete 76 weeks of treatment: 128  
Within the total number of subjects to be randomised up to 18 subjects will be on stable (i.e. 
minimum 6 months’) treatment with edaravone (see exclusion criterion 5). 
The statistical power considerations for the sample size are described in Section 8.1.  
The trial will be conducted at approximately 32 sites in approximately 13 countries in North 
America and Europe. 
4.3 
End of Trial Definition 
The end of the trial is defined as the date of the last visit of the last subject in the trial 
globally. 

 
 
 
 
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5. 
TRIAL POPULATION AND WITHDRAWAL 
5.1 
Subject Eligibility 
The investigator should only enrol subjects who meet all inclusion and none of the exclusion 
criteria, are not put at undue risk by participating in the trial and can be expected to comply 
with the protocol.  
The subject’s eligibility for the clinical trial must be checked according to the inclusion and 
exclusion criteria listed in Sections 5.2 and 5.3. 
In addition, section 10.4 should be consulted for any country-specific eligibility criteria. 
Any implementation of national requirements/law for the subject’s participation in the clinical 
trial will be ensured and described in the submission documentation to regulatory 
authorities/ethics committees, as applicable.  
5.2 
Inclusion Criteria 
1. Capable of- and willing to- provide written informed consent and comply with trial 
procedures. 
2. Subject is male or female ≥18 years of age. 
3. Subject meets revised El Escorial criteria for clinically possible, clinically probable / 
clinically probable ALS laboratory-supported, clinically definite ALS or clinically 
definite familial ALS laboratory-supported. 
4. 18 months or less since first appearance of weakness (e.g. limb weakness, dysarthria, 
dysphagia, shortness of breath). 
5. ALSFRS-R ≥35 and erect (seated) SVC % predicted ≥ 70% at Screening. 
6. Able and willing to travel to the site, and in the investigator’s opinion is likely to 
attend visits for at least 24 weeks. 
7. All sexually active female subjects of child-bearing potential (postmenarchal)* must 
agree not to intend to become pregnant and use a highly effective method of 
contraception** during the trial through 1 month after the last dose of trial medication. 
If the subject is a sexually active male with female partners of child-bearing potential 
(postmenarchal) he must 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. 
8. Stable dose of riluzole (50 mg twice daily) for a minimum of 14 days prior to Day 1 
(Baseline) or has not taken it for 14 days prior to Day 1. 

 
 
 
 
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* Non child-bearing potential is defined as post-menopausal (minimum of 12 months with no 
menses and follicle-stimulating hormone in the post-menopausal range) or sterilisation 
(hysterectomy, oophorectomy, or bilateral tubal ligation). 
** Highly effective methods of contraception include combined (oestrogen and progestogen 
containing) hormonal contraception associated with inhibition of ovulation (oral, 
intravaginal, or transdermal); progestogen-only hormonal contraception associated with 
inhibition of ovulation (oral, injectable, or implantable); intrauterine device; intrauterine 
hormone-releasing system; bilateral tubal occlusion; and vasectomised partner. 
According to the recommendations from the Clinical Trial Facilitation Group (CTFG, 2014), 
sexual abstinence is considered a highly effective birth control method only if it is defined as 
refraining from heterosexual intercourse during the trial until 1 week after the last dose of 
trial medication (for female subjects of child-bearing potential) and for 3 months after the last 
dose of trial medication (for male subjects with female partners of child-bearing potential). 
The reliability of sexual abstinence needs to be evaluated by the investigator in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject. 
5.3 
Exclusion Criteria 
1. Tracheostomy or use of non-invasive ventilation for more than 2 hours during waking 
hours at the time of Screening and Baseline visits. 
2. Pregnant or breast-feeding. 
3. Current or anticipated use of diaphragmatic pacing during the trial. 
4. Exposure to any investigational treatment within 4 weeks or <5 half-lives of the 
Screening visit, whichever is longest and/or advanced therapy medicinal product 
(ATMP), i.e. treatments based on genes, cells or tissues and/or participated in any 
prior ALS clinical trial receiving active drug treatment (with the exception described 
in exclusion criterion 5). 
5. Treatment with edaravone within 4 weeks of the Baseline visit. However, up to 18 
subjects on stable (i.e. minimum 6 months’) treatment with edaravone and who 
otherwise fulfil the eligibility criteria are planned for enrolment (limited to countries 
where edaravone has a marketing authorisation for treatment of ALS). 
6. Any of the following medically significant conditions: 
a. Neurological impairment/dysfunction or unstable psychiatric illness that in 
the investigator’s opinion is likely to interfere with assessment of ALS 
disease progression. 
b. Clinically significant unstable medical condition other than ALS, which 
would present a risk to a subject to participate in the trial. 
c. Presence of dementia that impairs the ability of the subject to provide 
informed consent, according to the PI decision. 
d. Known or suspected allergy or intolerance to the IMP (arimoclomol or 
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e. Chronic infection particularly HIV or Hepatitis B or C. 
f. Clinically significant renal or hepatic disease. 
g. Aspartate aminotransferase and/or alanine aminotransferase, and/or lactate 
dehydrogenase ≥3 times the upper limit of normal [ULN], bilirubin≥2 times 
the ULN, or creatinine ≥1.5 times the ULN. Laboratory tests may be repeated 
once at Screening. Reasons to repeat laboratory tests may include that the 
medication causing laboratory abnormality was suspended, any other 
suspected cause may no longer exist, or to rule out laboratory error. 
h. Cancer that is currently under active treatment or is likely to require treatment 
during the trial that may alter the subject´s function and thereby interfere with 
assessment of ALS disease progression. 
i. Any other condition that in the investigator’s opinion would present a risk to 
a subject to participate in the trial, interfere with the assessment of safety or 
has an increased risk of causing death during the trial. 
5.4 
Screening, Screening Failures and Randomisation Procedure  
Trial participation begins once written informed consent is obtained (see Appendix 10.2.2 for 
details on the informed consent process). Once informed consent is obtained, a subject 
identification number (subject ID) will be assigned by a central interactive response 
technology (IRT) and the screening evaluations to assess eligibility criteria may begin. The 
subject ID will be used to identify the subject during the screening process and throughout 
trial participation, if applicable. A master log of all consented subjects will be maintained at 
the trial site.   
Screening may be up to 4 weeks prior to Baseline if a washout period for an investigational 
treatment is required (see exclusion criterion 4). The minimum screening period is set as one 
week for practical reasons (to ensure all results are available to determine eligibility at 
Baseline). If laboratory re-tests are required, these should be completed within the maximal 
4 weeks’ screening period.  
Screening failures are defined as subjects who consent to participate in the trial but are not 
subsequently randomly assigned to trial treatment. A minimal set of screening failure 
information is required to ensure transparent reporting of screening failure subjects to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements (30) 
and to respond to queries from regulatory authorities. Minimal information includes 
demography, screening failure details, eligibility criteria, and any AEs and SAEs. Follow-up 
of SAEs must be carried out according to Section 7.5.7.6. 
In principle subjects may not be rescreened however if the reason for screen failure is deemed 
to be due to acute illness, the subject may be rescreened following recovery. Likewise, screen 
failure due to safety laboratory abnormality may be repeated on one occasion. Subjects who 
have failed to qualify for trial participation due to the requirements for SVC according to 
eligibility criteria contained in protocol version 1.0 and 2.0 may be re-screened for all 

 
 
 
 
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eligibility criteria of this protocol (amendment 4.0).  The appointed medical monitor should 
be notified of such occurrence. In the event of rescreening, the subject should be marked as a 
screen failure in IRT, electronic case report form (eCRF) for the first screening attempt and a 
new Subject ID should be generated for the second screening attempt. A cross reference 
between the two Subject IDs will be prompted in the IRT/eCRF. 
Only the assessment of ALSFRS-R and SVC at the Screening visit is used for determination 
of subject eligibility. The result of these assessments at the Baseline visit is used for analysis 
purposes and the value will not exclude the subject from trial participation. 
5.5 
Discontinuation  
A subject may withdraw from trial or from treatment at any time (prior to first dose or during 
treatment period) at his/her own request. A subject may be withdrawn at any time at the 
discretion of the investigator. Discontinued subjects will not be replaced. 
5.5.1 
Discontinuation from Treatment 
Reasons for permanent discontinuation of IMP are given in Section 6.5. 
If a subject discontinues treatment and does not meet any of the survival endpoint definitions 
the subject should be invited to attend the remaining trial visits as per the schedule of 
procedures. Additionally, a remote follow-up (Safety Follow Up) phone call should be 
scheduled for 2 weeks after the last treatment. 
Subjects who remain on the trial and do not take IMP will have telephone calls in place of in-
clinic visits and only the following assessments will be completed: ALSFRS-R, AE and 
concomitant medication (based on patient recall), and survival status.  If the subject has an 
ongoing AE possibly or probably related to an AE requiring clinical safety laboratory tests, 
in-clinic visits may be used to collect a central laboratory sample; samples should be collected 
until resolution or following agreement with the medical monitor. 
For subjects discontinuing treatment, the end of trial form must be completed in the eCRF and 
the final drug accountability must be performed. The reason for discontinuation of trial 
product must be recorded in subject’s medical records and the eCRF. 
5.5.2 
Discontinuation from the Trial 
Subjects who move to another CTIMP shall be withdrawn from this trial. Subjects who enter 
registry trials do not need to be withdrawn from this current trial. 
If a subject withdraws from the trial, the last in-person visit should be conducted as per the 
schedule of assessments for the End of Trial Visit and recorded as this visit in the eCRF. If 
the subject has not already discontinued treatment, the Safety Follow Up visit should also be 
scheduled for 2 weeks after the last treatment. 
If a subject withdraws from the trial, he/she may request the destruction of any samples taken 
and not tested however data and samples collected up to the point of withdrawal may not be 

 
 
 
 
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removed from the clinical database. The investigator must record this in the site’s trial records 
and notify the clinical research associate (CRA) and appointed medical monitor. 
Subjects and/or caregiver may be asked to sign an additional informed consent form prior to 
trial discontinuation to allow follow-up of the survival endpoints (PAV/tracheostomy/death) 
at the scheduled week 76. 
5.6 
Missed Visits and Lost to Follow-Up 
If a visit is missed, every effort should be made to ensure that as much information as 
practically possible is collected at a telephone contact as close to the scheduled visit date as 
possible. If the missed visit was expected to be in person, the assessments and procedures 
scheduled for remote visits should be followed. The subject should be advised to use IMP as 
supplied from the spare bottle and where the subject does not have sufficient IMP for the 
remaining visit interval, site staff should ensure that additional spare IMP is allocated via IRT 
and provided to the subject (by direct to patient shipment, as required). Subjects will be 
invited for the next scheduled visit according to visit schedule (Table 1). 
Subjects will be considered lost to follow-up if they repeatedly fail to return for scheduled in-
person visits and are unable to be contacted by the trial site (including remote visits or other 
appropriate means of follow-up). The threshold for being considered lost-to follow-up is set 
as 3 consecutive missed visits. 
The following actions must be taken if a subject fails to return to the trial site for a required 
visit: 
• The trial site must attempt to contact the subject and reschedule the missed visit as 
soon as possible and counsel the subject on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the subject wishes to and/or 
should continue in the trial. If a subject is no longer able to travel to the trial site an in-
person visit may be conducted in the subject’s home/residency (see section 7.1.7)  
• Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, if 
necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s 
medical record. 
• Should the subject continue to be unreachable, he or she will be considered to have 
withdrawn from the trial with a primary reason of lost to follow-up. 
As the subject has not withdrawn consent, a telephone call will be attempted at the scheduled 
week 76, and the following assessments will be completed: ALSFRS-R, AE, concomitant 
medication (based on patient recall), and survival status. 

 
 
 
 
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At any time during the trial, dose de-escalation from 1200 mg/day (400 mg t.i.d.) to 
600 mg/day (200 mg t.i.d.) for tolerability may be considered (see Section 6.5). The subject 
will continue on this decreased dose for the remainder of the trial. 
6.3 
Interactive Web Response System 
A trial-specific IRT will be used for (amongst others); forward logistics of the supply chain, 
inventory management and randomised treatment assignment. A full description of 
functionalities will be included in an IRT user manual which will be provided to each trial 
site. This IRT can be accessed at any time via the internet with a telephone helpdesk back-up 
solution for emergency situations. Access to the IRT must be restricted to and controlled by 
authorised persons.  
6.4 
Treatment Assignment 
6.4.1 
Randomisation 
Subjects found to be eligible will be randomised via the IRT in a 2:1 ratio to one of the 
following treatments: 
a. 
1200 mg/day arimoclomol (400 mg t.i.d.) 
b. 
Placebo (matching) 
 
Treatment assignment will also be stratified by the presence or absence of a background 
treatment with riluzole. 
6.4.2 
Blinding 
This is a double-blinded trial in which arimoclomol and placebo are visually identical and 
matched for taste. 
Neither the subject nor any of the investigator site staff or Orphazyme staff (included Contract 
Research Organisation (CRO) delegated staff) who are involved in the treatment or clinical 
evaluation and monitoring of the subjects will be aware of the treatment received. The 
packaging and labelling of the IMPs will contain no evidence of their identity.  
The DMC may have access to unblinded data. 
6.4.3 
Emergency Unblinding of Individual Subject Treatment  
The randomisation code for an individual subject may be broken if knowledge of the assigned 
treatment would influence the care of the subject in a medical emergency. Facility to unblind 
individual subject is provided for investigators. The circumstances under which an individual 
subject is unblinded should be discussed with the appointed medical monitor however the 

 
 
 
 
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immediate management of the subject should take precedence in an emergency situation and 
the final decision to unblind a subject is the sole responsibility of the investigator.  
Emergency unblinding is performed in the IRT. For clinicians outside of the clinical trial who 
do not have access to this system, unblinding will occur by proxy by the investigator. 
Investigator contact details will be provided via the subject trial card. 
Immediately after an unblinding event, the IRT will automatically distribute an unblinding 
notification email. This notification will be unblinded to the requester and will be blinded for 
all other nominated recipients; medical monitor and selected other representatives of the 
sponsor e.g. clinical safety, medical director, trial manager. 
Whenever a code is broken, the investigator must print the unblinding notification email, sign 
and date the document to acknowledge awareness of the event and file in the investigator site 
file. The reason for code break should be documented in the medical record. 
If the code has been broken, the subject must be discontinued from the trial.  
End of trial procedures should be observed, see Section 5.5. 
6.5 
Dose Modification and IMP Discontinuation  
6.5.1 
Permanent Discontinuation of IMP 
In case of a safety concern or unacceptable intolerability, the IMP may be permanently 
discontinued at the investigator’s discretion. In case of pregnancy or intention to become 
pregnant the trial product must be discontinued (see section 7.5.7.7 for reporting of 
pregnancies in the trial). The primary reason for discontinuation of the IMP must be specified 
in the eCRF.  
According to the FDA Guidance for Industry on Drug-Induced Liver Injury (DILI) (39), IMP 
must be permanently discontinued in the case of the following: 
• ALAT or ASAT >8 x ULN 
• ALAT or ASAT >5 x ULN for more than 2 weeks 
• ALAT or ASAT >3 x ULN and bilirubin >2 x ULN or International Normalised Ratio 
(INR) >1.5) 
• ALAT or ASAT >3 x ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
 
If a subject reaches a trial survival endpoint (e.g. tracheostomy or PAV), the IMP will be 
permanently discontinued. The subject will be offered to participate in an open-label 
extension which will be conducted as a separate trial. 
If a subject is no longer able to attend the clinic, nor have the option of a home visit via an 
appropriate trial site staff (e.g. nurse, sub-investigator or contract nursing services) for safety 

 
 
 
 
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monitoring, the IMP will be permanently discontinued. The subject may remain on the trial 
without IMP. 
For procedures related to discontinuation, see Section 5.5. 
6.5.2 
Temporary Halt of IMP and Dose Modification 
A temporary halt of IMP treatment of up to 4 weeks is permitted if a subject experiences an 
intolerable AE. The interruption of IMP should be as short as possible, and the appointed 
medical monitor should be consulted prior to re-initiation of the intended 1200 mg/day (400 
mg t.i.d.) dose.   
If the subject experiences the same intolerable AE after re-challenge with the intended dose, 
dose de-escalation from 1200 mg/day (400 mg t.i.d.) to 600 mg/day (200 mg t.i.d.) may be 
considered following consultation with the appointed medical monitor. The subject will 
continue this decreased dose for the remainder of the trial. If this reduced dose is not 
tolerated, the IMP must be discontinued permanently. 
This sequence of events can be implemented only once for intolerable AEs within a given 
organ/body system. If the subject experiences a different intolerable adverse event within a 
different organ/body system, this sequence of events can be repeated for that AE. 
Likewise, a temporary halt of IMP treatment of up to 4 weeks is permitted in circumstances 
where a concurrent procedure or concomitant treatment for an acute condition requires 
withdrawal of IMP administration. The circumstances under which a temporary halt is 
initiated should be discussed with the appointed medical monitor. 
Re-Challenge in Case of Increased Transaminases  
If in the Investigator’s judgement, a temporary halt in IMP is instituted because of elevated 
transaminases, a re-challenge must not occur if the patient had the following: 
• ALAT or ASAT > 5 x ULN 
• ALAT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
• ALAT or ASAT > 3 x ULN AND TBL >2 x ULN   
 
IMP must also be discontinued for subjects with elevated transaminases where close 
observation (repeated laboratory tests) is not possible, see Section 7.5.10.2.  
The missed doses must be recorded in the eCRF. 
An Safety Follow Up visit should not be conducted when a temporary halt of IMP is initiated. 

 
 
 
 
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6.6 
Treatment logistics and accountability 
6.6.1 
Labelling and packaging of IMPs 
The IMPs will be packaged into bottles containing 84 capsules. Each bottle will be given a 
unique number (bottle code). 
The labelling of IMPs will be in accordance with Annex 13 (31), local regulations and trial 
requirements. Label text will be translated into local languages, as required. 
6.6.2 
Storage of IMPs 
All IMPs must be stored in a secure and restricted area under the conditions specified on the 
label and remain in the original container until dispensed. 
The IMP must be stored at room temperature (15-25°C) at the site. The temperature during 
storage must be monitored by a calibrated, stationary and continuously recording system. 
Minimum requirement is a calibrated min/max thermometer.  
A temperature log must be kept documenting the storage within the permitted temperature 
interval. Storage facilities should be checked at least every working day. 
Storage of IMP may be delegated, e.g. to a hospital pharmacy, as locally applicable.  
Note that in the cases listed below, IMP should be placed into quarantine and should not be 
used. Site staff should immediately document the bottle status in IRT (refer to the IRT manual 
for further details) and contact their CRA for further guidance: 
• Temperature excursion upon receipt or during storage at the trial site. 
• Damaged kit upon receipt or during storage at the trial site. 
 
All excursions from the permitted storage conditions should be reported in accordance with 
the trial specific Pharmacy Manual. 
 
The sponsor will decide if the affected bottles may be released back into the inventory, 
returned to the depot or destroyed locally. 
6.6.3 
Drug Distribution and Dispensation 
At each in-person visit IMP will be dispensed according to the bottle codes allocated by the 
IRT. On each dispensing occasion, an adequate number of bottles will be dispensed to allow 
for the 2 x 200 mg t.i.d. dosing regimen across the visit interval (range: 4 to 12 weeks) unless 
dose de-escalation has occurred, in which case the IRT will adjust the number of bottles 
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A spare bottle will be assigned to the subject to cover the additional doses needed should visit 
scheduling require the +/- 7 day visit windows. All spare bottles used will have accountability 
performed on a capsule level by the end of the trial. 
In the event that a subject is unable to attend the trial site for a scheduled in-person site visit 
(e.g. due to ALS progression), a ‘direct-to-patient’ (DtP) logistics service may be used in 
accordance with local legislation or guidelines. This service will only be implemented where 
all required permissions are obtained.  
Once it is determined that a subject is unable to attend the trial site, a request for the use of the 
DtP shipment will be made to the service provider by a site staff member. Use of the service 
requires sponsor approval. The IMP should be dispensed per the schedule of procedures, via 
the IRT. The site will schedule for the approved courier to collect the IMP from the trial site 
and distribute directly to the subject’s home/residence. Accountability logs and temperature 
monitoring will be maintained throughout the chain of custody. The service should be used 
for reverse logistics to ensure that used and unused IMP (including empty packaging material) 
is returned to the trial site. 
The subject (or the primary caregiver) must acknowledge receipt of the IMP, using their trial 
specific subject ID as signature to ensure that their identity is not transferred to the sponsor 
via the paper records. 
Deviations from this process must be agreed with the Sponsor. 
6.6.4 
Drug Accountability and Destruction 
The IMP must be accounted for throughout the duration of the trial. The responsibility for the 
IMP is transferred from Orphazyme to the investigator from the time of IMP receipt to time of 
destruction. The investigator is fully responsible for the IMPs at the trial site and for 
maintaining adequate control of the IMPs and for documenting all transactions with them. 
The IMPs will be dispensed to each subject as required according to treatment group. The IRT 
will allocate IMP bottles to be dispensed to a subject in compliance with the trial 
randomisation code and packing list at randomisation and at each subsequent dispensing 
transaction (each in person visit). 
The investigator or delegated person is responsible for ensuring that: 

 
 
 
 
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• Drug accountability is performed using paper-based accountability logs for all IMP 
transactions and the IRT drug accountability module for forward logistics. 
• Subjects are instructed to return all used, partly used and unused IMP including empty 
packaging material at each dispensing visit and at End of Treatment visit. 
• Returned IMP (used/partly used or unused including empty packaging material) can 
be stored at room temperature and must be stored separately from non-allocated trial 
product. 
• Destruction will be performed in accordance with local procedures after accountability 
is finalised and verified by the CRA. If local destruction procedures or services are not 
adequate for clinical trial standards, IMP may be sent to a returns depot for destruction 
by the CMO. Destruction of products must be documented. 
 
6.6.5 
Treatment Compliance 
The subject or their nominated primary caregiver will maintain a diary record of compliance 
with t.i.d. IMP administration. These data (summarised as the number of missed applications 
per visit interval) will then be transcribed into the eCRF by site staff at the next in-person visit 
including the reason for non-adherence. If a subject is found to be non-compliant, the 
investigator should remind the subject of the importance of following the treatment 
instructions.  
If a dose of IMP is missed, the subject should not adjust their dosing schedule to 
accommodate the missed administration. The subject therefore should not reschedule dosing 
to achieve the t.i.d. dosing regimen or add the missed dose to the next scheduled 
administration. 
A compliance rate of 80% (visit interval and total trial) will be used as the threshold for 
protocol deviation reporting. 
6.7 
Mode of Administration 
The subject or their nominated primary caregiver will record the method of administration of 
IMP in the subject diary (swallowed whole, sprinkled/dispersed into liquid, 
sprinkled/dispersed into food or sprinkled/dispersed in water and fed via gastric tube). The 
data will then be summarised and transcribed into the eCRF. 
6.8 
Concomitant Medication and Procedures 
Any medication or vaccine that the subject receives from 3 months prior to Screening and 
until the End of Trial visit (Week 76) must be recorded in the subject’s medical record and the 
eCRF along with details such as: 

 
 
 
 
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• Trade name or generic name 
• Reason for use (indication) 
• Dates of administration including start and stop dates 
• Dosage information including dose, route and frequency 
 
 
Investigators may prescribe concomitant medications or treatments to provide adequate 
supportive care as deemed necessary, except for medications listed in Section 6.9. The 
appointed medical monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
Concomitant medication for conditions other than ALS may be continued throughout the trial 
without any change in dosage whenever possible. 
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 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. 
Additionally, in vitro studies show that arimoclomol is a direct inhibitor of CYP2D6 and may 
potentially cause increase in exposure of co-administered medications that are substrates of 
CYP2D6 when arimoclomol is dosed at 400 mg t.i.d (40). 
Since the magnitude of the potential increase cannot be predicted from in vitro data, caution is 
advised if arimoclomol is co-administered with medicinal products that are metabolised by 
CYP2D6. This may, for example, be relevant for Class I anti-arrhythmic, tricyclic 
antidepressants, betablockers, tramadol and selective serotonin reuptake inhibitors (SSRI’s) 
particularly if they are known to be sensitive and moderate sensitive CYP2D6 substrates 
and/or have a narrow therapeutic index.  
The product information for co-administered medicinal products should be consulted for 
guidance on concomitant treatment with a CYP2D6 inhibitor as dose adjustment of the 
CYP2D6 substrate may be appropriate. For compounds metabolised by CYP2D6 the dose 
may be reduced and for pro-drugs that are converted to the active compound by CYP2D6 the 
dose may be increased to ensure efficacy. 
 

 
 
 
 
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Nuedexta® (or compounded equivalent) is a treatment for pseudo-bulbar effect which is a 
combination of dextromethorphan and an ultra-low dose quinidine 20 and 10 mg, 
respectively. The main effect of Neudexta® is exerted by dextromethorphan which is 
metabolised by CYP2D6. The intended effect of quinidine as a strong inhibitor of the 
CYP2D6 isoenzyme is to reduce the metabolism of dextromethorphan. The collective 
information available to date on potential drug-drug interactions suggests that Neudexta® 
should be co-administered with arimoclomol with caution, since arimoclomol may inhibit the 
excretion of quinidine. Nuedexta® is known to prolong the QTc interval in a dose dependent 
matter (less than moxifloxacin) and concomitant therapy with medications that prolong the 
QT interval and are metabolized by CYP2D6 should be done with caution. 
 
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 concomitant medications related to 
ALS treatment are permitted from Screening and throughout the trial: 
• Stable dose of riluzole (50 mg twice daily) for a minimum of 14 days prior to Baseline 
(see inclusion criterion 8) 
• Stable dose of edaravone i.e. minimum 6 months of treatment (only applicable for 
subjects enrolled into the edaravone sub-population, limited to countries where 
edaravone has a marketing authorisation for treatment of ALS (see exclusion criterion 
5). The number of subjects in this sub-population will be tracked via eCRF data and 
investigators will be pro-actively notified when recruitment under this criterion will be 
closed. 
• Other medication or treatments that are deemed necessary to provide adequate 
supportive care. 
 
The use of non-invasive ventilation is permitted during the trial. 
Concomitant medication and non-invasive ventilation will be recorded in the subject diary in 
the interval between trial visits. 
6.9 
Prohibited Medication and Procedures 
The following medications are prohibited during the trial from the Screening or Baseline visit 
(see specific case) until the end of the trial defined as either the completion of 76 weeks of 
treatment or meeting a survival endpoint (PAV or tracheostomy): 
• Treatment with edaravone within 4 weeks of the Baseline visit (unless the subject is 
enrolled as part of the sub-population). 
• Commencement of riluzole treatment at any time throughout the trial if not established 
on a stable dose at Baseline (see inclusion criterion 8). Adjustment of riluzole dose, 

 
 
 
 
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including temporary halt due to tolerability may be permitted at the investigator’s 
discretion.  
• Other investigational treatments within 4 weeks or <5 half-lives of the Screening visit 
(whichever is longest). 
• ATMP (i.e. treatments based on genes, cells or tissues) at any time 
 
Diaphragmatic pacemakers are not permitted for the duration of the trial (see exclusion 
criterion 3). 
The use of non-invasive ventilation is not permitted at Screening or Baseline but may be 
commenced during the trial. 
The appointed medical monitor must be notified if a subject receives any of these therapies 
during the trial.  
6.10 
Provision for Subject Care Following Trial Completion 
To ensure appropriate treatment of the subjects after they have completed the trial, the 
subjects will be treated at the investigator’s discretion or referred to other physician(s) 
according to standard practice. Subjects who complete the 76 weeks of treatment will be 
offered participation in a separate open-label trial. 
Patients who complete the 76 weeks of treatment, but do not continue in the open-label trial 
will attend the Safety Follow Up visit. 
If a subject reaches a trial survival endpoint (e.g. tracheostomy or PAV), the IMP will be 
permanently discontinued. The subject will be offered to participate in an open-label 
extension which will be conducted as a separate trial. 
 

 
 
 
 
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7. 
TRIAL ASSESSMENTS AND PROCEDURES 
7.1 
General Principles 
7.1.1 
Investigator’s or Delegate’s Responsibilities 
The investigator may delegate responsibility for performance of clinical assessments and trial 
procedures to adequately trained and experienced site staff members. This delegation of 
authority must be documented prior to the individual undertaking any trial specific tasks. 
In addition to general experience and training, selected clinical assessment and procedures 
require trial specific rater-certification (see Section 7.1.3).  
Subjective measures for a specific subject should be administered by the same rater 
throughout the course of the trial. 
ALS diagnosis according to El Escorial criteria and neurological examination may only be 
delegated to qualified neurologists. 
The following clinical assessments and procedures may only be delegated to site staff with 
recognised medical qualification or similar as permitted according to local regulation; taking 
informed consent, interpretation of clinical safety laboratory reports, vital signs, ECGs, 
physical examination, lumbar puncture for CSF sampling and assessment of AEs. 
For clinical safety laboratory tests, values outside the reference range, the investigator must 
specify whether the value is clinically significant or not. All laboratory report printouts must 
be signed and dated by the investigator or delegate. The evaluation of screening results must 
be dated and signed prior to Visit 2 (Baseline) in order to confirm subject’s eligibility. For the 
subsequent laboratory sampling, all reports must be reviewed prior to the next subject visit.  
Review of ECGs must be documented as described in Section 7.5.5. 
Review of diaries must be documented either on the documents and/or in the subject’s 
medical record. If clarification of entries or discrepancies in the diary is needed, the subject 
must be questioned, and a conclusion made in the subject’s medical record. Care must be 
taken not to bias the subject. 
7.1.2 
Nomination of Primary Caregiver and Legal Representative 
The subject must nominate a primary caregiver and a legal representative (may be the same 
person). This will be by the time of the Baseline visit where possible, although for the legal 
representative this may be deferred to the appropriate time as per applicable country legal 
requirements and procedures.  
The primary caregiver should be a friend, family or spouse (i.e. not a healthcare professional 
assigned to care for the subject) and must be a regular caregiver who has substantial contact 

 
 
 
 
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with the subject. If the caregiver does not cohabitate with the subject, he/she ideally should 
have a minimum of 10 hours total and at least 3 days contact with the subject per week.  
The primary caregiver should be willing to attend visits with the subject where the Schedule 
of the Evaluation of Individual QoL (direct weighting) (SEIQoL) and Edinburgh Cognitive 
and Behavioral Screen (ECAS) questionnaires are administered. They should also oversee the 
subject’s compliance with protocol-specified procedures and IMP and report on subject’s 
status. Although day-to-day care of the subject is not expected at the time of trial inclusion, 
the primary caregiver may support the subject in completion of trial assessments such as 
interpretation of responses or completion of the subject diary in the event of deteriorating 
motor function or communication as considered appropriate by the investigator. 
The primary caregiver will be asked to complete the SEIQoL (see Section 7.4.2) and provide 
information about the subject  by completing the behavior and psychosis screens as part of the 
ECAS (see Section 7.3.4).  
If on any occasion the subject is accompanied to site by a different caregiver, they will not be 
asked to complete these assessments. If the nominated primary caregiver must change, the 
informed process must be repeated with this individual. In this circumstance the SEIQoL will 
not be completed but the ECAS behavior and psychosis screens are required. Caregiver non-
attendance at clinics resulting in missed SEIQoL and ECAS does not constitute a protocol 
deviation. 
Likewise, a legal representative should be nominated by the subject by the time of the 
Baseline visit. The legal representative will agree to make decisions regarding use of clinical 
trial data and biological samples during the trial in the event of diminished capacity of the 
trial subject. The legal representative must be consulted should re-consent processes be 
required due to unforeseen circumstances during trial conduct (e.g. new emerging safety 
information or a change to trial procedures) at a time where the subject is not capable of 
giving consent or in matters relating to trial participation in after-life situations. Legal 
representation certificate must be obtained as per applicable country legal requirements and 
procedures. 
7.1.3 
Rater Training and Certification 
To ensure consistency in administration and interpretation of subjective clinical outcome 
measures, a customised rater training program (described in separate rater training plans) will 
be delivered to qualified site staff. Management of rater training will be provided by the 
Clinical Assessment Technologies group of Worldwide Clinical Trials. 
For scales where the rater may be the subject or the subject’s nominated primary caregiver, 
the training of site staff will focus on instruction. 
Site staff delegated the responsibility of performing clinical assessment who hold 
accreditation from other recognised groups must undergo the trial specific training and 
certification program to ensure consistency between raters. 

 
 
 
 
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Training will be provided at face to face meetings and will also be available through the 
course of the trial as remediation including an on-line learning portal. 
Raters will be trained by completing the specific training courses for each scale. Certification 
will be issued as appropriate to each scale. 
7.1.4 
Subject Instruction 
7.1.4.1 
Investigational Medical Product 
IMP must be dispensed to subjects at the specified visits (see Table 1). IMP will be dispensed 
to the subject by the site, hospital pharmacy or equivalent. At the randomisation visit, the 
subjects will be instructed in the handling and administration of IMP (Section 6.2). 
7.1.4.2 
Subject Diary  
The subject must be provided with diaries to record IMP compliance, mode of administration, 
concomitant medication uses and use of non-invasive ventilation at the specified visits (see 
Table 1) the investigator or delegate should instruct the subjects on how to complete the diary 
at the Baseline visit and provide ongoing instruction as necessitated by data quality. The 
diaries dispensed to subjects should be collected at the specified visits (see Table 1) and data 
used to complete the eCRF. 
7.1.4.3 
Patient Reported Outcomes (PROs) 
Site staff who have undergone training will instruct subjects on the completion of 
questionnaires, measurements and assessments as described in Section 7.1.3. Education 
materials on minimising placebo response/ research alliance will be provided to all subjects 
and reviewed at the Screening visit. 
7.1.5 
Sequence of Assessments 
Assessments should be conducted in a sequence which allows for best clinical practice and 
patient experience while also ensuring protocol compliance. 
Patient and caregiver health-related quality of life (HRQoL) assessments should be completed 
prior to investigator efficacy assessments to minimise responder fatigue on most sensitive 
HRQoL scales and to limit investigator influence over patient and caregiver responses. 
Sequence of scale assessments; 
1. ALSFRS-R 
2. ECAS 
3. EuroQol Five-Dimensional, Five-Level Descriptive System (EQ-5D-5L) 
4. SEIQOL-DW 

 
 
 
 
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5. Columbia Suicide Severity Rating Scale (C-SSRS) 
7.1.6 
Visit Scheduling 
All visits should be scheduled within the visit window (+/- 7 days) relative to the date of the 
Baseline visit. Every effort should be made to ensure that the in-person visits at Week 52 and 
Week 76 are arranged as close as possible to the scheduled time-point. 
7.1.7 
Subject Assessment when Unable to Travel to the Trial Site 
Following baseline, if a subject is still on IMP and is unable to attend the trial site for a 
scheduled in-person visit (e.g. due to ALS progression) or at Weeks 8, 16 and 24, a sub-set of 
clinical assessments as listed below in Table 6 will be conducted, in accordance with Table 1, 
Schedule of Trial Procedures. 
The visit will be conducted both in attendance at the subject’s home/residency and by 
telephone call. If the subject does not give consent for attendance to their home/residency, 
only the telephone call will be conducted and the appropriateness for the subject to continue 
trial participation will be assessed by the investigator, considering the ability to assess safety. 
Clinical assessment in the subject’s home/residency may be performed by site staff or 
contract nursing service, according to Table 1, Schedule of Trial Procedures. 
 

 
 
 
 
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7.2.2   General Medical History 
Relevant past and concurrent medical history, as judged by the investigator, must be recorded. 
General medical history may include the history of any diagnostic testing such as 
electromyography and nerve conduction studies, imaging, muscle biopsy and antibodies. 
The following data should be recorded in the eCRF: 
• Diagnosis  
• Date of onset 
• Date of resolution or ongoing 
 
Any change to a concomitant illness should be recorded during the trial. A clinically 
significant worsening of a concomitant illness must be reported as an AE. 
7.2.3 ALS Characterisation 
Information on ALS characteristics will be recorded at Screening and consist of: 
• Date of symptom (weakness) onset  
• Date of diagnosis  
• Familial history of ALS 
• Riluzole use 
• Edaravone use 
• Site of onset (limb, bulbar [includes respiratory], both limb and bulbar, other) 
• ALS diagnosis (according to el Escorial diagnostic criteria) 
• Information on pathogenic mutation (if available) 
 
7.2.4 El Escorial Diagnostic Criteria for ALS 
The investigator (or delegate that is a neurologist by training) must use the ALS diagnostic 
criteria set forth at the El Escorial World Federation of Neurology. As part of the trial 
eligibility criteria, the subject must meet the criteria for clinically possible, clinically probable 
/ clinically probable ALS laboratory-supported, clinically definite ALS or clinically definite 
familial ALS laboratory-supported at Screening to be included in the trial (38). 
For a subject to meet the diagnostic criteria for clinically definite familial ALS laboratory-
supported, the following must apply; 
• Family history of ALS 
• Known pathogenic mutation 

 
 
 
 
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• Progressive UMN and/or LMN signs in at least a single region (in the absence of 
another cause for the abnormal neurological signs).  
However, in genetically determined cases where the gene has not been identified (even if 
linkage is established), the criteria for the diagnosis of sporadic ALS apply. 
7.2.5 
Respiratory Rate 
The respiratory rate (breaths per minute) will be recorded at the Screening visit and end-of-
trial visit only. This will be determined by manual visualisation and count. 
7.2.6 
Body Height 
The body height will be measured at Screening only, to be used for calculation of BMI in 
combination with body weight. Height should be measured without shoes in centimetres or 
inches and recorded in the eCRF to nearest ½ cm or 1/4 inch. For subjects where 
measurement of height is not possible (e.g. unable to stand), self-reported height will be 
accepted.  
7.2.7 
Use of Tobacco and Nicotine-Containing Products 
At Screening, the subject’s use of tobacco and nicotine-containing products should be 
recorded in the eCRF. The subject will be categorised as follows: 
• Never smoked; a subject who has never smoked, or who has smoked less than 
100 cigarettes in his or her lifetime. 
• Former smoker; a subject who has smoked at least 100 cigarettes in his or her lifetime 
but who had quit smoking at the time of interview. Cessation date and calculation of 
pack-years will also be recorded in the eCRF. 
• Current smoker; a subject who has smoked 100 cigarettes in his or her lifetime and 
who currently smokes cigarettes. Calculation of pack-years will be recorded in the 
eCRF. 
 
A pack-year is calculated by multiplying the number of packs of cigarettes (quantity 20) 
smoked per day by the number of years the subject has smoked e.g. 1 pack-year is equal to 
smoking 20 cigarettes (1 pack) per day for 1 year or 40 cigarettes (2 packs) for half a year 
etc.). 
7.3 Efficacy Assessments 
7.3.1 
Survival (PAV/Tracheostomy/Death) 
Should the subject reach one of the survival endpoints (permanent assisted ventilation (PAV), 
tracheostomy or death) this event and the date will be recorded (on the end-of-trial form) in 

 
 
 
 
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the eCRF. The time from Day 1 to PAV/tracheostomy/death or trial completion (at Week 76), 
whichever comes first will be derived. 
PAV will be defined as the first of 7 consecutive days on which PAV was used for >22 
hours/day as a direct consequence of symptom progression related to ALS. This will not 
apply for intercurrent acute reversible illness requiring temporary assisted ventilation for 7 
consecutive days or longer.  
7.3.2 ALS Functional Rating Scale – Revised (ALSFRS-R) 
The ALSFRS-R is a short (5 minute) ordinal rating scale used to determine subjects’ 
subjective assessment of their capability and independence with 12 functional activities 
(‘speech’, ‘salivation’, ‘swallowing’, ‘handwriting’, ‘cutting food and handling utensils’, 
‘dressing and hygiene’, ‘turning in bed and adjusting bed clothes’, ‘walking’, ‘dyspnoea’, 
‘orthopnoea’ and ‘respiratory insufficiency’). Each activity is rated on a 5-point scale (from 0 
to 4), giving a maximal ALSFRS-R score of 48. 
An ALSFRS-R assessment will be performed as scheduled in Table 1.  
Only the assessment of ALSFRS-R at the Screening visit is used for determination of subject 
eligibility. The result of this assessments at the Baseline visit is used for analysis purposes and 
the value will not exclude the subject from trial participation. 
The assessment may be made by a trained site staff member either in person or over the 
telephone. Rater certification is described in Section 7.1.3. The ALSFRS-R will be performed 
over the telephone for remote visits. If the scale is administered over the telephone and the 
patient is unable to respond because of significant bulbar impairment the caregiver should 
relay the questions and responses. If a subject is no longer able to travel to the site to attend 
the in-person visits, a certified rater will perform the assessment over the telephone as per a 
remote visit. 
The assessment outcome will be recorded on a source document and transcribed into the 
eCRF. 
7.3.3 Slow Vital Capacity (SVC) 
SVC measures the volume that can be exhaled from a full inhalation after exhaling to a 
maximum as slowly as possible. Measurements of SVC will be performed via standardised 
Flowscreen CT TM spirometer as scheduled in Table 1. SVC analysis will include SVC, 
predicted SVC and % of predicted SVC. Calibration of the spirometry equipment must be 
completed in accordance with user guides and spirometry manual. 
The SVC should be measured in the seated erect position. Before onset of measurement, the 
subject should be instructed to breathe normally through the pneumotach. After obtaining a 
stable breathing pattern with a minimum of four tidal breaths, the subject should be instructed 
to inspire slowly and maximally then exhale slowly and maximally. The subject should be 
instructed to return to normal breathing upon which the measurement is complete.  

 
 
 
 
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An acceptable manoeuvre has the following characteristics: 
• No hesitation or false start 
• Stable breathing pattern before onset of measurement 
• No cough 
• No glottis closure or obstruction by tongue or dentures 
• No early termination and no forced exhalation  
 
The quality of data generated will be analysed against recognised spirometry standards (32). 
Data will be subject to centralised analysis by spirometry experts. 
 
Only the assessment of SVC at the Screening visit is used for determination of subject 
eligibility. The result of this assessments at the Baseline visit is used for analysis purposes and 
the value will not exclude the subject from trial participation. 
If a subject is no longer able to travel to the site to attend the in-person visits, a member of 
trial site staff or the contract nursing service may instead perform this assessment at an in-
person visit at the subject’s home/residency. Measurement of SVC will be performed via the 
SpiroSphereTM spirometer. The source data from the machine will be provided to the clinical 
site for transcription into the eCRF and will not be subject to centralized over-read analysis. 
The reason for a missed spirometry measurement will be recorded in the eCRF to capture data 
on whether this is due to ALS progression. Missed spirometry measurements due to ALS 
progression do not constitute a protocol deviation. 
7.3.4 Edinburgh Cognitive and Behavioural ALS Screen (ECAS) 
ECAS determines cognitive and behavioural changes of patients suffering from ALS. It is a 
global measure for the evaluation of cognitive impairments in ALS patients.  
ECAS consists of 15 individual tasks, which rely on standard procedures and tests used in 
neuropsychology. These 15 individual tasks correlate with certain cognitive functions which 
are split up into 5 different subdomains of which; 3 are ALS-specific (‘language’, ‘verbal 
fluency’ and ‘further executive functions’) and 2 are non-specific functions (‘memory’ and 
‘visuospatial’). The ECAS-total score of 136 points is the sum of scores of all 15 individual 
tasks. 
ECAS evaluations will be performed as scheduled in Table 1. 
The assessment will be performed by a trained trial site staff member. Rater certification is 
described in Section 7.1.3.  
The ECAS may be performed in oral or written form. An adapted version of the scale is not 
available for general use in clinical trials however the simple completion is expected to allow 
subjects with significant impairment due to ALS to be able to adequately respond to the rater. 

 
 
 
 
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It will be up to the investigator’s discretion if the subject is unable to provide responses to the 
scale.  
If a subject is no longer able to travel to the site to attend the in-person visits this assessment 
will not be conducted since it requires administration by a certified rater and is not validated 
for use over the telephone. 
The primary caregiver will complete the behaviour screen and the psychosis screen (the latter 
is not to be completed in the vicinity of the subject). If the nominated primary caregiver 
changes during the trial, these assessments should continue to be collected. 
The scale will be available in all major recognised languages of the countries participating in 
the trial. 
The assessment will be recorded on a source document. The total score for each task and both 
screens will be transcribed into the eCRF. 
7.4 Health-Related Quality of Life Assessment 
The following HRQoL questionnaires will be used in this trial: 
• 
EQ-5D-5L (subject, clinician-led) 
• 
SEIQoL-DW (subject and primary caregiver) 
 
The questionnaires should be completed according to the schedule of procedures (Table 1).  
All results from the HRQoL questionnaires will be recorded on a source document and 
transcribed into the eCRF. 
7.4.1 EuroQol, Five-Dimensional, Five-Level Descriptive System (EQ-5D-5L) 
The EQ-5D5L will be used for exploratory assessments of the subject’s health-related quality 
of life. The EQ-5D-5L consists of 2 sections; the EQ-5D descriptive system and the health 
scale, an adaption of the EQ Visual Analogue Scale (EQ VAS). 
The descriptive system comprises 5 dimensions: ‘mobility’, ‘self-care’, ‘usual activities’, 
‘pain/discomfort’ and ‘anxiety/depression’. Each dimension has 5 levels: ‘no problems’, 
‘slight problems’, ‘moderate problems’, ‘severe problems’ and ‘extreme problems’. The 
subject is asked to indicate his/her health state by ticking the box next to the most appropriate 
statement in each of the 5 dimensions. This decision results in a 1-digit number that expresses 
the level selected for that dimension. The digits for the 5 dimensions can be combined into a 
5-digit number that describes the subject’s health state.  
The health scale records the subject’s self-rated health reported as an integer between 0 and 
100 where 0 represents ‘the best health you can imagine’ and 100 represents ‘the worst health 
you can imagine’. This health score can be used as a single quantitative measure of health 
status that reflects the subject’s own judgement based on a same day recall period. 

 
 
 
 
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The EQ-5D-5L scale adapted for interview (over the telephone) will be used from the outset 
despite the ability of subjects to self-report HRQoL on this scale from inclusion. The adapted 
version will ensure consistent utilisation of the scale, preventing the need to transfer from 
self-reported to clinician-led modes for subjects who develop significant impairment due to 
ALS. 
The assessment will be performed by a trained trial site staff member. Rater certification is 
described in Section 7.1.3. If a subject is no longer able to travel to the site to attend the in-
person visits, a certified rater will perform the assessment over the telephone as per a remote 
visit. 
The scale will be available in all major recognised languages of the countries participating in 
the trial. 
7.4.2 Schedule for the Evaluation of Individual Quality of Life-Direct Weighting 
(SEIQoL-DW) 
The SEIQoL-DW is a semi-structured interview for assessment of quality of life (QoL) of the 
individual. The interviewer first elicits the 5 areas of life considered most important by the 
individual in determining his/her QoL. The level of satisfaction/functioning in each area is 
recorded followed by the SEIQoL-DW task which allows the interviewer to determine the 
relative importance of each QoL area. 
This HRQoL interview will be administered to both the subject and their nominated primary 
caregiver.  
If the primary caregiver has any significant medical condition (e.g. cancer or significant co-
morbidities) which, in the opinion of the investigator, would prevent them from being able to 
distinguish the impact of caring for a patient with ALS on their personal QoL, this 
questionnaire may be omitted from the visit schedule. Missed assessments for this reason will 
not be considered protocol deviations. 
If the nominated primary caregiver changes during the trial, this assessment should not be 
completed. 
If a subject is no longer able to travel to the site to attend the in-person visits, this assessment 
will not be conducted since it requires administration by a certified rater and is not feasible for 
use over the telephone due to the tactile elements required during administration. 
The scale will be available in all major recognised languages of the countries participating in 
the trial. 

 
 
 
 
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7.5 Safety Assessments 
7.5.1 Physical Examination 
A physical examination including general appearance, head/neck, eyes, ears, nose/throat, 
cardiovascular, lungs, abdomen, musculoskeletal, CNS (non-ALS) extremities and skin will 
be carried out as scheduled in Table 1 and only for subjects who are able to attend the trial 
site.  
The outcome of each area evaluated will be recorded as either normal, abnormal or not done. 
If a result is abnormal at Screening and considered by the investigator to be clinically 
significant, it should be recorded as medical history or AE, as applicable. It will be up to the 
investigator’s discretion if the subject should be enrolled into the trial; if such a subject is 
enrolled, the investigator will provide a justification in the medical record.  
Any new clinically significant findings or deterioration of previous findings observed during 
the trial are to be recorded as AEs (see Section 7.5.7). 
If a subject is no longer able to travel to the site to attend the in-person visits, this assessment 
will not be done at patient’s home/residency. 
7.5.2    Neurological Examination 
A neurological examination including general, cranial nerves, reflexes, motor system, 
coordination/cerebellar function and sensation (see Appendix 10.2.13 for full criteria) will be 
carried out as scheduled in Table 1 and only for subjects who are able to attend the trial site.  
The outcome of each area tested will be recorded as either normal/none, abnormal or not 
done. If an abnormality is secondary to ALS this should be indicated. If a result is abnormal at 
Screening and considered by the investigator to be clinically significant it should be recorded 
as medical history or AE, as applicable. It will be up to the investigator’s discretion if the 
subject should be enrolled into the trial; if such a subject is enrolled, the investigator will 
provide a justification in the medical record.  
Any new clinically significant findings or deterioration of previous findings observed during 
the trial are to be recorded as AEs (see Section 7.5.7). Worsening of symptoms (e.g. 
progression of weakness) of ALS will not be recorded as an AE. 
If a subject is no longer able to travel to the site to attend the in-person visits, this assessment 
will not be performed in the subject’s home/residency. 
7.5.3 Vital Signs 
Vital signs (resting blood pressure, pulse, and body temperature) must be assessed as 
scheduled in Table 1. Vital signs will be measured in supine position (seated, if supine is not 
possible), with the legs uncrossed, the back and arms supported following at least 5 minutes 
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If an abnormal vital sign at Screening is considered by the investigator to be clinically 
significant, it should be recorded as medical history or AE, as applicable. It will be up to the 
investigator’s discretion if the subject should be randomised into the trial (respecting 
exclusion criterion 6).  Any clinically significant changes observed during the trial are to be 
recorded as AEs (see Section 7.5.7). 
If a subject is no longer able to travel to the site to attend the in-person visits, a member of 
trial site staff or the contract nursing service may instead perform this assessment at an in-
person visit at the subject’s home/residency. 
7.5.4 Body Weight 
The body weight will be measured as scheduled in Table 1, and only when possible. Body 
weight should be measured and recorded in the eCRF in kilogram or pound [kg or lb], with 
one decimal (without shoes and only wearing light clothing). 
If a subject is no longer able to travel to the site to attend the in-person visit at week 52 or 
week 76, this assessment will not be performed. 
7.5.5 Electrocardiogram – 12 lead 
12-lead ECGs will be performed as scheduled in Table 1 according to local procedure.  
At a minimum, date of ECG collection and assessment of clinical significance will be 
recorded in the source documents.  
The investigator must ensure evaluation of all ECGs by medically trained site staff with the 
interpretation recorded on the trace accompanied by signature and date. Where a cardiologist 
is delegated the responsibility of ECG interpretation a pre-evaluation of the ECGs must be 
performed by the investigators to assess immediate subject safety. The investigator has the 
final decision on the clinical significance of ECG abnormalities (‘clinically significant’ or 
‘not clinically significant’). If a result is abnormal at Screening and considered by the 
investigator to be clinically significant, it should be recorded as medical history or AE, as 
applicable. It will be up to the investigator’s discretion if the subject should be enrolled into 
the trial; if such a subject is enrolled, the investigator will provide a justification in the 
medical record. Refer to Appendix 10.2.6.3 for principles for data entry in the eCRF.  
Any clinically significant new findings or deterioration of previous findings observed during 
the trial are to be recorded as AEs (see Section 7.5.7).  
If a subject is no longer able to travel to the site to attend the in-person visits, this assessment 
will not be conducted in the subject’s home/residency. The Investigator should review AEs 
and vital signs with particular attention to signs related to conduction disorders to allow for 
appropriate follow-up, and to ensure that the subject is safe to continue trial participation.  

 
 
 
 
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7.5.6 Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a detailed questionnaire assessing both suicidal behaviour and suicidal 
ideation through a series of simple, plain-language questions (33). The questionnaire will be 
administered as an interview by the investigator or a qualified delegate according to the 
schedule of procedures (Table 1). All results from the questionnaire must be transcribed into 
the eCRF. 
Two versions of the scale will be used: a ‘Screening/Baseline’ version (lifetime assessment 
and recent history, used at Screening) and a ‘since last visit’ version (used on all subsequent 
occasions). 
The scale will be available in all major recognised languages of the countries participating in 
the trial. 
If a subject is no longer able to travel to the site to attend the in-person visits, a certified rater 
will perform the assessment (may be over the telephone). 
7.5.7 Adverse Events 
7.5.7.1     Definitions of Adverse Events and Serious Adverse Events 
Adverse Event Definition 
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. (ICH Harmonized Tripartite Guideline for Good Clinical Practice, 
E6 (R1)). 
This definition includes (but is not limited to): 
accidental injuries, clinically significant changes in safety laboratory tests, events related to 
trial procedures, reasons for any unfavourable and unplanned change in medication (drug 
and/or dose), clinically significant worsening of pre-existing conditions other than the disease 
under study, or reasons for admission to hospital or surgical procedures unless these were 
planned before enrolment. It also includes AEs commonly observed and AEs anticipated 
based on the pharmacological effect of the IMP.  

 
 
 
 
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Serious Adverse Event Definition 
An SAE is any AE that; 
• results in death. 
• is life-threatening. 
• requires inpatient hospitalisation or prolongation of existing hospitalisation. (Planned 
hospitalisation or planned prolonged hospitalisation do not fulfil the criteria for being 
an SAE but should be documented in the subject’s medical record). 
• results in persistent or significant disability/incapacity. 
• is a congenital anomaly/birth defect. 
or  
• is a medically important condition.  
 
A medically important condition is an event that may not be immediately life-threatening or 
result in death or hospitalisation but may jeopardise the subject or may require intervention to 
prevent one of the other outcomes listed in the definition above. Examples are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias and 
convulsions that do not result in hospitalisation, development of drug dependency or drug 
abuse. 
If there is any doubt as to whether an adverse event meets the definition of an SAE, a 
conservative viewpoint must be taken, and the adverse event must be reported as an SAE. 
7.5.7.2 Collection of adverse events 
Adverse Events should be obtained through observation of the patient, from any information 
volunteered by the patient and through asking non-leading questions such as “How have you 
been doing since your last visit?”  
 
Adverse events (including pre-treatment adverse events) must be recorded in the eCRF.  The 
investigator must provide information on the adverse event, preferably with a diagnosis, or at 
least with signs and symptoms; start and stop dates and start and stop time; severity; causal 
relationship to the IMP; action taken; and outcome.  If the adverse event is not related to the 
IMP, an alternative aetiology must be recorded, if available.   
 
If the adverse event 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 
7.5.7.6.). If individual adverse events are later linked to a specific diagnosis, the diagnosis 
should be reported instead of the symptoms. 
 
 

 
 
 
 
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Severity 
The severity of the AE will be graded according to the following categorisation: 
Mild 
An AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
Moderate 
An AE that is usually alleviated with additional specific therapeutic intervention. 
The event interferes with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the subject. 
Severe 
An AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
 
 

 
 
 
 
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Causality 
The causal relation of the AE to the use of the IMP should be described in terms of probable, 
possible or not related according to the following: 
Probably 
related 
AEs that are temporally linked and for which the study product is more likely to be 
the explanation than other causes, which may improve when not using study 
product or recurs on re-challenge 
Possibly 
related 
AEs that could equally well be explained by study product or other causes, which 
are usually temporally linked and may improve when not using study product but 
do not reappear when using study product 
Not related 
AEs that can be clearly explained by other causes or 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 IMP if it is at least possibly related. 
Outcome 
The outcome of the event should be classified and handled as follows: 
Recovered/ 
resolved 
The event has stopped. The stop date of the event must be recorded. 
Recovering/ 
resolving 
The subject is clearly recovering from an event. The event is not yet 
completely resolved.  
Not 
recovered/ 
not resolved 
Event is still ongoing.  
Recovered/re
solved with 
sequelae 
The event has reached a state where no further changes are expected and the 
residual symptoms are assumed to persist. An example is hemiparesis after 
stroke. 
The stop date of the event must be recorded. In case of a SAE, the sequelae 
should be specified. 
Fatal 
The subject has died as a consequence of the event. Date of death is recorded 
as stop date for the AE. 
Unknown 
Unknown to investigator, e.g. subject lost to follow-up. 
 

 
 
 
 
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7.5.7.3 Disease Progression 
Disease progression can be considered as a worsening of a patient’s condition that is being 
studied. It may be reflected by an increase in the severity of the condition or an increase in the 
symptoms. Disease progression and any events that are unequivocally due to disease 
progression should not be reported as an AE or SAE.  
Any AE or SAE which is secondary to ALS must always be reported (e.g. secondary lung 
infection in respiratory compromised subjects). 
7.5.7.4 Death 
All deaths that occur during the AE reporting period must be reported as follows: 
• Death clearly due to disease progression should be documented in the eCRF but 
should not be reported as an SAE.  
• Death that is not clearly due to disease progression should be documented in the eCRF 
and the reason for death should be reported as an SAE within 24 hours. 
Refer to Appendix 10.2.6.3 for principles for data entry in the eCRF. 
7.5.7.5 Follow-Up for Final Outcome of Adverse Events 
The investigator should follow up for final outcome on all AEs until resolution or the Safety 
Follow Up visit whichever comes first. SAEs must be followed up until a final outcome has 
been established, i.e. the follow-up may continue beyond the end of the clinical trial. For 
SAEs which have stabilised and 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.   
7.5.7.6 Reporting of Serious Adverse Events 
Any SAE must be reported to the Safety vendor on the (paper) SAE Form immediately 
(within 24 hours) of first knowledge.  
This report should contain as much information as possible and include an assessment of 
available information on seriousness, severity, causal relationship to the IMP or trial 
procedure, the action taken, the outcome to date, and a narrative description of the course of 
the event. 
Photocopies of the subject’s medical records should not be sent in lieu of completion of the 
SAE Form. Medical records, laboratory reports etc. should only be sent to the Safety vendor 
upon request. Importantly, when subject records are shared outside the site, all subject 
identifiers, with the exception of the subject number, shall be redacted on the copies of the 
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The completed SAE form must be faxed or scanned and e-mailed to the Safety vendor.  
Please refer to the SAE Reporting Contact Details document. 
Follow-up information received by the investigator concerning an SAE should be reported to 
the Safety vendor using the same time line (24 hours) as for the initial report. 
The Safety vendor may request further information in order to fully assess the SAE. The 
investigator must forward such information to the Safety vendor upon request by fax or e-mail 
(see contact details above). 
SAEs occurring after the completion of the clinical trial (i.e., after the Safety Follow Up visit) 
should not be routinely sought or collected. However, such events should be reported to the 
Safety vendor if the investigator becomes aware of them and considers them at least possibly 
related to IMP. 
Reporting to Competent Authorities and IRBs/IEC 
The investigator is responsible for reporting SAEs to the institutional review board(s) 
(IRB[s])/ independent ethics committee(s) (IEC[s]) 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. 
Oprhazyme is responsible for reporting all SAEs which are assessed as causally related to the 
IMP(s) by either the investigator or Orphazyme, and which are unexpected (suspected, 
unexpected serious 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 IRB(s)/IEC(s) that require unblinded 
reporting. 
7.5.7.7 Pregnancies 
Any pregnancy occurring during the clinical trial must be reported to the Safety vendor 
immediately (within 24 hours) of first knowledge using the (paper) Pregnancy Form. All 
pregnancies must be followed up until delivery or termination and final outcome must be 
reported on the (paper) Pregnancy Follow Up Form within 24 hours of first knowledge. 
The completed Pregnancy (Follow Up) Forms must be faxed or scanned and e-mailed to the 
Safety vendor. Please refer to the SAE Reporting Contact Details document. 

 
 
 
 
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7.5.7.8 Overdose 
Overdose is a dose taken by a subject that exceeds the dose prescribed to that subject.  All 
cases of overdose will be recorded in the subject diary (and transcribed into the compliance 
section of the eCRF) as an excursion from the prescribed dose. 
Any associated symptoms of an overdose must, as a minimum, be recorded as an AE.  
7.5.7.9 Handling of an Urgent Safety Measure 
An urgent safety measure is a measure taken to implement an action/protocol deviation under 
an emergency. This is defined within the EU Directive as “…the occurrence of any new event 
relating to the conduct of the trial or the development of the investigational medicinal product 
where that new event is likely to affect the safety of the subjects, the sponsor and the 
investigator shall take appropriate urgent safety measures to protect the subjects against any 
immediate hazard.” (34). 
If the investigator becomes aware of information that necessitates an immediate change in the 
clinical trial procedure or a temporary halt to the clinical trial in order to protect clinical trial 
subjects from any immediate hazard to their health and safety, the investigator must 
immediately inform Orphazyme of this change to; Orphazyme Clinical Safety at 
 
Orphazyme must act immediately upon receipt of the notification in accordance with the 
internal procedures. 
7.5.8 Pregnancy Test 
A serum pregnancy test must be taken at Screening in female subjects of child-bearing 
potential as scheduled in Table 1. 
A urine pregnancy test (human chorionic gonadotropin (hCG)) must be performed at the trial 
site at Day 1 prior to randomisation in female subjects of child-bearing potential. The test 
must be repeated during the trial as scheduled in Table 1. In addition, urine pregnancy tests 
must be performed at home for females of childbearing potential if a menstrual period is 
missed or if pregnancy is suspected. hCG urine pregnancy tests will be provided to the 
subjects. 
Note that pregnant subjects must discontinue IMP immediately (Section 6.5.1) and the 
pregnancy report must be expedited in accordance with Section 7.5.7.7. 
If a subject is no longer able to travel to the site to attend the in-person visits, a member of 
trial site staff or the contract nursing service may instead perform this assessment at an in-
person visit at the subject’s home/residency. 

 
 
 
 
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7.5.9 Clinical Safety Laboratory Assessments 
7.5.9.1 Central Laboratory 
The clinical safety laboratory parameters (chemistry, haematology, virology and serum 
pregnancy) analysed by a central laboratory are presented in Table 7. Urine samples will be 
tested at the trial site with a dipstick and the result recorded in the eCRF. 
The subject’s fasting status will be recorded in the eCRF to aid the interpretation of the 
results. 
A laboratory manual will be provided to the sites that specifies the procedures for collection, 
processing, storage, and shipment of samples, as well as laboratory contact information 
specific to this trial. 
Samples for laboratory testing will be collected according to the schedule of procedures 
(Table 1). Clinical safety laboratory tests may be repeated once at Screening. Reasons to 
repeat laboratory tests may include that the medication causing laboratory abnormality was 
suspended, any other suspected cause may no longer exist or to rule out laboratory error. 
If an abnormal clinical safety laboratory finding at Screening is considered by the investigator 
to be clinically significant, it should be recorded as medical history or AE, as applicable. It 
will be up to the investigator’s discretion if the subject should be randomised into the trial 
(respecting exclusion criterion 6). Any clinically significant new findings or deterioration of 
previous findings observed during the trial are to be recorded as AEs (see Section 7.5.7.2)   
If an abnormal clinical safety laboratory value is found when using the urine dipstick, further 
urine sampling and analysis may be performed locally according to normal local practice and 
at the investigator’s discretion. 
Clinical safety laboratory findings will be classified as potentially clinically significant 
abnormalities based on pre-defined thresholds for laboratory alert reporting. These potentially 
clinically significant abnormalities will be used for analysis purposes. 
If a subject is no longer able to travel to the site to attend the in-person visits, a member of 
trial site staff or the contract nursing service may instead perform this assessment at an in-
person visit at the subject’s home/residency. 
 

 
 
 
 
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7.5.9.2 Local Laboratory 
In addition to the above clinical safety laboratory parameters which are analysed and reported 
by a central laboratory, local laboratory services are required for the analysis and reporting of 
coagulation parameters and thrombocytes prior to performing lumbar puncture. Local safety 
laboratory assessments may also occur in case of close monitoring for increased 
transaminases (see Section 7.5.10.2).  
7.5.10 Follow-up for Specific Laboratory Abnormalities 
7.5.10.1 
Increased Serum Creatinine 
Serum creatinine values > 2-3-fold compared to the subject’s baseline value should be further 
investigated for signs of kidney injury. Estimation of the subject’s GFR based on BUN, 
creatinine, and cystatin C should be performed. 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. 
 
In addition, follow-up should be done according to local hospital guideline (if applicable) or 
may include the consultation of a local nephrologist if required in the opinion of the 
investigator. 
 
7.5.10.2 
Increased Transaminases 
Transaminases (ASAT, ALAT) > 3 x ULN must be further investigated in line with the FDA 
Guidance on Drug-Induced Liver Injury (39). 
 
Upon first observation of transaminases (ASAT, ALAT) > 3 x ULN, a repeat test must be 
performed within 48-72 hours (ALAT, ASAT, ALP, bilirubin) and the subject should be 
enquired for presence of symptoms (fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, or rash). 
 
If the increase is confirmed, close observation must be performed: 
 
• Repeating of ALAT, ASAT, 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. 
• 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. 

 
 
 
 
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performing an abdominal ultrasound or Magnetic resonance 
cholangiopancreatography (MRCP)). 
• Obtaining a history of exposure to environmental chemical agents. 
• Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct 
bilirubin). 
• 
Considering gastroenterology or hepatology consultations. 
 
If close observation is not possible, IMP must be interrupted or discontinued (see section 6.5  
Dose modification and IMP discontinuation). 
 
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 eCRF including the appropriate reference ranges. 
For scenarios where a permanent halt in the IMP is required, please see Section 6.5. 
 
 
7.6 
Biological Sample Assessments 
7.6.1 
Genomic Assessments 
At Screening, blood samples will be drawn to test for the presence of genetic mutations 
identified and described in subjects with ALS.  
The analysis of these samples will be reported in a specific genomic assessment report, 
separate to the clinical trial report.  
The subjects and/or caregivers will not be informed of the results of this genomic assessment 
unless mandated by local regulation or law. 
The genomic assessment will only be performed where all required permissions are granted 
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7.6.2 Pharmacokinetics Assessments 
The plasma and CSF samples will be analysed for arimoclomol using a bioanalytical method 
validated in accordance with the US FDA Guidance for Industry (35) and EMA Guideline on 
bioanalytical method validation (36). If other ongoing research studies identify significant 
metabolites, these may be analysed in samples collected from this trial using a scientifically 
validated bioanalytical method or by a method validated in accordance with the US FDA 
Guidance for Industry (35). 
The bioanalysis will be performed by Covance (see Appendix 10.3.6.3) according to a 
protocol approved by Orphazyme before the samples are analysed. 
Selected plasma samples will be subject to incurred sample re-analysis (ISR) as part of the in-
study validation of the bioanalytical method.  
The plasma concentration values will be reported in the clinical trial report and the results will 
be used for population PK analyses. In addition to the population PK analysis an exposure 
response analysis, evaluating correlation between exposure of arimoclomol and e.g. change in 
biomarker levels, will be performed. A separate modelling analysis plan will be issued before 
DBL and results will be reported separately. 
If a subject is no longer able to travel to the site to attend the in-person visits, samples 
required for PK assessment will not be drawn in the subject’s home/residency. 
7.6.2.1 Blood Samples 
Blood samples will be taken for bioanalysis of concentrations of arimoclomol in plasma at 
Week 20 and Week 52 (see Table 1).  
At Week 20 a blood sample will be drawn pre-dose and at 0.5 hours post-dose. At Week 52 
blood samples will be drawn pre-dose and at 1.5 hours post-dose. 
The exact time for drawing the samples must be recorded in the eCRF.  
The first dose of IMP will be administered while at the site to allow for PK assessment on the 
day of the Week 20 and Week 52 site visit. 
The subject must not administer IMP within 8 hours of the site visit to allow for a trough PK 
sample to be taken. The time of the last dose administered prior to the visit should be recorded 
in the subject diary and transcribed to the eCRF. 
Blood sampling and handling procedures will be described in a separate laboratory manual. 
7.6.2.2 Cerebrospinal Fluid (CSF) Samples 
Lumbar puncture will be taken for bioanalysis of concentrations of arimoclomol in CSF 
according to the schedule of procedures in Table 1. Lumbar puncture will only be performed 
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The CSF sample should be drawn at 3 hours post-dose at Week 20 and Week 52 (see 
Table 1).  
The exact time for drawing the samples must be recorded in the eCRF.  
CSF sampling and handling procedures are described in a separate laboratory manual. 
Lumbar puncture will be performed by the investigator (or delegate that is a physician by 
training) in accordance with local clinical practice including procedural guidelines and/or 
regulation. CSF sample handling procedures are described in a separate laboratory manual. 
Coagulation parameters and thrombocytes should be reviewed via local laboratory services 
prior to performing lumbar puncture. The results of the local analysis will not be recorded in 
the eCRF. Subjects should not undergo lumbar puncture if local laboratory results indicate an 
abnormality, the subject is receiving concomitant therapy with anti-coagulants or if in the 
opinion of the investigator the procedure is not appropriate (including for reasons related to 
ALS progression or practical reasons).  
Examinations will only be conducted in those subjects able to attend the trial site. If a lumbar 
puncture is missed it will not be considered a protocol deviation. 
7.6.3 Biomarker Assessments 
Blood samples, urinalysis and CSF samples will be taken for exploratory bioanalysis of 
biomarkers in blood, urine and CSF according to the schedule of procedures in Table 1.  
For details regarding lumbar puncture see Section 7.6.2.2. 
The biomarkers (see Table 8) will be analysed at the bioanalysis laboratory (see Appendix 
10.3.6.3) using a validated method.  
Guidance for biomarker sample handling are provided in the laboratory manual. 
If a subject is no longer able to travel to the site to attend the in-person visits, samples 
required for biomarker assessment will not be drawn in the subject’s home/residency. 

 
 
 
 
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single occasion will not exceed 30 mL. The expected CSF sampling volume will not exceed 5 
mL on a single occasion. 
7.6.6 
Destruction of Biological Material 
All biological material, except material collected for the biorepository, will be retained until 
the results have been reported. The material will subsequently be destroyed by the responsible 
laboratory. For destruction of samples collected for the biorepository, see Section 7.6.4. 
7.7 
Home Visit / Contract Nursing Service 
Following the baseline visit, if a subject is no longer able to attend the site, appropriate trial 
site staff (e.g. nurse, sub-investigator or contract nursing service as required) may assess the 
subject by conducting a home visit, as permitted by local laws and regulations. 

 
 
 
 
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8 
STATISTICAL METHODS 
Prior to unblinding, a separate statistical analysis plan (SAP) will be finalised, providing 
detailed methods for the analyses outlined below.  
Any deviations from the planned analyses will be described and justified in the final clinical 
trial report (CTR). 
Planned analyses will be described and justified in the SAP and the CTR.  
8.1 
Sample Size 
Two hundred and thirty-one (231) subjects are planned for randomisation This number 
includes 213 subjects according to the main trial eligibility criteria and up to an additional 18 
subjects on stable (i.e. minimum 6 months’) treatment with edaravone and who otherwise 
fulfil the eligibility criteria. The sample size calculation has been made for the 213 subjects in 
the main trial population (not including the additional subjects in the edaravone sub-
population). 
The primary endpoint is the CAFS over a 76 weeks’ treatment period comparing 1200 mg/day 
arimoclomol 400 mg t.i.d. vs. placebo. The trial will be powered for the primary endpoint.   
In the Phase 2 trial in ALS patients with pathogenic SOD1 mutation associated with rapid 
progression (please see Section 2.3.2), the effect size in CAFS between arimoclomol and 
placebo ranged between 0.41 (entire subject population) to 0.5 (subjects with baseline 
ALSFRS-R ≥35). An examination of the Pooled Resource Open-Access ALS Clinical Trials 
(PRO-ACT) Database reveals that the effect of active drugs versus placebo increases from 12 
to 18 months on both survival and change in ALSFRS-R. While the precise magnitude of the 
increase in the comparative efficacy from 12 to 18 months is difficult to assess, the rate of 
increase appears to be greater than a linear increase. Applying this observation to the effect of 
arimoclomol compared to placebo, it is expected that the effect size (which is estimated to be 
at least 0.41 at 12 months) will be no less than 0.48 assuming a minor increase from 12 to 18 
months, and as high as 0.61 with a linear increase from 12 to 18 months. Assuming an effect 
size of 0.48, 213 subjects randomised 2:1 to arimoclomol and placebo will provide 90% 
power to detect a statistically significant difference between arimoclomol and placebo, at a 
two-sided type-1 error of 0.05. 
Table 9 provides scenarios for power and sample sizes. The power shown are: 
 
 
 

 
 
 
 
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8.3.3 
Exposure and Treatment Compliance 
8.3.3.1 
Exposure 
Treatment exposure will be summarised by treatment group, by mean number of days 
exposed, mean daily dose and standard errors. 
8.3.3.2 
Treatment Compliance 
Compliance data will be summarised for each subject by treatment group overall and by trial 
visit.  
8.3.4 
Analysis of Efficacy 
8.3.4.1 
Primary Efficacy Analysis 
The primary efficacy endpoint is the Combined Assessment of Function and Survival (CAFS) 
(22). The CAFS will be calculated over a treatment period of 76 weeks for 1200 mg/day 
arimoclomol 400 mg t.i.d. compared to placebo. The CAFS compares each trial subject’s 
outcome to others in the trial in a series of pairwise comparisons, based on function and 
survival (22). For each pairwise comparison, a trial patient is assigned a score and then the 
summed scores are ranked for all participants. The score is assigned based on the change in 
ALSFR-S from baseline and the survival endpoint (PAV, tracheostomy or death) where a 
shorter survival corresponds to a lower rank. In the pairwise comparisons a score of 1 is 
assigned when the subject has a better function or reached the survival endpoint later than the 
comparison. A score of 0 is assigned when the subject and the comparison have the same 
function or reached the survival endpoint at the same time, A score of –1 is assigned when the 
subject has a worse function or reached the survival endpoint earlier than the comparison.  
The mean rank score for each treatment group is calculated. A higher mean CAFS score 
indicates a better group outcome. The CAFS will be analysed using nonparametric rank 
analysis of covariance (37), adjusting for baseline ALSFRS-R, SVC and riluzole use 
(Yes/No).  
8.3.4.2 
Secondary Efficacy Analysis 
The endpoint ‘PAV/tracheostomy-free survival over treatment period of 76 weeks for 1200 
mg/day arimoclomol (400 mg t.i.d.) compared to placebo’ will be analysed using a log-rank 
test stratified by riluzole use. Subjects who drop-out prior to Week 76 will be censored. 
The endpoint ‘ALSFRS-R change from Baseline to Week 76 for 1200 mg/day arimoclomol 
(400 mg t.i.d.) compared to placebo’ will be analysed using an analysis of covariance 
(ANCOVA). The model will include treatment, baseline ALSFRS-R, baseline SVC, and 
riluzole use. 
The endpoint ‘SVC change from Baseline to Week 76 for 1200 mg/day arimoclomol (400 mg 
t.i.d.) compared to placebo’ will be analysed using an ANCOVA. The model will include 
treatment, baseline ALSFRS-R, baseline SVC, and riluzole use. 

 
 
 
 
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Secondary endpoints will be tested sequentially at a two-sided 0.025 level of significance. 
Testing for treatment difference will stop if no treatment difference in favour of arimoclomol 
is found. See section 8.3.6 for details. 
8.3.5 
Analysis of Safety 
8.3.5.1 
Adverse Events 
AEs will be coded by system organ class (SOC) and preferred term from the current version 
of Medical Dictionary for Medical Activities (MedDRA). TEAEs will be summarised overall, 
by seriousness, severity, and relationship to treatment. AEs causing premature treatment 
discontinuation, and incidence of SAEs will be summarised.  
All AEs, severe AEs, SAEs, AEs causing premature treatment discontinuation, will be listed 
by subject. 
8.3.5.2 
Other Safety Parameters 
The C- SSRS will be summarised at each visit and overall by treatment using descriptive 
statistics.  
Vital signs and clinical safety laboratory values will be summarised by visit and changes from 
Baseline using descriptive statistics.  
The incidence of potentially clinically significant abnormal values for vital signs and safety 
laboratory values will be summarised. 
8.3.6 
Exploratory Analysis 
8.3.6.1 
Efficacy 
Change from Baseline to Week 76 for 1200 mg/day arimoclomol (400 mg t.i.d.) compared to 
placebo in cognitive and behavioural changes as evaluated by ECAS, sub-group analyses by 
demographic, baseline, and regional differences may be conducted. 
Change in ALSFRS-R and SVC will be evaluated for 1200 mg/day arimoclomol (400 mg 
t.i.d.) compared to placebo on a longitudinal basis. 
8.3.6.2 
Health-related Quality of Life 
The EQ-5D-5L, SEIQOL for subject and SEIQOL for caregiver will be summarised at each 
visit by treatment using descriptive statistics.  
8.3.6.3 
Pharmacokinetics 
CSF and plasma concentrations of arimoclomol will be listed. The pharmacokinetic results 
will be used for population PK analyses and reported separately. 

 
 
 
 
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8.3.6.4 Biomarkers 
Absolute values and changes from Baseline in biomarkers will be summarised by treatment at 
Weeks 20, 52, and 76, using means and standard errors, minimum and maximum for 
continuous variables or by frequency and percentages. Correlations by biomarkers and 
efficacy measures will be explored.  
8.3.7 
General Principles 
Unless otherwise stated, all significance tests will be two-sided using the 5% significance 
level. All confidence intervals (CIs) will be presented with 95% degree of confidence. 
An observed-cases approach will be used for tabulations of data by visit (i.e. involving only 
those subjects who attended each specific visit). 
Categorical data will be summarised using the number and percentage of subjects in each 
category and treatment group. Continuous data will be summarised using the mean, median, 
standard deviation (SD), minimum and maximum values. 
All the analyses specified in the protocol will be reviewed in relation to the blinded data 
actually obtained and the statistical analysis plan will be finalised before breaking the 
randomisation code. 
Any changes from the statistical analysis planned in this clinical trial protocol will be 
described and justified in a protocol amendment, the statistical analysis plan and/or in the 
CTR dependent on the type of deviation and when it occurs. 
8.3.8 
Handling of Missing Values 
The primary efficacy endpoint, the CAFS, will handle missing data in a manner that allows 
the comparison of each subject to another subject at time when each of the two subjects 
compared have an ALSFRS-R evaluable result. Thus, for the CAFS analysis, no missing data 
imputation is needed. The first secondary endpoint, PAV/tracheostomy-free survival, will be 
analysed using survival analysis methods (log-rank test) in which subjects who drop-out from 
the trial will be censored at their last visit. No data imputation will be used for the analysis of 
this endpoint. For change from Baseline in ALSFRS-R and SVC, the multiple imputation 
method will be used as the primary method of handling missing data. Other methods for 
handling missing data such as observed case, last observation carried forward (LOCF) and 
others will be used as sensitivity analyses for this endpoint. 
 

 
 
 
 
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9 
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22. Berry, James D., Robert Miller, Dan H. Moore, Merit E. Cudkowicz, Leonard H. Van 
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Douillet, Andrew a Eisen, Lucette Lacomblez, P Nigel Leigh, and Wim Robberecht. 
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30. Schulz KF, Altman DG, Moher D, CONSORT Group. CONSORT 2010 statement: 
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31. European Union. The rules governing medicinal products in the European Union, 
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Wanger, J,. 2005. Standardisation of spirometry. Series ‘‘ATS/ERS Task Force: 
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Mumber 2 in this Series. Eur Respir J 2005; 26: 319–338.  
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34. European Parliament and Council of The European Union. Directive 2001/20/EC of 4 
April 2001 on the approximation of the laws, regulations and administrative 
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Bioanalytical method validation. May 2001. 
36. European Medicines Agency (EMA). Committee for Medicinal Products for Human 
Use (CHMP). Guideline on bioanalytical method validation. 
EMEA/CHMP/EWP/192217/2009. 21 July 2011. 
37. Stokes, Maura E., Davis, Charles S., Koch, Gary G.: Categorical Data Analysis Using 
SAS, Third Edition 2012. 
38. Brooks, B. R., Miller, R. G., Swash, M., & Munsat, T. L. (2000). El Escorial revisited: 
Revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotrophic 
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39. FDA Guidance for Industry on Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation, July 2009  
40. Addendum version 1.0 to Investigator’s Brochure v3.0 dated 13-Sep-2019. 
Arimoclomol. Niemann-Pick disease type C, Gaucher’s disease, amyotrophic lateral 
sclerosis, sporadic inclusion body myositis. Release date 04-Jun-2020. 
 

 
 
 
 
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10 APPENDICES 
10.1 
Protocol summary 
 
Title 
A Phase 3, Randomised, Placebo-Controlled Trial of 
Arimoclomol in Amyotrophic Lateral Sclerosis 
 
ICI 
, MD, PhD 
 
Phase 
3 
 
Indication 
Arimoclomol in Amyotrophic Lateral Sclerosis (ALS) 
 
Design 
A multicentre, randomised, double-blind, placebo-controlled, 
parallel group trial to evaluate the efficacy and safety of 1200 mg 
arimoclomol (400 mg t.i.d.) over a 76 weeks’ treatment period 
 
Screening period 
Screening may be up to 4 weeks prior to Baseline if a washout 
period for an investigational treatment is required. The minimum 
screening period is set as one week for practical reasons (to 
ensure all results are available to determine eligibility at 
Baseline). 
 
Following confirmation of eligibility during the 
Screening/Baseline period (Day -28 to Day 1), subjects will be 
randomised in a 2:1 ratio to receive either 1200 mg/day 
arimoclomol (400 mg t.i.d.) or placebo orally t.i.d. 
Randomisation will be stratified by background riluzole use. 
 
Treatment period 
The first post-baseline assessment will take place in-person at the 
investigator site 4 weeks after the Baseline visit; subsequent 
assessments will consist of a combination of in-person visits and 
remote visits (telephone calls). 
 
Subjects will attend the investigator site for an in-person visit on 
a 4-weekly basis for the initial 6 months of treatment (on Weeks 
4, 8, 12, 16, 20, 24, 28), followed by an 8-weekly basis to 12 
months (on Weeks 36, 44 and 52) and then for the following 6 
months of treatment in-person visits are scheduled on a 12-
weekly basis until the Safety Follow Up (on Weeks 64 and 76). 
 

 
 
 
 
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On the remaining weeks of the treatment period (Weeks 32, 40, 
48, 56, 60, 68 and 72) a remote visit will be conducted by the 
subject receiving a telephone call from the trial site staff.  
 
Following baseline, if a subject is unable to attend the trial site 
for a scheduled in-person visit (e.g. due to ALS progression) or 
at Weeks 8, 16 and 24, a sub-set of clinical assessments as listed 
in Table 6 of the main body of the protocol should be conducted 
by trial site staff or via contract nursing service. 
 
At any time during the trial, the IMP may be temporarily halted 
for up to 4 weeks for an intolerable AE. Following re-challenge 
at the intended dose, de-escalation from 1200 mg/day (400 mg 
t.i.d.) to 600 mg/day (200 mg t.i.d.) may be considered. The 
subject will remain on this decreased dose for the remainder of 
the trial. Re-challenge with IMP in cases of elevation of 
transaminases should only be done as specified in Section 6.5 of 
the main clinical trial protocol which relates to dose modification 
and IMP discontinuation. 
 
Safety Follow Up 
Subjects who discontinue treatment will be encouraged to attend 
all planned visits as per protocol after drug discontinuation.  
 
A Safety Follow Up visit is to be conducted 2 weeks after last 
administration of IMP in case of a) premature IMP 
discontinuation or b) subject completing trial but not continuing 
into open label extension trial 
 
End of trial 
All randomised subjects will attend an end of trial visit.  
 
If a subject reaches a trial survival endpoint (e.g. tracheostomy or 
PAV), the IMP will be permanently discontinued. The subject 
will be offered to participate in an open-label extension trial 
which will be conducted as a separate trial. 
 
Subjects who complete the 76 weeks randomised treatment 
period will be offered participation in a separate open-label 
extension trial through means of a separate clinical trial protocol. 
 
IMP 
Subjects found to be eligible will be randomised via the IRT in a 
2:1 ratio to one of the following treatments: 
a. 
1200 mg/day arimoclomol (400 mg t.i.d.) 
b. 
Placebo (matching) 
 

 
 
 
 
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Treatment assignment will also be stratified by background 
treatment with riluzole. 
 
Primary objective 
To determine the efficacy of chronic treatment with 1200 mg/day 
arimoclomol (400 mg t.i.d.) compared to placebo over 76 weeks 
in subjects with ALS as assessed with Combined Assessment of 
Function and Survival (CAFS) 
 
Primary endpoint 
Combined assessment of function and survival (CAFS) over a 
treatment period of 76 weeks (or end-of-trial) 
 
Secondary 
objective 
To evaluate the impact of 1200 mg/day arimoclomol (400 mg 
t.i.d.) compared to placebo on: 
• Time to permanent assisted ventilation 
(PAV)/tracheostomy free survival 
• Disease progression as measured by change from Baseline 
of the ALSFRS-R 
• Progression of respiratory dysfunction as measured by 
change from Baseline of the slow vital capacity (SVC) 
 
Secondary 
endpoints 
• Time to PAV/tracheostomy/death from Baseline 
• Change from Baseline to Week 76 (or end-of-trial) in 
ALSFRS-R  
• Change from Baseline to Week 76 (or end-of-trial) in SVC  
 
Safety objective 
To assess the safety and tolerability of 1200 mg/day arimoclomol 
(400 mg t.i.d.) compared to placebo 
 
Safety endpoints 
• Incidence and severity of treatment-emergent adverse 
events (TEAEs) over a treatment period of 76 weeks 
• Mean and change from Baseline to Week 76 (or end-of-
trial) in clinical safety laboratory tests, and vital signs 
• Incidence of clinically significant abnormalities in clinical 
safety laboratory tests and vital signs over a treatment 
period of 76 weeks 
• Columbia Suicide Severity Rating Scale (C-SSRS) over a 
treatment period of 76 weeks 
 
Exploratory 
objectives 
Efficacy 
To explore the potential effect of 1200 mg/day arimoclomol (400 
mg t.i.d.) compared to placebo on cognitive and behavioural 
changes 
 
 

 
 
 
 
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Health-related quality of life 
To evaluate the effect of 1200 mg/day arimoclomol (400 mg 
t.i.d.) compared to placebo on health-related quality of life 
 
Pharmacokinetics 
To investigate CSF and plasma levels of arimoclomol following 
administration 1200 mg/day arimoclomol (400 mg t.i.d.). 
 
Biomarkers 
To evaluate the effect of 1200 mg/day arimoclomol (400 mg 
t.i.d.) compared to placebo on candidate biomarkers of target 
engagement, disease activity (markers reflecting ongoing 
neurodegeneration), and disease progression in blood, urine, and 
CSF compared to placebo. 
 
Exploratory 
endpoints 
Efficacy 
• Change from Screening to Week 76 in cognitive and 
behavioural changes as evaluated by ECAS 
 
Health-related quality of life 
• The SEIQoL-DW for the subject over a treatment period of 
76 weeks 
• The SEIQoL-DW for the caregiver over a treatment period 
of 76 weeks 
• EQ-5D-5L over a treatment period of 76 weeks 
 
Pharmacokinetics 
• Plasma and CSF concentrations of arimoclomol at weeks 
20 and 52. 
 
Biomarkers 
Absolute values and change from Baseline to Week 20, Week 52, 
and Week 76 for 1200 mg/day arimoclomol (400 mg t.i.d.) 
compared to placebo in blood, urine, and CSF for the following 
biomarker endpoints: 
• HSP70 in CSF and blood 
• Neurofilament light chain (NfL) in CSF and blood 
• Urinary p75 neurotrophin receptor extracellular domain 
(p75ECD) 
• Chitotriosidase in CSF 
 
Sample size 
Two hundred and thirty-one (231) subjects are planned for 
randomisation This number includes 213 subjects according to 
the main trial eligibility criteria and up to an additional 18 
subjects on stable (i.e. minimum 6 months’) treatment with 
edaravone and who otherwise fulfil the eligibility criteria.  

 
 
 
 
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The sample size calculation has been made for the 213 subjects 
in the main trial population (not including the additional subjects 
in the edaravone sub-population). 
 
Anticipated 
disposition 
Number of subjects planned to be screened: Approximately 298 
Estimated screen failure rate: 25% 
Number of subjects planned to be randomised: Approximately 
231  
Estimated trial discontinuation rate: 40% 
Number of subjects expected to complete 76 weeks of treatment: 
128  
 
Within the total number of subjects to be randomised up to 18 
subjects will be on stable (i.e. minimum 6 months’) treatment 
with edaravone 
 
Statistical methods 
Primary analysis 
The CAFS will be calculated over a treatment period of 76 weeks 
for 1200 mg/day arimoclomol (400 mg t.i.d.) compared to 
placebo. The CAFS will be analysed using nonparametric rank 
analysis of covariance (29), adjusting for Baseline ALSFRS-R, 
SVC and riluzole use (Yes/No). 
 
Secondary analysis 
The endpoint ‘PAV/tracheostomy-free survival over treatment 
period of 76 weeks for 1200 mg/day arimoclomol (400 mg t.i.d.) 
compared to placebo’ will be analysed using a log-rank test 
stratified by riluzole use. Subjects who drop-out prior to Week 
76 will be censored. 
 
The endpoint ‘ALSFRS-R change from Baseline to Week 76 for 
1200 mg/day arimoclomol (400 mg t.i.d.) compared to placebo’ 
will be analysed using an analysis of covariance (ANCOVA). 
The model will include treatment, baseline ALSFRS-R, baseline 
SVC, and riluzole use. 
 
The endpoint ‘SVC change from Baseline to Week 76 for 1200 
mg/day arimoclomol (400 mg t.i.d.) compared to placebo’ will 
be analysed using an ANCOVA. The model will include 
treatment, baseline ALSFRS-R, baseline SVC, and riluzole use. 
 
Secondary endpoints will be tested sequentially at a two-sided 
0.025 level of significance. Testing for treatment difference will 
stop if no treatment difference in favour of arimoclomol is found.  
 

 
 
 
 
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Safety analysis 
Adverse events (AEs) will be coded by system organ class 
(SOC) and preferred term from the current version of MedDRA. 
Treatment emergent adverse events (TEAEs) will be summarised 
overall, by seriousness, severity, and relationship to treatment. 
AEs causing premature treatment discontinuation, and incidence 
of SAEs will be summarised.  
 
All AEs, severe AEs, SAEs, AEs causing premature treatment 
discontinuation, will be listed by subject. 
 
The Columbia Suicide Severity Rating Scale (C- SSRS) will be 
summarised at each visit and overall by treatment using 
descriptive statistics.  
 
Vital signs and safety laboratory values will be summarised by 
visit and changes from Baseline will be summarised using 
descriptive statistics.  
 
The incidence of potentially clinically significant abnormal 
values for vital signs and safety laboratory values will be 
summarised. 
 
Trial committees 
An independent Data Monitoring Committee (DMC) will be 
established to monitor benefit:risk and ensure that subjects are 
not unnecessarily exposed to the investigational medical product 
(IMP) in the event that the expected benefit:risk should change.  
 
The DMC will act in accordance with the DMC charter and may 
have access to unblinded data. 
Eligibility criteria 
Inclusion criteria 
1. Capable of- and willing to- provide written informed 
consent and comply with trial procedures. 
2. Subject is male or female ≥18 years of age. 
3. Subject meets revised El Escorial criteria for clinically 
possible, clinically probable / clinically probable ALS 
laboratory-supported, clinically definite ALS or clinically 
definite familial ALS laboratory-supported. 
4. 18 months or less since first appearance of weakness (e.g. 
limb weakness, dysarthria, dysphagia, shortness of breath). 
5. ALSFRS-R ≥35 and erect (seated) SVC % predicted ≥ 
70% at Screening. 
6. Able and willing to travel to the site, and in the 
investigator’s opinion is likely to attend visits for at least 
24 weeks. 

 
 
 
 
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7. All sexually active female subjects of child-bearing 
potential (postmenarchal)* must agree not to intend to 
become pregnant and use a highly effective method of 
contraception** during the trial through 1 month after the 
last dose of trial medication. If the subject is a sexually 
active male with female partners of child-bearing potential 
(postmenarchal) he must 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. 
8. Stable dose of riluzole (50 mg twice daily) for a minimum 
of 14 days prior to Day 1 (Baseline),or has not taken it for 
14 days prior to Day 1. 
 
Exclusion criteria 
1. Tracheostomy or use of non-invasive ventilation for more 
than 2 hours during waking hours at the time of 
Screening and Baseline visits. 
2. Pregnant or breast-feeding. 
3. Current or anticipated use of diaphragmatic pacing during 
the trial. 
4. Exposure to any investigational treatment within 4 weeks 
or <5 half-lives of the Screening visit, whichever is 
longest and/or advanced therapy medicinal product 
(ATMP), i.e. treatments based on genes, cells or tissues 
and/or participated in any prior ALS clinical trial 
receiving active drug treatment (with the exception 
described in exclusion criterion 5).  
5. Treatment with edaravone within 4 weeks of the Baseline 
visit. However, up to 18 subjects on stable (i.e. minimum 
6 months’) treatment with edaravone and who otherwise 
fulfil the eligibility criteria are planned for enrolment 
(limited to countries where edaravone has a marketing 
authorisation for treatment of ALS). 
6. Any of the following medically significant conditions: 
a. 
Neurological impairment/dysfunction or unstable 
psychiatric illness that in the investigator’s 
opinion is likely to interfere with assessment of 
ALS disease progression. 
b. 
Clinically significant unstable medical condition 
other than ALS, which would present a risk to a 
subject to participate in the trial 
c. 
Presence of dementia that impairs the ability of 
the subject to provide informed consent, 
according to the PI decision. 

 
 
 
 
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d. 
Known or suspected allergy or intolerance to the 
IMP (arimoclomol or constituents)  
e. 
Chronic infection particularly HIV or Hepatitis B 
or C. 
f. 
Clinically significant renal or hepatic disease 
g. 
Aspartate aminotransferase and/or alanine 
aminotransferase and/or lactate dehydrogenase ≥3 
times the upper limit of normal [ULN], bilirubin 
≥2 times the ULN, or creatinine ≥1.5 times the 
ULN). Laboratory tests may be repeated once at 
Screening. Reasons to repeat laboratory tests may 
include that the medication causing laboratory 
abnormality was suspended, any other suspected 
cause may no longer exist, or to rule out 
laboratory error. 
h. 
Cancer that is currently under active treatment or 
is likely to require treatment during the trial that 
may alter the subject´s function and thereby 
interfere with assessment of ALS disease 
progression. 
i. 
Any other condition that in the investigator’s 
opinion would present a risk to a subject to 
participate in the trial, interfere with the 
assessment of safety or has an increased risk of 
causing death during the trial. 
 
* Non child-bearing potential is defined as post-menopausal 
(minimum of 12 months with no menses and follicle-stimulating 
hormone in the post-menopausal range) or sterilisation 
(hysterectomy, oophorectomy, or bilateral tubal ligation). 
 
** Highly effective methods of contraception include combined 
(oestrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or 
transdermal); progestogen-only hormonal contraception 
associated with inhibition of ovulation (oral, injectable, or 
implantable); intrauterine device; intrauterine hormone-
releasing system; bilateral tubal occlusion; and vasectomised 
partner. 
 
According to the recommendations from the Clinical Trial 
Facilitation Group (CTFG, 2014), sexual abstinence is 
considered a highly effective birth control method only if it is 
defined as refraining from heterosexual intercourse during the 
trial until 1 week after the last dose of trial medication (for 
female subjects of child-bearing potential) and for 3 months after 

 
 
 
 
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the last dose of trial medication (for male subjects with female 
partners of child-bearing potential). The reliability of sexual 
abstinence needs to be evaluated by the investigator in relation 
to the duration of the clinical trial and the preferred and usual 
lifestyle of the subject. 
 
Anticipated trial 
period 
First Subject First Visit: Jul 2018 
Last Subject First Visit: May 2019 
Last Subject Last Visit: Dec 2020 
 
Countries & 
centres 
The trial will be conducted at approximately 32 sites in 
approximately 13 countries in North America and Europe. 
 
 

 
 
 
 
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10.2 
Trial governance considerations 
10.2.1 
Regulatory and ethical considerations 
This trial will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
current version of the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines. 
• Current version of applicable ICH Good Clinical Practice (GCP) Guidelines. 
• Applicable laws and regulations. 
 
The appropriate regulatory authority(ies) must be notified of/approve the clinical trial as 
required.  
The protocol, protocol amendments, subject information leaflet including the informed 
consent form (ICF), Investigator’s Brochure, and other relevant documents (for example 
advertisements) must be submitted to an IRB/IEC by the investigator (in collaboration with 
Orphazyme, if applicable) and reviewed and approved by the IRB/IEC prior to enrolment of 
subjects.  
Any amendments to the protocol must be approved by/receive favourable opinion from 
relevant regulatory authorities and IRBs/IECs as required prior to the implementation. 
The investigator or the assigned responsible CRO will be responsible for ensuring the 
following: 
• Provision of written summaries of the status of the trial to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
• Notification of the local IRB/IEC of SAEs or other significant safety findings as 
required by IRB/IEC procedures. 
• Oversight of the conduct of the trial at the trial site and adherence to applicable 
national and international legislation. 
10.2.2 Informed consent process 
Subjects shall receive written and verbal information concerning the clinical trial. This 
information will emphasise that participation in the clinical trial is voluntary and that the 
subject may withdraw from the clinical trial at any time and for any reason. All subjects will 
be given an opportunity to ask questions and will be given sufficient time to consider before 
consenting. 
The subject’s signed and dated informed consent to participate in the clinical trial must be 
obtained prior to any clinical trial related procedure being carried out in accordance with ICH 

 
 
 
 
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GCP (4.8) and all applicable laws and regulations. The authorised person obtaining the 
informed consent must also sign the ICF. 
Subjects unable to provide informed consent prior to the commencement of the screening and 
baseline visits cannot participate in the trial. 
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the trial.  
A copy of the ICF(s) must be provided to the subject or the subject’s legally authorised 
representative.  
Since ALS is a rapidly progressing neurological condition, the ability of a trial subject to 
confirm ongoing / provide new consent may be diminished (i.e. the trial subject may decline 
to a legal status of an incapacitated adult). Since there is the possibility of needing to 
reconsent subjects in the clinical trial due to unforeseen circumstances, a primary caregiver 
will be nominated as a legal representative prior to commencement of the trial will be 
nominated by the time of the Baseline visit to ensure that this occurs while the subject is 
competent. In this circumstance (and in accordance with local legislation or guidelines) a 
legal representative will ensure the subject’s best interests and legal rights are protected 
throughout the trial should the subject become incompetent. Legal representation certificate 
must be obtained as per applicable country legal requirements and procedures. While the 
subject is competent, informed consent for any research procedure or intervention is sought 
from the subject only. The subject may freely decline consent and the legal representative will 
not be consulted. Based on the selection criteria, this trial will not prompt legislation 
regarding enrolment of incapacitated adults into clinical trials in emergency situations.  
Additionally, this individual will give consent to be contacted during the conduct of the trial 
should contact with the subject become challenged. 
For competent trial subjects who have lost dexterity in the hands and cannot personally sign 
and date the informed consent form, an impartial witness signature may be used to document 
that the participant understands the study, the consent process, and has consented to continue 
to participate in the trial (if permitted by local regulations). 
10.2.3 Subject card 
At Screening, subjects will be provided with a card stating that they are participating in a 
clinical trial and which contains contact address(es) and telephone number(s) of relevant trial 
site staff. The subject will use this card to notify non-investigator physicians of their trial 
participation. The contact details of the appointed medical monitor will be included on the 
card should medical information be required by the non-investigator physician. These contact 
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10.2.4 Subject and data confidentiality 
This clinical trial protocol as well as all other information, data and results relating to this 
clinical trial and/or to the IMP is confidential information of Orphazyme and shall not be used 
by the investigator for purposes other than this clinical trial. 
The investigator agrees that Orphazyme may use any and all information, data and results 
from this clinical trial in connection with the development of the IMPs and, therefore, may 
disclose and/or transfer information, data and/or results to other investigators, regulatory 
authorities and/or commercial partners. 
Subjects will be assigned a unique identifier (subject ID) by Orphazyme. Any subject’s 
records or datasets that are transferred to Orphazyme will contain the identifier only; subject 
names or any information which would make the subject identifiable will not be transferred.  
Subjects must be informed that their personal trial-related data will be used by Orphazyme in 
accordance with local data protection law.   
The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by Orphazyme, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.2.5 Processing of personal data 
This protocol specifies the personal data on trial subjects (for example age, gender, health 
condition, height, medical history, test results, etc.) which shall be collected as part of the 
clinical trial and processed during and after trial completion. 
Personal data collected as part of the clinical trial will be transferred to/from the 
institution/investigator, Orphazyme and third parties acting on behalf of Orphazyme. 
Processing of personal data on behalf of Orphazyme requires a written agreement between 
Orphazyme and the relevant party which covers collection, processing and transfer of 
personal data in the clinical trial. In certain cases an agreement on transfer of personal data 
may also be required. 
Investigators and Orphazyme must ensure that collection, processing and transfer of personal 
data are in compliance with applicable legislation on data protection and privacy. 
Subjects (or their legally acceptable representative) must be asked to consent to the collection, 
processing and transfer of their personal data to EU and non-EU countries for the purpose of 
conducting the clinical trial, research and development of new or existing products/services, 
improving existing products/services, applying for marketing authorisations for 
products/services, marketing of products/services and other related activities. 
Orphazyme has obtained the necessary authorisations for the processing of personal data 
collected in the trial. 

 
 
 
 
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10.2.6 Record keeping, quality control and data handling 
10.2.6.1 
Investigator Logs 
The investigator must keep a subject screening log, a subject identification code list and a 
subject enrolment log. The subject screening log and subject enrolment log may be combined 
in one list and may be generated from IRT. 
In addition, the investigator must keep a log of staff and a delegation of task(s) list at the trial 
site. Investigator must sign the log of staff and the delegation of task(s) at the trial site prior to 
the delegation of tasks. 
10.2.6.2 
Case report forms 
Data will be collected by means of electronic data capture unless transmitted to Orphazyme or 
designee electronically (e.g., laboratory data). The investigator or staff authorised by the 
investigator will enter subject data into eCRFs. Data recorded in the eCRFs will be accessible 
to the trial site and Orphazyme personnel immediately after entry. The eCRFs must be 
maintained in an up-to-date state by the trial site at all times. 
The investigator must verify the correctness of the data entered by the site by electronically 
dating and signing all eCRFs used. This signature information will be kept in the audit trail 
and cannot be altered. Any correction(s) made by the investigator or authorised site staff to 
the eCRF after original entry will be documented in the audit trail. Changes to data already 
approved will require the re-signature by the investigator. The person making the change to 
the data, and the date, time and reason for the change will be identified in the audit trail. 
10.2.6.3 
Principles for data entry 
Clinically significant abnormal findings at the (first) Screening visit will be documented as 
medical history in the eCRF. 
If an abnormal finding (vital signs, physical examination, laboratory tests, ECG) at any other 
visit than the (first) Screening visit is considered by the investigator to be clinically 
significant, it will be reported as an AE in accordance with Section 7.5.7. Further, any 
clinically significant deterioration of a pre-existing condition as well as any new clinically 
significant sign, symptom or illness observed after Screening will be reported as an AE in 
accordance with Section 7.5.7. 
10.2.6.4 
Source data 
For all data recorded, the source document must be defined in a source document agreement 
or similar document at each trial site. There must only be one source defined at any time for 
any data elements. 
Source data should as a general rule be recorded in the subject’s medical record or other 
defined document normally used at the trial site. Source data not normally collected as a 

 
 
 
 
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routine part of the clinical practice at the site may be entered on a worksheet. Clinical 
assessments/safety evaluations must be signed by medically qualified investigators.  
If the worksheet does not become part of the subject’s medical record, the following should as 
a minimum be added to the subject’s medical record: 
• Date(s) of conducting the informed consent process, including date of provision of 
subject information. 
• A statement from the investigator to verify that each of the eligibility criteria are met. 
• Subject ID. 
• The fact that the subject is participating in a clinical trial in ALS with arimoclomol for 
up to 76 weeks. 
• Other relevant medical information. 
 
Source records used to document assessments conducted in the subject’s home/residency and 
local laboratory reports will be retained at the trial site and handled as per all other source 
records. 
 
10.2.6.5 
Trial monitoring 
During the course of the trial, CRA(s) will visit the trial site. These visits have the following 
objectives: (i) to perform ongoing source data verification to confirm that data entered into the 
eCRF by authorised site personnel are accurate, complete, and verifiable from source 
documents; (ii) to confirm that the safety and rights of subjects are being protected; and (iii) 
to confirm that the trial is being conducted in accordance with the currently approved protocol 
and any other study agreements, ICH GCP, and all applicable regulatory requirements. 
The monitoring visit intervals will depend on the trial site’s recruitment rate, the compliance 
of the trial site with the protocol and GCP. 
In order to perform their role effectively, CRAs and persons involved in quality assurance and 
inspections will need direct access to source data, e.g. medical records, laboratory reports, 
appointment books, etc. If the electronic medical record does not have a visible audit trail, the 
investigator must provide the CRA with signed and dated printouts. In addition, relevant site 
staff should be available for discussions at monitoring visits and between monitoring visits 
(e.g. by telephone). 
10.2.6.6 
Protocol compliance 
Protocol deviations will be documented and notified to the investigator. Protocol deviations 
will be assessed by Orphazyme and those considered important (and fulfilling the ICH E6 
guideline definition) will be included in the CTR. 

 
 
 
 
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10.2.6.7 
Sponsor audits, IRB/IEC review and regulatory agency inspections 
The clinical trial will be subject to audits conducted by Orphazyme or inspections from 
domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
take place during or after the trial. The investigator and the site staff as well as Orphazyme 
staff have an obligation to cooperate and assist in audits and inspections. This includes giving 
auditors and inspectors direct access to all source documents and other documents at the trial 
site relevant to the clinical trial. This includes permission to examine, verify and reproduce 
any records and reports that are important to the evaluation of the trial. 
If the trial site is contacted for an inspection by competent authorities, Orphazyme must be 
notified immediately. 
10.2.6.8 
Data handling 
Subject data should be entered into the eCRF no later than 5 business days after each visit or 
in accordance with the requirements described in the Clinical Trial Agreement, if applicable. 
Queries for discrepant data will be generated automatically by the system upon entry or 
manually by the CRA, sponsor’s medical expert, or the data manager. All queries will be 
raised electronically within the electronic data capture system. This systematic validation will 
ensure that a clean and consistent database is provided for the statistical analysis. 
External data transfers between databases including from vendors to Orphazyme will be 
transmitted and handled via a secure file transfer protocol site.  
Transmissions of electronic data from external data providers (centralised spirometry and 
central laboratory) to the clinical database are illustrated in Panel 1. 

 
 
 
 
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10.2.6.9 
Archiving of trial documentation 
The investigator at each trial site must make arrangements to store the essential trial 
documents including the Investigator Trial File (ICH E6, Guideline for Good Clinical 
Practice) for a retention period of approximately 15 years or in accordance to national/local 
standards as stated in the clinical trial agreement or until Orphazyme informs the investigator 
that the documents are no longer to be retained or longer if required by local regulations. 
In addition, the investigator is responsible for the archiving of all relevant source documents 
so that the trial data can be compared against source data after the completion of the trial (for 
example in case of an inspection from regulatory authorities). 
The investigator is required to ensure the continued storage of the documents even if the 
investigator leaves the trial site or retires before the end of the required storage period. 
No records may be destroyed during the retention period without the written approval of 
Orphazyme. No records may be transferred to another location or party without written 
acceptance from Orphazyme. 
The destruction process must ensure confidentiality of data and must be done in accordance 
with local regulatory requirements. 
For archiving purposes, each investigator will be supplied with a copy of the eCRFs 
(including audit trail, closed queries and metadata), centralised spirometry and laboratory data 
for all subjects enrolled at the trial site. This is done after completion of the trial and before 
access to the eCRF is revoked. Audit trail information will be included. eCRFs and 
centralised spirometry and laboratory data must be available for inspection by authorised 
representatives from Orphazyme, from regulatory authorities and/or IEC/IRBs. 
10.2.7 Registration, reporting and publication policy 
Basic information of this clinical trial will be registered in the global data registry, 
www.clinicaltrials.gov before the first subject enters into the trial. The trial may also become 
registered in other online data registries, according to applicable law and regulations. 
Orphazyme will report the results of this trial on www.ClinicalTrials.gov, 
www.clinicaltrialsregister.eu and national data registries in accordance with applicable law 
and regulations after clinical trial completion or premature termination. Results may also be 
posted on the corporate website of Orphazyme or be otherwise communicated as deemed 
appropriate by the Orphazyme Management Team.  
The first publication will be a joint multi-centre publication. Multi-centre publications will be 
prepared in collaboration between Orphazyme and the members of a writing group, which 
shall be appointed by Orphazyme. The Chair of the Arimoclomol in ALS Advisory 
Committee will lead the writing group. 
Publication by an investigator of his/her trial results shall not be made public before the first 
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If no multi-centre publication has been submitted for publication within 18 months (or in 
accordance with national/local standards) after the clinical trial has been completed or 
terminated at all trial sites and all data have been received, defined as database lock of the 
clinical trial, the investigator shall have the right to publish the results from the clinical trial 
generated by the investigator, subject to the following notice requirements: 
At least 60 days prior to submitting or presenting a manuscript relating to the clinical trial to a 
publisher, reviewer or other outside person, or in accordance with national/local standards as 
agreed in the Clinical Trial Agreement, the investigator shall provide to Orphazyme a copy of 
all such manuscripts, and Orphazyme shall have rights to review and comment. Upon the 
request of Orphazyme, the investigator shall remove any confidential information (other than 
results generated by the investigator) prior to submitting or presenting the manuscripts.  
The investigator shall, upon the request of Orphazyme, delay the publication or presentation 
for up to 90 days (or in accordance with national/local standards, as agreed in the Clinical 
Trial Agreement) to allow Orphazyme to protect its inventions and other intellectual property 
rights described in any such manuscripts. In case the first multi-centre publication is still 
ongoing and has not been made public at the time of notification, Orphazyme and the writing 
group may also delay the publication or presentation if the manuscript is deemed to harm the 
ongoing multi-centre publication. 
In case of publications made by the investigator after the first multi-centre publication has 
been published, the above-mentioned requirements must still be followed. 
10.2.8 Insurance 
Orphazyme has taken out relevant insurances covering the subjects in the present clinical trial 
in accordance with applicable laws and regulations. 
10.2.9 Financial disclosure 
Investigators will provide Orphazyme with sufficient, accurate financial information as 
requested to allow Orphazyme to submit complete and accurate financial certification or 
disclosure statements to the appropriate regulatory authorities as required by local legislation. 
Investigators are also responsible for providing information on financial interests during the 
course of the clinical trial and for 1 year after completion of the clinical trial, or for a longer 
period of time if required by local legislation. 
10.2.10 Data Monitoring Committee 
Subject safety will be carefully assessed by an independent DMC. All members will be 
independent of the trial (i.e. they will not be participating investigators or employees at 
participating sites) and of Orphazyme (i.e. they will not be Orphazyme employees). The DMC 
members are experienced with clinical trials and will be responsible for assessing the safety of 
the subjects through assessment of the safety of the treatment regimen during the trial and 

 
 
 
 
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through monitoring the overall conduct of the trial. Further specification and operational 
procedures are included in the DMC Charter.  
10.2.11 Trial and site disclosure 
10.2.11.1 Premature termination of trial or trial site 
Orphazyme, the investigator, the IRB/IECs or competent authorities may decide to stop the 
clinical trial, part of the trial or a trial site at any time, but agreement on procedures to be 
followed must be obtained. 
If a clinical trial is suspended or prematurely terminated, the investigator must inform the 
subjects promptly and ensure appropriate therapy and follow-up. As specified by applicable 
regulatory requirements, the investigator or Orphazyme must promptly inform IRB/IECs and 
provide a detailed written explanation. Relevant competent authorities must be informed. 
The trial must be terminated if the perception of the benefit/risk ratio (judged from clinical 
signs and symptoms, (S)AEs and/or remarkable safety laboratory changes) becomes 
unfavourable for the continuation of the trial. 
Reasons for the early closure of a trial site by Orphazyme or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, Orphazyme’s procedures, or GCP guidelines. 
• Inadequate recruitment of subjects by the investigator. 
• Discontinuation of further IMP development. 
 
10.2.11.2 Completion of trial 
Investigators will be informed when subject recruitment is to cease. Trial enrolment will be 
stopped at a trial site when the total requested number of subjects for the clinical trial has 
been obtained, irrespective of the specific site’s planned inclusion number. 
Trial sites will be closed upon trial completion. Orphazyme will undertake arrangements for 
the collection and disposal of any unused trial material that the investigator is not required to 
keep in his/her files. A trial site is considered closed when all required documents and trial 
supplies have been collected and a trial site closure visit has been performed. 
When the randomisation code has been broken, the investigators will receive information 
about the treatment allocation for the subjects randomised at their respective sites and will be 
asked to record this in the subject’s medical record. 

 
 
 
 
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10.2.12 Responsibilities 
The international coordinating investigator (ICI) is responsible for the approval of the 
(consolidated) clinical trial protocol, including any amendment(s) and the CTR on behalf of 
all clinical trial investigators as agreed to in an International Coordinating Investigator 
Agreement. 
The national coordinating investigator (NCI) is responsible for the representation of the 
trial at IEC/IRB meetings (if required) as agreed to in a National Coordinating Investigator 
Agreement. Appointment of an NCI will only be made if required by local regulation. The ICI 
will also serve as an NCI. 
Each participating investigator is responsible for all aspects of the clinical trial conduct at 
his/her trial site as agreed to in a Clinical Trial Agreement. 
10.2.13 Neurological examination criteria 
A neurological examination will be made by a neurologist in accordance with the schedule of 
procedures (Table 1). The examination parameters presented in Table 10 will be considered as 
either normal or abnormal. Abnormalities will be described and indicated if secondary to 
ALS. 
 
 

 
 
 
 
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Table 10 
Parameters for neurological examination 
 
General 
Level of Consciousness 
Level of Appearance/ Facial/Motor Expression 
Mental Status 
Language 
Cranial Nerves 
Vision (II) 
Eye Movements (III, IV, VI) 
Jaw movement and facial sensation (V) 
Facial motion (VII) 
Hearing (VIII) 
Swallowing, pharynx, larynx (IX, X) 
SCM, trapezious (XI) 
Tongue (XII) 
Reflexes 
Biceps 
Brachioradialis 
Triceps 
Knee Jerk 
Achilles tendon 
Motor System 
General Movement 
Muscle Bulk/ Mass 
Muscle Strength: 
Trunk 
Upper Extremities 
Lower Extremities 
Muscle Tone: 
Upper Extremities 
Lower Extremities 
Coordination / Cerebellar 
Function 
Gait 
Romberg 
Nystagmus 
Tremor 
Finger-Nose 
Heel-shin 
Rapid Rhythmic Movement 
Sensation: 
Upper Extremities 
Pain/ Temperature 
Light Touch 
Position 
Vibration 
Lower Extremities 
Pain/ Temperature 
Light Touch 
Position 
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Returns depot and destruction, North America; 
Catalent CTS (Kansas City), LLC, Attn: Returned Goods Dock 10, 10245 Hickman Mills 
Drive, Kansas City, Missouri 64137-9724 
World Courier 
Responsible for ‘direct to patient’ (DtP) distribution and logistics as agreed in a contract. 
World Courier Denmark A/S, Avedøreholmen 96-98, Hvidovre, DK-2650, Denmark 
10.3.6.3 
Contract Laboratory Services 
Covance Laboratories 
Responsible for centralised bioanalysis of safety laboratory parameters (biochemistry, 
haematology and urinalysis), PK and biomarkers and biorepository management as agreed in 
a contract. 
Pharmacokinetic analysis; 
Covance Laboratories Ltd., Otley Road, Harrogate, North Yorkshire, HG3 1PY England 
Biomarker analysis; 
Covance Laboratories Inc., Translational Biomarker Solutions, 220 Building/Dock 229, 671 
South Meridian Road, Greenfield IN 46140  
Covance Laboratories Inc., 3635 Concorde Parkway, Suite 100, Chantilly, VA 20151 
Biorepository; 
Covance Laboratories Inc., Covance Biorepository, Building 210, 671 South Meridian Road, 
Greenfield IN 46140  
Clinical Safety Laboratory, North America; 
Covance Inc., 8211 SciCor Drive, Indianapolis, IN 46214 USA 
Clinical Safety Laboratory, EU; 
Covance Central Laboratory Sàrl, 7 rue Marcinhes, 1217 Geneva, Meyrin Switzerland 

 
 
 
 
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10.4 
Country-Specific Requirements 
The following provisions account for national requirements where the competent authorities 
have mandated such content be included in the Clinical Trial Protocol. 
10.4.1 Canada 
Reporting of Serious Adverse Events 
Orphazyme will inform Health Canada, in an expedited manner, of any serious and 
unexpected adverse drug reaction, regardless of whether the event has occurred inside or 
outside of Canada.  
a) Where it is neither fatal nor life-threatening, report will be submitted within 15 days after 
becoming aware of the information; 
b) Where it is fatal or life-threatening, report will be submitted within 7 days after becoming 
aware of the information. Orphazyme will submit as complete a report as possible within 8 
days of the initial report. Follow-up reports of fatal or life-threatening reactions must include 
an assessment of the importance and implication of the findings, including relevant previous 
experience with the same or similar drugs. 
Archiving of Trial Documentation 
Under Canadian Law, the retention period for clinical trial records is 25 years. This will be 
enforced via the clinical trial agreement with each site and furthermore each subject will be 
made aware of this retention period via the informed consent form. 
10.4.2 France 
Inclusion Criteria 
An additional eligibility criterion for subjects recruited in France is mandatory under this 
protocol. Criterion number nine as described below is required to ensure compliance with this 
additional national requirement.   
9. 
Affiliated to a social security system (requirement for France only) 
Temporary halt of IMP and Dose Modification 
For subjects in France, the following process should be adhered to for subjects with an 
intolerable AE; 
A temporary halt of IMP treatment of up to 4 weeks is permitted if a subject experiences an 
intolerable AE. The interruption of IMP should be as short as possible and the appointed 
medical monitor should be consulted prior to re-initiation of the intended 1200 mg/day (400 
mg t.i.d.) dose.   
If the subject experiences the same intolerable AE after re-challenge with the intended 1200 
mg/day (400 mg t.i.d.) dose, the IMP must be discontinued permanently.  

 
 
 
 
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If a subject discontinues treatment and does not meet any of the survival endpoint definitions 
the subject should be invited to attend the remaining trial visits as per the schedule of 
procedures. Additionally, an in-person follow-up visit should be scheduled for 2 weeks after 
the last treatment. 
ECG Assessments 
For subjects in France, the ECG examinations should be conducted in all subjects for visits at 
week 20, 52 and 76 regardless of whether the visit is at the trial site or a home visit. Hence 
footnote k is not applicable. 
 
Adverse Events 
For subjects in France, the wording below on AE collection is added to the protocol. The 
wording was removed in error as the actual data collection is performed as requested in the 
sentence.   
AEs must be collected from the time that the subject has signed the informed consent. 
10.5 
Coronavirus (COVID) operational changes 
The document ORARIALS-01 (COVID-19) Addendum 1.0 dated 24-Mar-2020 shall remain in 
effect with this Clinical Trial Protocol. The Addendum to the Clinical Trial Protocol is 
designed to mitigate the operational impact resulting from COVID-19, and shall only be 
applied as an interim solution during the period that normal Clinical Trial Protocol logistics 
cannot be adhered to. Once containment measures have ceased and operations return to 
normal on both a site and subject level, procedures will resume as per the site’s currently 
approved Clinical Trial Protocol. 
 

Protocol number: ORARIALS-01 
Date: 16-Sep-2020 
Version: Final 1.0 
(CYP2D6 DDI) Addendum 1.0 to 
Clinical Trial Protocol v7.0 dated 08-Jun-2020 
A Phase 3, Randomised, Placebo-Controlled Trial of 
Arimoclomol in Amyotrophic Lateral Sclerosis
Sponsor: Orphazyme A/S, Ole Maaløes Vej 3, DK-2200 Copenhagen N, Denmark 
Coordinating investigator: 
, MD PhD 
Protocol number: ORARIALS-01 
EudraCT No.: 2018-000137-13 
ClinicalTrials.gov Identifier: NCT03491462
Trial product name: Arimoclomol Capsules 
Date of Addendum: 16-Sep-2020 
The trial will be conducted according to the protocol and in compliance with Good Clinical Practice (GCP), with 
the Declaration of Helsinki and with other applicable regulatory requirements 
Orphazyme A/S - Strictly Confidential 
(IB, CYP2D6 DDI) Addendum 1.0 to CTPv7.0, dated 16-Sep-2020 
Page 1 of 9 
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.

 
 
 
 
Protocol number: ORARIALS-01 
Date: 16-Sep-2020 
Version: Final 1.0 
 
 
 
Orphazyme A/S - Strictly Confidential 
(IB, CYP2D6 DDI) Addendum 1.0 to CTPv7.0, dated 16-Sep-2020 
 
Page 3 of 9 
 
Contents 
 
Approval Statement, Orphazyme A/S ............................................................................................................... 2 
Acknowledgement Statement Investigators ...................................................................................................... 2 
Justification for Addendum ............................................................................................................................ 4 
Modification to the Clinical Trial Protocol due to update of Investigator Brochure version 4.0 dated 
15-SEP-2020 ..................................................................................................................................................... 5 
 
 
 

 
 
 
 
Protocol number: ORARIALS-01 
Date: 16-Sep-2020 
Version: Final 1.0 
 
 
 
Orphazyme A/S - Strictly Confidential 
(IB, CYP2D6 DDI) Addendum 1.0 to CTPv7.0, dated 16-Sep-2020 
 
Page 4 of 9 
 
Justification for Addendum 
 
Results from an in vitro study showed that arimoclomol is a direct inhibitor of CYP2D6 with an IC50 of190 
µM which is > 25 times higher than clinical exposure (Cmax) 
The investigator’s Brochure was previously updated with these findings and correspondingly the Clinical 
trial Protocol (CTP) was updated to indicate that concomitant treatment with CYP2D6 substrates should be 
done with caution (since their exposure could increase as a result of their metabolism being inhibited). 
By using mechanistic static modelling, instead of basic equations, it has since been evaluated that the in vitro  
CYP2D6 inhibition is not clinically relevant. These findings have been included in the annual update of the 
Investigator’s Brochure and the updated guidance on use of concomitant medications are included in this 
CTP addendum. 
The changes described are done to ensure continued safety and well-being of the subjects and the integrity of 
the clinical trial. A sponsor risk assessment has concluded that the changes in this addendum are not likely to 
affect the safety and well-being of the participants or the scientific value of the trial. Therefore, the Sponsor 
confirms that the benefit-risk evaluation for arimoclomol in ALS is not changed.