Conditions: Amyotrophic Lateral Sclerosis
Keywords: Arimoclomol ALS
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 120
Healthy volunteers: no

Brief summary:
A multicenter, non-randomized, open label trial, to assess long term safety and efficacy of Arimoclomol in subjects with Amyotrophic Lateral Sclerosis (ALS) who have completed the ORARIALS-01 trial.

Detailed description:
The planned duration of the open-label trial was 152 weeks, but the trial was terminated early as a consequence of the results of ORARIALS-01 which did not meet any of its efficacy endpoints. Therefore, the actual mean duration of open-label treatment was approximately 28 weeks (range approximately 2 to 71 weeks).

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

Interventions: intervention 1: Arimoclomol
Intervention descriptions: intervention 1: 2 capsules (2 x 124 mg arimoclomol base; equivalent to 2 x 200 mg arimoclomol citrate) taken 3 times daily

Protocol document:
Prot_000.pdf: 
Protocol number: ORARIALS-02 
Date: 08-Jun-2020 
Version: 6.0 
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Page 1 of 91  
CLINICAL TRIAL PROTOCOL 
Arimoclomol in ALS – Open-Label Extension Trial
Open-label, Non-randomised Extension Trial to Assess the 
Long-Term Safety and Efficacy of 1200 mg/day 
Arimoclomol 400 mg Three Times a Day (t.i.d.) in 
Subjects with Amyotrophic Lateral Sclerosis (ALS) who 
have Completed the ORARIALS-01 Trial
Sponsor: Orphazyme A/S, Ole Maaløes Vej 3, DK-2200 Copenhagen N, Denmark 
Coordinating investigator: 
, MD PhD 
Protocol number: ORARIALS-02 
EudraCT No.: 2019-000374-39  
Trial product name: Arimoclomol Capsules 
Date of protocol amendment: 08 June 2020 
Strengths of arimoclomol are presented throughout this document by weight of the citrate 
salt. 
Clinicaltrials.gov ID: NCT03836716
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. 
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 




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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:
June 10, 2020


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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:
 MD, 
PhD
Digitally signed by 
, MD, 
PhD 
Date: 2020.06.10 
10:20:11 -04'00'


 
 
 
 
 
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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 10.3. 
 


 
 
 
 
 
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Protocol Amendment 
 
This document is a Consolidated Clinical Trial Protocol, which includes protocol 
amendments. 
The details of content amended from the Clinical Trial Protocol versions 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 12-Feb-2019 
• Clinical Trial Protocol version 2.0 dated 08-Apr-2019 
• Clinical Trial Protocol version 2.1 dated 04-Jun-2019 (applicable only in France) 
• Clinical Trial Protocol version 3.0 dated 19-Jul-2019 
• Clinical Trial Protocol version 4.0 dated 04-Nov-2019 
• Clinical Trial Protocol version 5.0 dated 28-Feb-2020 
• Clinical Trial Protocol version 6.0 dated 08-Jun-2020 (this latest version) 
 
The sponsor confirms that the changes introduced in version 6.0 qualify for classification as 
substantial amendments. 
This Consolidated Clinical Trial Protocol, version 6.0 is applicable globally. Country specific 
information are contained in Section 10.3. 
 
 
 


 
 
 
 
 
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Table of Contents 
 
APPROVAL STATEMENT, ORPHAZYME A/S.......................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................. 10 
1 
SCHEDULE OF TRIAL PROCEDURES ......................................................... 12 
2 
INTRODUCTION AND RATIONALE ............................................................. 16 
2.1 
Amyotrophic Lateral Sclerosis ....................................................................... 16 
2.2 
Arimoclomol .................................................................................................... 17 
2.3 
Experience with Arimoclomol ........................................................................ 18 
2.3.1 
Nonclinical Experience ........................................................................ 18 
2.3.2 
Clinical Experience .............................................................................. 18 
2.4 
Trial Rationale ................................................................................................. 20 
2.4.1 
Justification for Trial Design ............................................................... 20 
2.4.2 
Justification for Selected Dose............................................................. 20 
2.4.3 
Justification for Endpoints ................................................................... 21 
2.4.4 
Benefit-Risk Assessment ..................................................................... 22 
2.5 
Ethical Considerations .................................................................................... 23 
3 
OBJECTIVES AND ENDPOINTS .................................................................... 25 
4 
TRIAL DESIGN................................................................................................... 26 
4.1 
Overall Trial Design ........................................................................................ 26 
4.1 
Number of Subjects ......................................................................................... 28 
4.2 
End of Trial Definition .................................................................................... 28 
5 
TRIAL POPULATION AND WITHDRAWAL ............................................... 29 
5.1 
Subject Eligibility ............................................................................................ 29 
5.2 
Inclusion Criteria ............................................................................................ 29 
5.3 
Exclusion Criteria ........................................................................................... 29 
5.4 
Subject Enrolment Procedure ........................................................................ 30 
5.5 
Discontinuation ................................................................................................ 31 
5.5.1 
Discontinuation from Treatment .......................................................... 31 
5.5.2 
Discontinuation from the Trial ............................................................. 31 
5.6 
Missed Visits and Lost-to-Follow-Up ............................................................ 32 
6 
TREATMENTS.................................................................................................... 33 
6.1 
Trial Product ................................................................................................... 33 
6.2 
Administration of Investigational Medicinal Product ................................. 34 
6.3 
Treatment Assignment .................................................................................... 34 
6.3.1 
Randomisation ..................................................................................... 34 
6.3.2 
Blinding................................................................................................ 35 
6.3.3 
Emergency Unblinding of Individual Subject Treatment .................... 35 


 
 
 
 
 
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6.4 
IMP Discontinuation ....................................................................................... 35 
6.4.1 
Permanent Discontinuation of IMP ..................................................... 35 
6.4.2 
Temporary Halt of IMP ....................................................................... 36 
6.5 
Treatment Logistics and Accountability ....................................................... 36 
6.5.1 
Labelling and Packaging of IMPs ........................................................ 36 
6.5.2 
Storage of IMPs ................................................................................... 37 
6.5.3 
Drug Distribution and Dispensation .................................................... 37 
6.5.4 
Drug Accountability and Destruction .................................................. 38 
6.5.5 
Treatment Compliance ......................................................................... 38 
6.6 
Mode of Administration ................................................................................. 39 
6.7 
Concomitant Medication ................................................................................ 39 
6.8 
Prohibited Medication and Procedures ........................................................ 41 
6.9 
Provision for Subject Care Following Trial Completion ............................. 41 
7 
TRIAL ASSESSMENTS AND PROCEDURES ............................................... 42 
7.1 
General Principles ........................................................................................... 42 
7.1.1 
Investigator’s or Delegate’s Responsibilities....................................... 42 
7.1.2 
Nomination of Primary Caregiver and Legal Representative .............. 42 
7.1.3 
Rater Training and Certification .......................................................... 43 
7.1.4 
Subject Instruction ............................................................................... 44 
7.1.5 
Sequence of Assessments .................................................................... 44 
7.1.6 
Visit Scheduling ................................................................................... 44 
7.1.7 
Transitioning of Subjects from ORARIALS-01 to ORARIALS-02.... 44 
7.1.8 
Subject Assessment When Unable to Travel to the Trial Site ............. 45 
7.2 
Baseline Characteristics .................................................................................. 47 
7.3 
Efficacy Assessments ....................................................................................... 47 
7.3.1 
Survival (permanent assisted ventilation/tracheostomy/death) ........... 47 
7.3.2 
ALS Functional Rating Scale – Revised .............................................. 47 
7.3.3 
Slow Vital Capacity ............................................................................. 48 
7.3.4 
EuroQoL Five-Dimensional, Five-Level Descriptive System ............. 49 
7.4 
Safety Assessments .......................................................................................... 50 
7.4.1 
Physical Examination........................................................................... 50 
7.4.2 
Vital Signs ............................................................................................ 50 
7.4.3 
Body Weight ........................................................................................ 50 
7.4.4 
Electrocardiogram – 12-lead ................................................................ 51 
7.4.5 
Columbia-Suicide Severity Rating Scale ............................................. 51 
7.4.6 
Adverse Events .................................................................................... 52 
7.4.7 
Pregnancy Test ..................................................................................... 57 
7.4.8 
Clinical Safety Laboratory Assessments ............................................. 58 
7.4.9 
Follow-up for specific laboratory abnormalities .................................. 59 
7.5 
Biological Sample Assessments ...................................................................... 61 
7.5.1 
Pharmacokinetics Assessments ............................................................ 61 
7.5.2 
Biorepository........................................................................................ 62 
7.5.3 
Estimate of Total Blood Volume Collected ......................................... 62 
7.5.4 
Destruction of Biological Material ...................................................... 63 


 
 
 
 
 
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7.6 
Home Visit / Contract Nursing Service ......................................................... 63 
8 
STATISTICAL METHODS ............................................................................... 64 
8.1 
Sample Size ...................................................................................................... 64 
8.2 
Trial Analysis Sets ........................................................................................... 64 
8.3 
Statistical Analysis .......................................................................................... 64 
8.3.1 
Disposition of Subjects ........................................................................ 64 
8.3.2 
Demographics and Other Baseline Characteristics .............................. 64 
8.3.3 
Exposure and Treatment Compliance .................................................. 65 
8.3.4 
Analysis of Efficacy ............................................................................. 65 
8.3.5 
Analysis of Safety ................................................................................ 65 
8.3.6 
Exploratory Analysis ........................................................................... 66 
8.3.7 
General Principles ................................................................................ 66 
8.3.8 
Handling of Missing Values ................................................................ 66 
9 
REFERENCE LIST ............................................................................................. 67 
10 
APPENDICES ...................................................................................................... 71 
10.1 
Protocol Summary .......................................................................................... 71 
10.2 
Trial Governance Considerations .................................................................. 76 
10.2.1 
Regulatory and Ethical Considerations ................................................ 76 
10.2.2 
Informed Consent Process ................................................................... 76 
10.2.3 
Subject Card ......................................................................................... 77 
10.2.4 
Subject and Data Confidentiality ......................................................... 78 
10.2.5 
Processing of Personal Data................................................................. 78 
10.2.6 
Record Keeping, Quality Control and Data Handling ......................... 79 
10.2.7 
Registration, Reporting and Publication Policy ................................... 83 
10.2.8 
Insurance .............................................................................................. 84 
10.2.9 
Financial Disclosure............................................................................. 84 
10.2.10 
Trial and Site Disclosure ...................................................................... 84 
10.2.11 
Responsibilities .................................................................................... 85 
10.2.12 
International Coordinating Investigator ............................................... 86 
10.2.13 
National Coordinating Investigator ...................................................... 86 
10.2.14 
Investigators ......................................................................................... 86 
10.2.15 
Sponsor ................................................................................................ 86 
10.2.16 
Service Providers ................................................................................. 87 
10.3 
Country-Specific Requirements ..................................................................... 88 
10.3.1 
Canada.................................................................................................. 88 
10.3.2 
France ................................................................................................... 89 
10.4 
Coronavirus (COVID) operational changes ................................................. 91 
 
 
 
 


 
 
 
 
 
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Tables in Text 
Table 1-1: Schedule of Trial Procedures ............................................................................ 12 
Table 3-1: Objectives and Endpoints .................................................................................. 25 
Table 6-1: Description of Investigational Medicinal Product ............................................ 33 
Table 6-2: Quantities of Ingredients in Trial Product ........................................................ 34 
Table 7-1: Clinical Assessments for when an in-person visit is conducted at the subject’s 
home/residency ........................................................................................................... 46 
Table 7-2: Clinical Safety Laboratory Parameters ............................................................. 59 
Table 10-1 Parameters for neurological examination: ....................................................... 90 
 
Figures in Text 
Figure 4-1: Trial Design..................................................................................................... 27 
Figure 10-1: Transmission of Electronic Data ................................................................... 82 
 
 
 


 
 
 
 
 
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List of Abbreviations and Definitions of Terms 
AE 
Adverse event 
ALS 
Amyotrophic lateral sclerosis 
ALSFRS-R 
ALS Functional Rating Scale-Revised 
ATMP 
Advance therapy medicinal product 
CI 
Confidence interval 
CNS 
Central nervous system 
CMO 
Contract Manufacturing Organisation 
CRA 
Clinical research associate 
CRO 
Contract Research Organisation 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTIMP 
Clinical Trial of an Investigational Medicinal Product 
CTR 
Clinical trial report 
CYP2D6 
Cytochrome P450 2D6 
DILI 
Drug-induced liver injury 
DNA 
Deoxyribonucleic acid 
DtP 
Direct-to-patient 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
EQ-5D-5L 
EuroQol Five-Dimensional, Five-Level Descriptive System 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
hCG 
Human chorionic gonadotropin  
HDPE 
High density polyethylene 
HPMC 
Hydroxypropyl methylcellulose 
HRQoL 
Health-related quality of life 
HSP70 
Heat shock protein-70 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICI 
International coordinating investigator 
ID 
Identification 
IEC 
Independent ethics committee 


 
 
 
 
 
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IMP 
Investigational medicinal product 
INR 
International Normalised Ratio 
IRB 
Institutional review board 
IRT 
Interactive response technology 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
MATE 
Multidrug and toxin extrusion 
NASH 
Non-Alcoholic Steatohepatitis 
NCI 
National coordinating investigator 
NPC 
Niemann-Pick disease type C 
OCT 
Organic cation transporter 
OLE 
Open-label extension 
Ph. Eur. 
European Pharmacopeia 
PAV 
Permanent assisted ventilation  
PIL 
Patient Information Leaflet 
PK 
Pharmacokinetics 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOD1 
Superoxide 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 a day 
ULN 
Upper limit of normal 
US 
United States 
USP-NF 
United States Pharmacopeia-National Formulary 
VC 
Vital capacity 


 
 
 
 
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1 
SCHEDULE OF TRIAL PROCEDURES 
Table 1-1: Schedule of Trial Procedures 
 
Baseline a 
Open-label treatment b 
Safety Follow Up 
Visit name 
Baseline c 
In-person visits c 
In-person 
visits 
Remote visits 
(telephone calls) 
End of trial d 
(in person) 
Safety Follow Up e 
(telephone call) 
Visit number 
1 
2, 4, 6, 8, 11, 14 
and 17 
3, 5, 7, 
9, 10, 12, 13, 15, 16, 18 and 
19 
20 
21 
Time in relation to Baseline 
Day 1 
Weeks 4, 12, 20, 
28, 40, 52, 64  
8, 16, 24 
Weeks 32, 36, 44, 48, 56, 60, 
68 and 72  
Week 76 
 (or early 
termination) 
2 weeks after treatment discontinuation 
Visit window, days 
 
± 7 days 
 
± 7 days 
± 7 days 
± 7 days 
SUBJECTS 
 
Written Informed Consent 
X r 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
Demographics f 
(X) 
 
 
 
 
 
Medical History g 
(X) 
 
 
 
 
 
Respiratory rate 
(X) 
 
 
 
X 
 
Diary instruction h 
X 
 
 
 
 
 
Diary completion h 
<========================================================================> 
 
Collect diary and record diary 
data in eCRF h 
(X) 
X 
 
 
X 
 
Concomitant Medication 
(X) 
X 
X 
X 
X 
X 
EFFICACY 
Survival (PAV/ tracheostomy/ 
death) 
<===================================================================================================================> 
ALSFRS-Ri 
(X) 
X 
X 
X 
X 
 
SVC 
(X) 
X 
 
 
X 
 
SAFETY 


 
 
 
 
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Baseline a 
Open-label treatment b 
Safety Follow Up 
Visit name 
Baseline c 
In-person visits c 
In-person 
visits 
Remote visits 
(telephone calls) 
End of trial d 
(in person) 
Safety Follow Up e 
(telephone call) 
Visit number 
1 
2, 4, 6, 8, 11, 14 
and 17 
3, 5, 7, 
9, 10, 12, 13, 15, 16, 18 and 
19 
20 
21 
Time in relation to Baseline 
Day 1 
Weeks 4, 12, 20, 
28, 40, 52, 64  
8, 16, 24 
Weeks 32, 36, 44, 48, 56, 60, 
68 and 72  
Week 76 
 (or early 
termination) 
2 weeks after treatment discontinuation 
Visit window, days 
 
± 7 days 
 
± 7 days 
± 7 days 
± 7 days 
Physical Examination 
(X) 
X 
 
 
X 
 
Vital Signs 
(X) 
X 
 
 
X 
 
Body Weight j 
(X) 
X (Week 52 only) 
 
 
X 
 
C-SSRS k 
(X) 
X 
X 
X 
X 
 
ECG 
(X) 
X (Weeks 20 and 
52 only) 
 
 
X 
 
AEs 
(X) 
X 
X 
X 
X 
X l 
Pregnancy Test m 
(X) 
X 
 
 
X 
 
Clinical Safety Laboratory Test n p 
(X) 
X 
Xq 
 
X 
 


 
 
 
 
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Baseline a 
Open-label treatment b 
Safety Follow Up 
Visit name 
Baseline c 
In-person visits c 
In-person 
visits 
Remote visits 
(telephone calls) 
End of trial d 
(in person) 
Safety Follow Up e 
(telephone call) 
Visit number 
1 
2, 4, 6, 8, 11, 14 
and 17 
3, 5, 7, 
9, 10, 12, 13, 15, 16, 18 and 
19 
20 
21 
Time in relation to Baseline 
Day 1 
Weeks 4, 12, 20, 
28, 40, 52, 64  
8, 16, 24 
Weeks 32, 36, 44, 48, 56, 60, 
68 and 72  
Week 76 
 (or early 
termination) 
2 weeks after treatment discontinuation 
Visit window, days 
 
± 7 days 
 
± 7 days 
± 7 days 
± 7 days 
HEALTH-RELATED QUALITY OF LIFE 
EQ-5D-5L 
(X) 
X 
 
 
X 
 
BIOLOGICAL SAMPLE COLLECTION 
BIOREPOSITORY 
Blood collection 
(X) 
X (Weeks 20 and 
52 only) 
 
 
X 
 
Urine collection  
(X) 
X (Weeks 20 and 
52 only) 
 
 
X 
 
PHARMACOKINETICS 
Blood sampling (arimoclomol) o 
 
X (Weeks 20 and 
52 only) 
 
 
X 
 
INVESTIGATIONAL MEDICINAL PRODUCT 
Dispensing of IMP  
X 
X 
 
 
 
 
Drug Accountability 
 
X 
 
 
X 
 
Footnotes: 
a. 
Baseline visit will be conducted on the same date as the End of Trial Visit (Visit 21) of the ORARIALS-01. Assessments marked as (X) will be data collected in 
the ORARIALS-01 trial (either as part of the Screening Visit or End of Trial Visit) and duplicated into the clinical database of ORARIALS-02. Items marked X 
are to be conducted specifically at the Baseline visit for ORARIALS-02. 
b. 
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.  


 
 
 
 
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c. 
At Day 1, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44, 52 and 64 subjects will visit the site. If a subject is no longer able to attend the site, appropriate trial site staff 
(e.g., nurse, sub-investigator as required) may assess the subject by conducting a home visit (if permitted by local regulations). All other visits will be conducted 
remotely by telephone. 
d. 
The End of Trial Visit (Visit 20) is applicable for all subjects participating in ORARIALS-02. Subjects discontinuing treatment prior to Week 76 should 
continue in the trial up to Week 76 according to the visit schedule. For subjects withdrawing from the trial prematurely, the investigator should conduct the 
last in-person visit as per the end of trial visit. Subjects discontinuing treatment prior to Week 76 yet remaining in the trial will have telephone calls in place 
of the scheduled in-clinic visits with only the following assessments completed: 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. 
e. 
The Safety Follow Up Visit (Visit 21) must be conducted 2 weeks after the last IMP administration for all subjects. 
f. 
Demographics include age, sex, race and ethnicity 
g. 
General medical history, as well as the history of any diagnostic testing such as electromyography and nerve conduction studies; imaging; muscle biopsy; and 
antibodies. 
h. 
The diary consists of logs to record: IMP compliance, mode of administration, concomitant medication, and ventilation support. The time of the dose prior to 
Weeks 20, 52 and 76 (visits involving pharmacokinetics blood sampling) should be recorded in the subject diary and transcribed to the eCRF. 
i. 
The ALSFRS-R will be performed over the telephone for remote visits. If the scale is administered over the telephone and the subject is unable to respond 
because of significant bulbar impairment the caregiver should relay the questions and responses. 
j. 
Body weight will only be collected when feasible. 
k. 
The C-SSRS assessment will use the ‘Since the last visit’ version. 
l. 
Only stop dates for ongoing AEs and new SAEs will be collected. 
m. Women of child-bearing potential only. A urine pregnancy test will be obtained at all required visits. 
n. 
Clinical safety laboratory tests include haematology, chemistry (including Cystatin C), and urinalysis. 
o. 
At Week 20, PK samples will be collected pre-dose and at 0.5 hours post-dose. At Week 52 and Week 76 PK samples will be collected pre-dose and at 1.5 hours 
post-dose. PK samples will not be collected if the subject has an early termination visit. 
p. 
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. 
q. 
Cystatin C will not be required for these visits. 
r. 
Must occur prior to any trial related procedure; may be acquired prior to Visit 1 (Baseline). 
 
Abbreviations: AE = adverse event; ALS = amyotrophic lateral sclerosis; ALSFRS-R = ALS Functional Rating Scale-Revised; C-SSRS = Columbia-Suicide Severity 
Rating Scale; ECG = electrocardiogram; eCRF = electronic case report form; IMP = investigational medicinal product; PAV = permanent assisted ventilation; 
PK =pharmacokinetics; SAE = serious adverse event; SVC = slow vital capacity; t.i.d. = three times a day. 
 


 
 
 
 
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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 (US) 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 the European Union 
(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, 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 


 
 
 
 
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voltage-dependent sodium channels, and/or ability to interfere with intracellular events that 
follow transmitter binding at excitatory amino acid receptors. 
Riluzole has since been approved as a 5 mg/mL oral suspension (Teglutik®, Tiglutik®) with a 
recommended dose of 100 mg 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 in more than 20 years. Edaravone is 
thought to act as a free-radical scavenger which prevents oxidative stress damage to neurones. Itis 
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 the 
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 superoxide 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) deoxyribonucleic acid (DNA) binding protein 43 (TDP-43) in 
cytoplasmic inclusions in affected areas of the central nervous system (CNS) (8). 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 (8), and is involved in regulation of RNA splicing 
and modulation of microRNA biogenesis (9). TDP-43 plays an important role in neuronal 
plasticity by regulating protein synthesis in dendrites (10), and mutated and misfolded forms are 
prone to toxic fibrillization in stress granules (9). 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 (11). 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 (12). Thus, augmentation of the heat shock response might 


 
 
 
 
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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 13). 
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.  
Strengths of arimoclomol are presented throughout this document by weight of the citrate salt. 
2.3 
Experience with Arimoclomol 
2.3.1 
Nonclinical Experience 
In valosin-containing protein transgenic mice, which have prominent TDP-43 pathology in motor 
neurons and motor neuron loss similar to the pathology associated with human ALS, 
arimoclomol citrate treatment at exposures corresponding to 1200 mg/day in humans was 
associated with upregulation of heat shock protein-70 in neurons (demonstrating target 
engagement), correction of TDP-43 pathology, and preservation of large motor neurons in the 
spinal cord, indicating a treatment effect on the hallmark pathology of ALS (unpublished data).   
Nonclinical safety studies support chronic dosing of arimoclomol citrate 1200 mg/day 
(2 × 200 mg three times a day [t.i.d.]). A package of nonclinical studies has been performed to 
evaluate the safety of arimoclomol. See the current version of the Investigator’s Brochure (IB) for 
further information (17). 
2.3.2 
Clinical Experience 
Clinical experience with arimoclomol in ALS originates from seven Phase 1 trials in healthy 
subjects and 2 Phase 2a trials (trial AALS-01 [14] and trial AALS-01 OL [15]) in patients with 
ALS. Moreover, one investigator-led Phase 2 trial has been conducted in ALS patients with 
pathogenic SOD1 mutations (16). 
In addition, 50 patients with Niemann-Pick disease type C (NPC) have also been exposed to 
arimoclomol (CT-ORZY-NPC-002). 
The Phase 1 trials were conducted in healthy subjects for evaluation of single-dose, 
multiple-doses, food effects, absorption, distribution, metabolism and elimination, as well as 
renal safety. A total of 106 healthy subjects were exposed to arimoclomol and 24 received 
placebo in these trials. Arimoclomol was safe and well-tolerated in all trials. 
Based on data from the clinical pharmacology trials in healthy subjects and from clinical trials in 
ALS (AALS-001) and NPC patients (CT-ORZY-NPC-002), arimoclomol may lead to an increase 
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function or renal haemodynamics. This suggests an inhibitory effect of arimoclomol on tubular 
secretion of creatinine and is supported by the finding that arimoclomol is an inhibitor of organic 
cation transporter 2 (OCT-2) and the multidrug and toxin extrusion (MATE) transporters 
responsible for creatinine secretion in the kidneys.  
One elderly patient with inclusion body myositis experienced severe tubulointerstitial nephritis 
with acute tubular injury and acute tubular necrosis approximately 1 month after initiation of 
arimoclomol. The patient had autoimmune disease (Sjögren’s syndrome) and was treated with 
omeprazole, both of which may have contributed to the event. The investigator judged this event 
to be probably related to the investigational medicinal product (IMP) and Orphazyme considered 
the causality to be possibly related. See the current version of the IB for further information (17). 
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 
(14).  
A total of 62 subjects with ALS received arimoclomol citrate 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 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.  
In the open-label extension (OLE) to this trial (15), 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 citrate 300 mg/day (100 mg t.i.d.) for up to 
6 months. Arimoclomol citrate 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 OLE 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 (VC), body weight or body 
mass index. 
In the investigator-led randomised, double-blinded, placebo-controlled clinical trial, ALS patients 
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arimoclomol (17 patients) or placebo t.i.d. (19 patients) for 12 months (16). The patients 
randomised to arimoclomol citrate 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) (27). 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 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. 
For further information on experience with arimoclomol, see the current edition of the IB (17). 
2.4 
Trial Rationale 
2.4.1 
Justification for Trial Design 
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 to the recommendations of the FDA draft guidance 
document for industry (18) and the European Medicines Agency (EMA) guideline on clinical 
investigation of medicinal products for the treatment of ALS (19). 
This trial will evaluate the safety and efficacy of long-term treatment of 1200 mg/day 
arimoclomol citrate (400 mg t.i.d.) in those subjects who have completed the double-blind 
ORARIALS-01 trial (i.e., the subject has met the survival endpoint of either tracheostomy or 
permanent assisted ventilation (PAV) or the subject as completed 76 weeks of randomised 
treatment). The clinical safety assessments included in the present trial (safety assessment type, 
frequency of assessment, schedule of assessment from first exposure) have been selected 
considering that there is the possibility for subjects to be transitioning from placebo in 
ORARIALS-01 to first exposure to arimoclomol.  
2.4.2 
Justification for Selected Dose  
The dose of arimoclomol citrate selected for ORARIALS-01 is 1200 mg/day (400 mg t.i.d.). 
Since the present trial is designed as an open-label extension the same dose will be applicable to 
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Subjects who have dose de-escalated to 600mg/day (200 mg t.i.d.) in the ORARIALS-01 and are 
transitioning into this extension protocol should remain on the deescalated dose throughout the 
present trial.  
Dose de-escalation will not be utilised in the present trial. 
2.4.3 
Justification for Endpoints 
The proposed primary endpoint in the present trial is the safety of long-term arimoclomol use for 
up to 76 weeks (and for up to 152 weeks for patients previously treated with arimoclomol and 
completing ORARIALS-01). AEs as well as changes in vital signs, CSSRS, and clinical safety 
laboratory tests will be evaluated.  
The secondary endpoints evaluate the efficacy of long-term arimoclomol use for up to 76 weeks: 
 Permanently Assisted Ventilation- and Tracheostomy-free Survival: 
In accordance with the completed SOD1-ALS Phase 2 trial (16) this endpoint is defined as 
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. 
• For subjects that have completed the 76 weeks randomized treatment period in the 
ORARIALS-01 trial, all of the survival endpoints; PAV, tracheostomy or death may be 
recorded as the survival outcome which will be used as the endpoint for the secondary 
objective of survival. 
• For subjects who meet one of the surrogate survival endpoints (tracheostomy or PAV) 
during the ORARIALS-02 trial, the subject may continue in the trial and time to event for 
death will also be recorded (as applicable). 
• For subjects having met one of the surrogate survival end-points during the ORARIALS-
01 trial, time to event for death will be recorded however the subjects will not contribute 
to the secondary objective of survival. 
 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 (20,21,22,23) The functional decline averages about 1 point per month in 
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 Decline of Respiratory Function, as Quantified by Change from Baseline on the 
Slow Vital Capacity as Percentage of Predicted: 
Vital capacity has been most thoroughly studied and has been shown to decline by about 3% per 
month throughout much of the disease course (25). 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 (26) 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 VC can be impacted by treatments. 
The slow vital capacity (SVC) is a valid and robust measurement of the pulmonary function and 
is highly correlated with survival. 
2.4.4 
Benefit-Risk 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 (AALS-001-OL) 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. The 
current benefit-risk ratio is favourable and supports the administration of arimoclomol for the 
purposes of achieving the objectives of this trial. 


 
 
 
 
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2.5 
Ethical Considerations 
Subjects will only be enrolled in this trial if they provide written informed consent. This trial is 
open to subjects that have completed the 76 weeks randomised treatment period or who met one 
of the surrogate survival end-points (tracheostomy or PAV) in the ORARIALS-01 trial.  
The open label design was chosen as it was considered most ethical to allow active therapy for all 
patients. Although the results of ORARIALS-01 will not be known at the start of the open label 
trial, the open label approach is in line with the Declaration of Helsinki, stating that “sponsors, 
researchers and host country governments should make provisions for post-trial access for all 
participants who still need an intervention identified as beneficial in the trial.” 
No paediatric patients or other vulnerable subject’s or women who are pregnant, breastfeeding, or 
trying to become pregnant will 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 foetuses are exposed to the IMP. 
Since ALS is a rapidly progressing neurological condition, and subjects may be up to 36 months 
from first symptom onset (signs of weakness) due to their involvement in ORARIALS-01 trial, it 
is possible that some subjects may be incapable of providing informed consent at the point of 
entry to the present trial (i.e., the trial subject may have significantly declined, including signs of 
fronto-temporal dementia, to a legal status of an incapacitated adult). Other subjects that are 
competent at the time of trial entry may also face significant decline. 
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. 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. Where permitted, a legal representative will be nominated by 
the time of the Baseline visit to ensure that this occurs while the subject is competent. 
Additionally, this individual will give consent to be contacted during the conduct of the trial, 
should contact with the subject become challenged. 
As a further consequence of the progressing condition of the disease, some subjects may be 
incapable of attending the clinic for the eligibility screening and informed consent acquisition. It 
is considered unethical to deny subjects fulfilling the eligibility criteria access to arimoclomol 
solely based on their inability to be transported to the clinic. Therefore, the possibility of having 
the eligibility screening and informed consent acquisition performed by appropriate trial site staff 
remotely is allowed (if permitted by local regulations). 


 
 
 
 
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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 to ensure subject safety. 
In conclusion, the trial design chosen for this safety and efficacy trial on arimoclomol is regarded 
as ethically justified and adherent with ethical requirements. 


 
 
 
 
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3 
OBJECTIVES AND ENDPOINTS 
Table 3-1: Objectives and Endpoints 
Objectives 
Endpoints 
Primary objective 
Primary endpoint 
To assess the long-term safety of 
arimoclomol treatment of ALS. 
• 
Incidence and severity of TEAEs over a treatment period 
of 76 weeks 
• 
Mean and change from Baseline (of the present trial) to 
Week 76 (or end of trial) in clinical safety laboratory 
tests and vital signs 
• 
Incidence of potentially clinically significant 
abnormalities in clinical safety laboratory tests and vital 
signs over a treatment period of 76 weeks 
• 
C-SSRS over a treatment period of 76 weeks 
 
Secondary objectives 
Secondary endpoints 
To evaluate the long-term efficacy of 
arimoclomol treatment of ALS. 
• 
Time to PAV/tracheostomy/death (for subjects entering 
this trial having completed 76 weeks of randomised 
treatment in ORARIALS-01) 
• 
Change in ALSFRS-R from Baseline (of the present  
trial) to the end of the trial 
• 
Change in SVC from Baseline (of the present trial) to the 
end of the trial (for subjects who did not meet the 
survival endpoint in the ORARIALS-01 trial) 
 
Exploratory objectives 
Exploratory endpoints 
Health-Related Quality of Life 
To evaluate the effect of arimoclomol on 
health-related quality of life 
• 
EQ-5D-5L over a treatment period of 76 weeks 
 
Pharmacokinetics (will be reported separately from the main Clinical Trial Report) 
To investigate plasma levels of 
arimoclomol following administration of 
1200 mg/day arimoclomol citrate (400 mg 
t.i.d.) 
• 
Plasma concentrations of arimoclomol at weeks 20, 52 
and 76 
 
Abbreviations: ALS = amyotrophic lateral sclerosis; ALSFRS-R = ALS Functional Rating Scale-Revised; 
C-SSRS = Columbia-Suicide Severity Rating Scale; EQ-5D-5L = Euroqol Five-Dimensional, Five-Level 
Descriptive System; PAV = permanent assisted ventilation; SVC = slow vital capacity; 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, non-randomised, open-label, uncontrolled trial to evaluate the safety and 
efficacy of long-term treatment with 1200 mg/day arimoclomol citrate (400 mg t.i.d.) (Figure 
4-1: T). 
Subjects diagnosed with ALS according to the revised El Escorial criteria must have completed 
the double-blinded ORARIALS-01 trial. They will either have met the surrogate survival 
endpoint (tracheostomy or PAV) or they will have completed the 76 weeks randomised treatment 
period. The end-of-treatment visit of the double-blinded ORARIALS-01 trial corresponds to the 
Visit 1 of the OLE trial. All subjects will receive open-label arimoclomol treatment. 
Subjects will attend the investigator site for an in-person visit on a 4-weekly basis for the initial 6 
months of treatment (on Day 1, Weeks 4, 8, 12, 16, 20, 24, 28). Following Week 28, in-person 
visits will be conducted on a 12-weekly basis until Week 76 (i.e., weeks 40, 52, 64 and 76) with  
remote visits (conducted by telephone) every 4 weeks in the intervening period (Table 1-1). All 
visits should be scheduled within the visit window of ± 7 days. 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. 
In the event that a subject is no longer able to attend the trial site, an in-person visit may be 
conducted in the subject’s home/residency. 
Subjects who discontinue treatment will be encouraged to attend all planned visits as per protocol 
after drug discontinuation. Additionally, these subjects will have a remote visit 2 weeks after the 
premature IMP discontinuation. 
Subjects completing this trial may be offered continued treatment with arimoclomol via an early 
access program as permitted by local regulation. Early access programs may vary depending on 
location and include: compassionate use, named patient, expanded access and managed access 
programs. Continued access to treatment will be contingent on the continued favourable benefit-
risk profile of arimoclomol in ALS as assessed by Orphazyme. Access may cease if development 
of arimoclomol in ALS is terminated, if the marketing application is rejected by a Health 
Authority or if the product becomes commercially available. 
 


 
 
 
 
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Figure 4-1: Trial Design 
 


 
 
 
 
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4.1 
Number of Subjects 
The anticipated disposition of subjects is as follows: 
Number of subjects planned to be enrolled: theoretically all 231 subjects in ORARIALS-01 may 
join the trial, however it is estimated that approximately 60% (i.e., 144 subjects) will be available 
for the OLE trial.  
The trial will be conducted at approximately 32 sites in approximately 13 countries in North 
America and Europe. 
4.2 
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 10.3 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. Subject is able to comprehend and is willing to provide written informed consent and is 
capable and willing to comply with trial procedures or in the circumstance that the 
subject is incompetent, informed consent/assent is provided in accordance with local 
regulation and/or procedures. 
2. Subject has completed the ORARIALS-01 trial (i.e., met one of the surrogate survival 
endpoints of tracheostomy or PAV or has completed the 76 weeks randomised treatment 
period). 
3. Subject completed ORARIALS-01 while on treatment, where on treatment is defined as 
having taken the last dose of IMP within 2 weeks of the End of Trial visit (whether at 
week 76 or prior) 
5.3 
Exclusion Criteria 
1. Known or suspected allergy or intolerance to the IMP (arimoclomol or constituents). 
2. Exposure to any other investigational treatment, advanced therapy medicinal product 
(ATMP) or use of any other prohibited concomitant medications (see Section 6.8) 


 
 
 
 
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3. Women who are lactating or pregnant, or men or women unwilling to use a highly 
effective method of birth control if not surgically sterile (defined as bilateral tubal 
ligation, bilateral oophorectomy, or hysterectomy for women; vasectomy for men) for 
female participants until 4 weeks after last dose and for male participants until 3 months 
after last dose. Pre-menopausal women must have a negative pregnancy test prior to 
dosing with trial medication. Acceptable methods of birth control are: 
a. Hormonal methods associated with inhibition of ovulation such as oral, 
implantable, injectable, or transdermal contraceptives for a minimum of 1 full 
cycle (based on the subject’s usual menstrual cycle period) before IMP 
administration. 
b. Total abstinence from sexual intercourse since the last menses before IMP 
administration. (The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical trial and the preferred and usual lifestyle of 
the subject. Periodic abstinence methods [calendar, symptothermal, post-ovulation 
methods] are not acceptable methods of contraception). 
c. Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS). 
4. Any of the following medically significant conditions: 
a. Clinically significant renal or hepatic disease OR clinical laboratory assessment 
(results ≥ 3 times the upper limit of normal [ULN] for aspartate aminotransferase 
and/or alanine aminotransferase, bilirubin ≥ 2 times the ULN, or creatinine 
≥ 1.5 times the ULN). 
b. Any new condition or worsening of existing condition which, in the opinion of the 
investigator would put the subject at undue risk. 
5. Any serious adverse event or moderate/severe adverse event from the ORARIALS-01 
trial which is ongoing at the time of transitioning to ORARIALS-02 and assessed as 
probably related to IMP.  
5.4 
Subject Enrolment Procedure  
Trial participation begins once written informed consent is obtained (see Appendix 10.2.2 for 
details on the informed consent process) and the subject has met the eligibility criteria for joining 
the ORARIALS-02 trial. A subject will retain the identification (ID) number (subject ID assigned 
during ORARIALS-01) and the Baseline evaluations to assess eligibility criteria may begin. The 
subject ID will be used to identify the subject throughout trial participation, if applicable. A 
master log of all consented subjects will be maintained at the trial site.  
The end-of-trial visit in ORARIALS-01 will constitute the Baseline visit in ORARIALS-02.  


 
 
 
 
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5.5 
Discontinuation  
A subject may withdraw from the 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 
Medical reasons for permanent discontinuation of IMP are given in Section 6.4.  
If a subject discontinues treatment they 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 final dose of IMP. 
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 electronic 
case report form (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. 
Subjects meeting the surrogate endpoint of PAV or tracheostomy in the present trial may 
continue on treatment. 
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 
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 will be asked to provide (optional) consent via the informed consent to 
allow follow-up of the survival endpoints (PAV/tracheostomy/death) at the scheduled week 76. 


 
 
 
 
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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 interactive response technology 
(IRT) and provided to the subject (by direct to patient shipment, as required). Subjects will 
coordinate the next scheduled visit according to visit schedule (Table 1-1). 
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 7.1.8) 
• 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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6 
TREATMENTS 
6.1 
Trial Product 
Arimoclomol is considered the IMP. It is formulated into size “0”, white hard capsules for oral 
administration either in whole or sprinkled and dispensed in liquid or food stuff will be 
manufactured and supplied by Orphazyme, Denmark. 
Each trial site will be supplied with sufficient IMP for the trial on an on-going basis as controlled 
via an IRT. The contract manufacturing organisation (CMO) selected for this trial is Catalent 
Pharma Solutions who will control IMP with regards to Good Manufacturing Practice (GMP) and 
release by qualified person. 
The description of IMP is provided in Table 6-1 and the quantification of ingredients in 
Table 6-2. 
Table 6-1: Description of Investigational Medicinal Product 
 
Active treatment 
Name of active ingredient 
Arimoclomol citrate 
Chemical name 
N-[(2R,Z)-2-hydroxy-3-(1-piperidyl)propoxy]pyridine-3-carboximidoyl chloride, 
1-oxide, citrate 
Pharmaceutical form 
Capsule 
Appearance 
White capsule with white to off-white powder 
Strength (calculated as salt) 
200 mg 
Stability 
Stable in original container 
Storage 
Room temperature (15-25°C) in original container 
Shelf-life 
24 months*  
Manufacturer 
Catalent Pharma Solutions 
Batch number(s) 
To be printed on the label 
Expiry date(s) 
To be printed on the label 
* The shelf-life may be extended based on available stability data. 
The capsules are packed in 185 mL high density polyethylene (HDPE) bottles, each containing 
84 capsules. The bottles are heat sealed and closed with an HDPE child-resistant closure. 


 
 
 
 
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Table 6-2: Quantities of Ingredients in Trial Product 
Ingredient 
Function 
Grade 
Content 
(mg/capsule) 
OR 003 (BRX-345) arimoclomol citrate1 
Active 
- 
200.0 
Microcrystalline Cellulose PH102 
Filler 
Ph. Eur./USP-NF 
178.1 
Magnesium stearate 
Lubricant 
Ph. Eur./USP-NF 
1.9 
HPMC capsule shells  
(Size 0, white) 
Coni-Snap sprinkle 
capsules® 
Ph. Eur./USP-NF 
- 
Abbreviations: HPMC = hydroxypropyl methylcellulose; Ph. Eur. = European Pharmacopeia; USP-NF = United 
States Pharmacopeia-National Formulary 
 
Footnote: 
1 In placebo capsules, the active is replaced by 1ppm denatonium benzoate as bitter tasting agent 
6.2 
Administration of Investigational Medicinal Product 
Arimoclomol citrate 2 x 200 mg will be taken orally t.i.d. for up to 76 weeks. If required, the 
capsules can be opened and dispersed in 10-20 mL (i.e., 1-2 tablespoons) of liquid (water or 
apple juice) or in a tablespoon of soft food material (yoghurt or apple puree). Once dispersed in 
water, the IMP can also be administered via a gastric tube (as applicable). For full administration, 
the tube should be flushed with 5 mL of water. 
The method of oral administration (swallowed whole, sprinkled/dispersed into liquid, 
sprinkled/dispersed into food or sprinkled/dispersed in water and fed via gastric tube) will be 
recorded in a subject diary and a summary transcribed into the eCRF. 
The investigator must document that verbal direction for use and the Patient Information Leaflet 
(PIL) is provided on or prior to the first dispensing visit (Day 1). At the later dispensing visits the 
investigator or delegate should ensure that subjects comply with treatment procedure and 
dispersion (see Section 6.2); if needed, additional instruction should be provided, including 
provision of a further copy of the PIL. 
For subjects who received the reduced dose of 600 mg/day (200 mg t.i.d.) in ORARIALS-01, the 
same dose should be administered to the subject in this present trial.  
6.3 
Treatment Assignment 
6.3.1 
Randomisation 
There is no randomisation in this trial as it is an OLE where all subjects will receive active 
therapy of the same IMP-. Subjects will take 1200 mg/day arimoclomol citrate (400 mg t.i.d.) 
throughout the trial regardless of the IMP to which the subject was randomised to in 


 
 
 
 
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ORARIALS-01. Subject that received a deescalated dose in ORARIALS-01 will continue on this 
reduced dose of 600 mg (200 mg t.i.d.) in the present trial. 
6.3.2 
Blinding 
This is an open-label trial; there is no blinding required in this trial since only a single IMP is 
administered to all eligible subjects. 
6.3.3 
Emergency Unblinding of Individual Subject Treatment 
Emergency unblinding provisions are not required for this trial as all subjects will receive open-
label IMP.  
6.4 
IMP Discontinuation  
6.4.1 
Permanent Discontinuation of IMP 
In case of a safety concern or unacceptable intolerability, the IMP must be permanently 
discontinued. In case of pregnancy or intention to become pregnant the trial product must be 
discontinued. 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) (34), 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 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 
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. 


 
 
 
 
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6.4.2 
Temporary Halt of IMP 
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 treatment.  
A temporary halt of IMP treatment can be implemented only once for intolerable AEs within a 
given organ/body system. If the subject experiences a different intolerable AE within a different 
organ/body system, a further temporary halt can be initiated 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 of 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 7.4.9.2. 
The missed doses must be recorded in the eCRF. 
An end-of-treatment visit should not be conducted when a temporary halt of IMP is initiated. 
6.5 
Treatment Logistics and Accountability 
6.5.1 
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) in addition to the bulk batch number. 
The labelling of IMPs will be in accordance with Annex 13 (28), local regulations and trial 
requirements. Label text will be translated into local languages, as required. 


 
 
 
 
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6.5.2 
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 the interactive response technology 
(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. In certain circumstances, excursions between 2°C-30°C may be 
permitted by the Orphazyme Clinical Trial Supply Coordinator based on certificates of analysis 
and stability statements. 
The sponsor will decide if the affected bottles may be released back into the inventory, returned 
to the depot or destroyed locally. 
6.5.3 
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 × 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 dispensed. 
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. The use of such service will receive all required 
permissions prior to being implemented.  


 
 
 
 
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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 with the service provider, which requires sponsor approval. The IMP 
should be dispensed per the schedule of procedures (Table 1-1), 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 
through the chain of custody. The service should be used for reverse logistics to ensure that used 
and unused IMP 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.  
6.5.4 
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 IMP at the trial site and for maintaining 
adequate control of the IMPs and for documenting all transactions with them. 
The IRT will allocate IMP bottle codes from the site level inventory to a subject at each 
dispensing transaction (each in person visit).  
The investigator or delegated person is responsible for ensuring that: 
• 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 in-person 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. 
6.5.5 
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.  


 
 
 
 
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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. 
6.6 
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. 
6.7 
Concomitant Medication 
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: 
• Trade name or generic name 
• Reason for use (indication) 
• Dates of administration including start and stop dates 
• Dosage information including dose, route and frequency 
All concomitant medications that are ongoing at the time of transitioning from the 
ORARIALS-01 trial to the present trial will be duplicated into the eCRF of ORARIALS-02. 
Investigators may prescribe concomitant medications or treatments to provide adequate 
supportive care as deemed necessary, except for medications listed in Section 6.8. 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, multidrug and toxin extrusion (MATE)-1, and 
MATE-2K transporters and consequently may inhibit the elimination of cationic drugs that are 
significantly eliminated by tubular secretion. In addition, arimoclomol is an in vitro substrate of 
the MATE-1 and MATE-2K transporters. Arimoclomol undergoes renal tubular secretion and 
concomitant treatment with drugs that are MATE1 or MATE-2K inhibitors may therefore lead to 
increased exposure of arimoclomol. Consequently, the concomitant use of cationic drugs that are 
significantly eliminated by tubular secretion as well as drugs which are MATE1 or MATE-2K 
inhibitors should be administered with caution. These include but are not limited to: amantadine, 


 
 
 
 
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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 (35). 
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. 
Nuedexta® (or compounded equivalent) 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 corrected QT (QTc) 
interval in a dose-dependent matter (less than moxifloxacin); hence, concomitant therapy with 
medications that prolong the QT interval and are metabolized by CYP2D6 should be used with 
caution.  
Animal studies have indicated a possible pharmacodynamic interaction between arimoclomol and 
furosemide resulting in increased urinary volume and increased urinary creatinine, potassium, 
sodium, phosphorus and calcium (additive effect) at high doses. Consequently, concomitant 
treatment with furosemide should be used with caution.  
The following concomitant medications related to ALS treatment are permitted if used during 
participation in the ORARIALS-01 trial: 
• Stable dose of riluzole (50 mg twice daily). 
• Stable dose of edaravone. 


 
 
 
 
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• Other medication or treatments that are deemed necessary to provide adequate supportive 
care. 
The use of non-invasive ventilation is permitted at any time during the trial. 
Concomitant medication and non-invasive ventilation will be recorded in the subject diary in the 
interval between trial visits. 
6.8 
Prohibited Medication and Procedures 
The following medications are prohibited during the trial from the Baseline visit until the end of 
the trial: 
• Commencement of treatment with edaravone  
• Commencement of riluzole treatment. Adjustment of riluzole dose, including temporary 
halt due to tolerability may be permitted at the investigator’s discretion. 
• Other investigational treatments or ATMP. 
Diaphragmatic pacemakers are not permitted for the duration of the trial. 
The appointed medical monitor must be notified if a subject receives any of these therapies 
during the trial.  
6.9 
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.  


 
 
 
 
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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 assessments 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. 
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, ECG, physical 
examination, 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 any Baseline tests must be 
dated and signed to confirm subject’s eligibility prior to the dispensing of IMP. 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 7.4.4. 
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 with 


 
 
 
 
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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, 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. 
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 operational rater training 
plans) will be delivered to qualified site staff. Certification on designated scales and management 
of rater training will be provided by the Clinical Assessment Technologies group of Worldwide 
Clinical Trials following the adequate completion of the training program. 
For scales in which 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. 
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. 


 
 
 
 
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7.1.4 
Subject Instruction 
 Investigational Medical Product 
IMP must be dispensed to subjects at the specified visits (see Table 1-1). IMP will be dispensed 
to the subject by the site, hospital pharmacy or equivalent. Subjects will be instructed in the 
handling and administration of IMP prior to or at the Baseline visit (Section 6.2). 
 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 1-1). The investigator or delegate should instruct the subjects on how to complete the diary 
and provide ongoing instruction as necessitated by data quality. The diaries dispensed to subjects 
should be collected at the specified visits (see Table 1-1) and data used to complete the eCRF. 
 Patient-Reported Outcomes 
Site staff who have undergone training will instruct subjects on the completion of questionnaires, 
measurements and assessments as described in Section 7.1.3.  
7.1.5 
Sequence of Assessments 
Assessments should be conducted in a sequence which allows for best clinical practice and 
subject experience while also ensuring protocol compliance. 
Sequence of scale assessments: 
1. ALSFRS-R 
2. EuroQol Five-Dimensional, Five-Level Descriptive System (EQ-5D-5L) 
3. 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 timepoint. 
7.1.7 
Transitioning of Subjects from ORARIALS-01 to ORARIALS-02 
The end of trial visit (Visit 21) of ORARIALS-01 will be performed for all subjects completing 
the ORARIALS-01 trial (i.e., met one of the surrogate survival endpoints of tracheostomy or 


 
 
 
 
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PAV or has completed the 76 weeks randomised treatment period). For subjects withdrawn from 
the trial prematurely, the investigator should conduct the last in-person visit as per the end of trial 
visit. 
The end of trial visit (Visit 21) of ORARIALS-01 and Baseline visit (Visit 1) of ORARIALS-01 
must be conducted on the same day.  
Assessments which are made as part of ORARIALS-01 Screening Visit (Visit 1) or End of Trial 
Visit (Visit 21) will not be repeated for this trial and will be duplicated into the clinical database 
of ORARIALS-02. 
7.1.8 
Subject Assessment When Unable to Travel to the Trial Site 
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), a sub-set of clinical assessments as listed below in Table 7-1: will 
be conducted, in accordance with Table 1-1, 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 arranged by the contract research organisation (CRO), as applicable. 


 
 
 
 
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Table 7-1: Clinical Assessments for when an in-person visit is conducted at the subject’s 
home/residency 
Day 1 (Baseline) 
Telephone call 
In-Person at Subject’s home/residency 
Conducted by investigator and rater 
Conducted by trial site staff or via contract nursing services 
• 
Informed Consent 
• 
Inclusion/Exclusion Criteria 
• 
AEs & concomitant medication (from 
ORARIALS-01) b 
• 
ALSFRS-R (from ORARIALS-01) 
• 
C-SSRS (from ORARIALS-01) 
 
• 
AEs & concomitant medication (from ORARIALS-
01) b 
• 
SVC (from ORARIALS-01) 
• 
Vital signs (from ORARIALS-01) 
• 
Clinical safety laboratory sampling (from 
ORARIALS-01) 
• 
Pregnancy test (urine) (from ORARIALS-01) 
• 
Collection of subject diary (from ORARIALS-01), 
provision of new diary (for ORARIALS-02) 
• 
Confirmation of DtP IMP shipment (as applicable) 
Weeks: 8, 16, 24 
Telephone call 
In-Person at Subject’s home/residency 
Conducted by investigator and rater 
Conducted by trial site staff or via contract nursing services 
• 
AEs  & concomitant medication 
• 
ALSFRS-R 
• 
C-SSRS 
 
• 
AEs & concomitant medication a 
• 
Clinical safety laboratory sampling 
 
All other weeks 
Telephone call 
In-Person at Subject’s home/residency 
Conducted by investigator and rater 
Conducted by trial site staff or via contract nursing services 
• 
AEs & concomitant medication 
• 
ALSFRS-R 
• 
C-SSRS 
 
• 
AEs & concomitant medication a 
• 
SVC 
• 
Vital signs 
• 
Clinical safety laboratory sampling 
• 
Pregnancy test (urine) 
• 
Collection of subject diary, provision of new diary 
• 
Confirmation of DtP IMP shipment (as applicable) 
a) Information about potential AEs noticed during a home visit must be provided to the investigator within 
24 hours.  
b) At the Visit 1 (Baseline), AEs and concomitant medication must be assessed by an Investigator as part of 
the eligibility review. Any AEs noted by the home nurse must be reported to the Investigator immediately to 
assist with their eligibility review. 
 
Abbreviations: AE = adverse events; ALSFRS-R = ALS Functional Rating Scale-Revised; C-SSRS = Columbia-
Suicide Severity Rating Scale; DtP = direct to patient; IMP = investigational medicinal product; SVC = slow 
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7.2 
Baseline Characteristics 
Demographic data (i.e., age, sex, race [according to local regulation], and ethnic origin 
[according to local regulation]), medical history, and ALS characteristics will be recorded as part 
of the ORARIALS-01 trial and will be duplicated into the database for ORARIALS-02 trial.  
The respiratory rate (breaths per minute) will be determined by manual visualisation and count as 
scheduled in Table 1-1. 
7.3 
Efficacy Assessments 
7.3.1 
Survival (permanent assisted ventilation/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 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.  
The following principles are applicable to survival reporting in this present trial: 
• For subjects that have completed the 76 weeks randomized treatment period in the 
ORARIALS-01 trial, all of the survival endpoints; PAV, tracheostomy or death may be 
recorded as the survival outcome which will be used as the endpoint for the secondary 
objective of survival 
• For subjects who meet one of the surrogate survival endpoints (tracheostomy or PAV) 
during the ORARIALS-02 trial, the subject may continue in the trial and time to event for 
death will also be recorded (as applicable). 
• For subjects having met one of the surrogate survival end-points during the ORARIALS-
01 trial, time to event for death will be recorded however the subjects will not contribute 
to the secondary objective of survival. 
7.3.2 
ALS Functional Rating Scale – Revised 
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’, 
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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 1-1.  
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 
subject 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 
Slow vital capacity 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 CTTM spirometer as scheduled in Table 1-1. SVC analysis will include SVC, 
predicted SVC and percentage 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.  
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 (29). Data 
will be subject to centralised analysis by spirometry experts. 
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 


 
 
 
 
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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 
EuroQoL Five-Dimensional, Five-Level Descriptive System  
The EQ-5D5L will be used for exploratory assessments of the subject’s health-related quality of 
life (HRQoL). The EQ-5D-5L consists of 2 sections; the EQ-5D descriptive system and the 
health scale, an adaptation of the EQ Visual Analogue Scale. 
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. 
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. 


 
 
 
 
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7.4 
Safety Assessments 
7.4.1 
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 1-1 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 Baseline 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 7.4.6). 
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 subject’s home/residency. 
7.4.2 
Vital Signs 
Vital signs (resting blood pressure, pulse, and body temperature) must be assessed as scheduled 
in Table 1-1. 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 rest.  
Any clinically significant changes observed during the trial are to be recorded as AEs (see 
Section 7.4.6). 
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 centralised contract nursing service may instead perform this assessment at an in-
person visit at the subject’s home/residency. 
7.4.3 
Body Weight 
The body weight will be measured as scheduled in Table 1-1, and only when feasible. 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 visits, this assessment will 
not be performed. 


 
 
 
 
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7.4.4 
Electrocardiogram – 12-lead 
12-lead ECGs will be performed as scheduled in Table 1-1 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 Baseline 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. In this situation, the Investigator should review 
AEs and vital signs with particular attention to clinical signs related to conduction disorders to 
allow for appropriate follow-up, and to ensure that the subject is safe to continue trial 
participation. 
7.4.5 
Columbia-Suicide Severity Rating Scale 
The C-SSRS is a detailed questionnaire assessing both suicidal behaviour and suicidal ideation 
through a series of simple, plain-language questions (30). The questionnaire will be administered 
as an interview by the investigator or a qualified delegate according to the schedule of procedures 
(Table 1-1). All results from the questionnaire must be transcribed into the eCRF. 
The ‘since last visit’ version will be used throughout the trial. 
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 over the telephone. 


 
 
 
 
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7.4.6 
Adverse Events 
 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. (2). 
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.  
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 AE meets the definition of an SAE, a conservative 
viewpoint must be taken, and the AE must be reported as an SAE. 


 
 
 
 
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 Collection of Adverse Events 
AEs will be collected from the completion of the ORARIALS-01 trial until the end of trial visit. 
Any SAEs reported to the investigator after the end of trial shall be reported if they are 
considered at least possibly related to arimoclomol. 
Adverse events should be obtained through observation of the subject, from any information 
volunteered by the subject and through asking non-leading questions such as “How have you 
been doing since your last visit?”  
Adverse events (including pre-treatment AEs) must be recorded in the eCRF. The investigator 
must provide information on the AE, 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 AE is not related to the IMP, an alternative aetiology must be 
recorded, if available.  
If the AE is serious, this must be indicated on the Adverse Event Form. Furthermore, the 
investigator must fill out a Serious Adverse Event Form and report the SAE to the Safety vendor 
immediately (within 24 hours) after becoming aware of it (see Section 7.4.6.6). 
If individual AEs 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. 
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.  


 
 
 
 
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Recovered/ 
resolved 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. 
All AEs that are ongoing at the time of transitioning from the ORARIALS-01 trial to the present 
trial will be duplicated into the eCRF of ORARIALS-02. 
 Disease Progression 
Disease progression can be considered as a worsening of a subject’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). 
 Death 
All deaths that occur during the AE reporting period must be reported. 
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. 
 Follow-Up for Final Outcome of Adverse Events 
The investigator should follow up for final outcome on all AEs until resolution or the 
end-of-treatment 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.  


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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 medical records before 
submission. 
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 (see contact details above) 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. 


 
 
 
 
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Orphazyme is also responsible for reporting to the IRB(s)/IEC(s) that require unblinded 
reporting. 
 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 Form and Pregnancy Follow Up Form must be faxed or scanned and 
e-mailed to the Safety vendor. Please refer to the SAE Reporting Contact Details document.  
 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.  
 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.” (31). 
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. 
7.4.7 
Pregnancy Test 
A urine pregnancy test (human chorionic gonadotropin [hCG]) must be performed at the trial site 
at Baseline prior to dispensing OLE IMP to female subjects of child-bearing potential. The test 
must be repeated during the trial as scheduled in Table 1-1. In addition, urine pregnancy tests 


 
 
 
 
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must be performed at home for females of child-bearing 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 6.4.1) and the pregnancy 
report must be expedited in accordance with Section 7.4.6.7. 
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 centralised contract nursing service may instead perform this assessment at an in-
person visit at the subject’s home/residency. 
7.4.8 
Clinical Safety Laboratory Assessments 
 Central laboratory 
The clinical safety laboratory parameters (chemistry and haematology) analysed by a central 
laboratory are presented in Table 7-2. Urine samples will be tested at the trial site and the result 
recorded in the eCRF (urinalysis and pregnancy test). 
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 1-1). Clinical safety laboratory tests may be repeated between the end-of-trial visit in 
ORARIALS-01 and the Baseline visit. 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 is noted at the end-of-trial visit in the 
ORARIALS-01 trial and 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 enrolled into the trial (respecting exclusion criterion 4). 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 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. 


 
 
 
 
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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 centralised contract nursing service may instead perform this assessment at an in-
person visit at the subject’s home/residency. 
Table 7-2: Clinical Safety Laboratory Parameters 
Biochemistry 
Haematology 
• 
Creatinine 
• 
Alanine aminotransferase (ALAT) 
• 
Aspartate aminotransferase (ASAT) 
• 
Alkaline phosphatase (ALP) 
• 
Sodium 
• 
Potassium 
• 
Albumin 
• 
Bilirubin (direct, indirect, and total) 
• 
Total protein 
• 
Blood urea nitrogen (BUN) 
• 
Creatine kinase (CK) 
• 
Calcium (total, albumin corrected 
calcium, ionised) 
• 
Cystatin Cb 
• 
Lactate dehydrogenase (LDH) 
• 
Gamma-glutamyltransferase (GGT) 
• 
Glucose 
• 
Low density lipoprotein (LDL) 
• 
High density lipoprotein (HDL) 
• 
Triglycerides 
• 
Cholesterol 
• 
Haemoglobin 
• 
Haematocrit 
• 
Thrombocytes  
• 
Erythrocytes 
• 
Leucocytes 
• 
Differential count (% )(eosinophils, 
neutrophils, basophils, monocytes and 
lymphocytes) 
Urinalysis (dipstick) 
• 
Blood  
• 
Protein  
• 
Glucose 
Urine Pregnancy Test a 
• 
Human chorionic gonadotropin (hCG) 
a Females of child-bearing potential only 
b Not required at visit 3, 5 and 7. 
 Local laboratory 
Local safety laboratory assessments may also occur in case of close monitoring for increased 
transaminases (see Section 7.4.9.2).  
7.4.9 
Follow-up for specific laboratory abnormalities 
 Increased serum creatinine 
Serum creatinine values > 2-3-fold compared to the subject’s baseline value (of the present trial) 
should be further investigated for signs of kidney injury. Estimation of the subject’s glomerular 
filtration rate 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 


 
 
 
 
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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. 
 Increased transaminases 
Transaminases (ASAT, ALAT) > 3 x ULN must be further investigated in line with the FDA 
Guidance on Drug-Induced Liver Injury (34). 
 
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. 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 6.4). 
 
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.  


 
 
 
 
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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 6.4. 
7.5 
Biological Sample Assessments 
7.5.1 
Pharmacokinetics Assessments 
The plasma samples will be analysed for arimoclomol using a bioanalytical method validated in 
accordance with the US FDA Guidance for Industry (32) and EMA Guideline on bioanalytical 
method validation (33). 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 (32). 
The bioanalysis will be performed by Covance (see Appendix 10.2.16.3) 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. 
Blood Samples 
Blood samples will be taken for bioanalysis of concentrations of arimoclomol in plasma at Week 
20, 52 and 76 (see Table 1-1).  
At Week 20 a blood sample will be drawn pre-dose and at 0.5 hours post-dose. At weeks 52 and 
76, 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.  


 
 
 
 
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The first dose of IMP will be administered while at the site to allow for PK assessment on the day 
of the weeks 20, 52 and 76 site visits. 
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. 
7.5.2 
Biorepository 
If consent is given by the subject, Orphazyme will submit samples of biological fluids to a 
biorepository for long-term storage to allow for future testing of disease-specific biomarkers. The 
location of the biorepository is detailed in Appendix 10.2.16.3. 
The samples will be used for future research approved by Orphazyme. Donation of the samples 
for future research is voluntary and subjects must give their written consent to expressly confirm 
donation and storage and the terms associated herewith. The samples will be transferred from the 
central laboratory to the biorepository at the end of the trial. The samples will be labelled with the 
trial ID, subject ID, and the sample date to protect the privacy of the subjects and to allow 
continued blinding for future analyses. The samples from this trial will be stored for up to 
15 years after the end of the trial and will then be destroyed. 
Samples will only be submitted to the biorepository where all required permissions are granted 
and in accordance with local regulation or law. 
Samples will be collected in accordance the schedule of procedures (see Table 1-1). Residual 
blood and urine from clinical safety laboratory sampling will also be submitted to the 
biorepository. 
If a subject is no longer able to travel to the site to attend the in-person visits, sample collection 
with the specific purpose of submission to the biorepository will not be drawn in the subject’s 
home/residency (i.e., residual volume from clinical safety laboratory assessment may continue to 
be submitted to the biorepository). 
7.5.3 
Estimate of Total Blood Volume Collected 
Blood samples will be drawn for analysis of safety (chemistry, haematology, pregnancy test). The 
total volume of blood drawn for a subject competing all trial visits and procedures will not 
exceed 250 mL, which is less than the volume of blood drawn during a blood donation 
(approximately 500 mL). The maximum blood volume drawn on a single occasion will not 
exceed 30 mL. 


 
 
 
 
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7.5.4 
Destruction of Biological Material 
All biological material will be retained until the results have been reported. The material will 
subsequently be destroyed by the responsible laboratory. 
7.6 
Home Visit / Contract Nursing Service 
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 
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 
A maximum of 231 subjects are planned to be enrolled. However, it is estimated that 
approximately 60% (i.e., 144 subjects) will be available for the OLE from ORARIALS-01. As 
this trial is an OLE planning to include subjects from the previous trial, no calculation for sample 
size was performed.  
8.2 
Trial Analysis Sets 
Safety analyses will be performed on the safety population which consists of subjects receiving at 
least one dose of arimoclomol in the OLE trial. 
Efficacy analyses will be performed on subjects receiving at least one dose of IMP in the in the 
OLE trial, with a Baseline (of the present trial) and at least one post-baseline value of ALSFRS-R 
and SVC if applicable. 
8.3 
Statistical Analysis 
8.3.1 
Disposition of Subjects 
Trial completion status and reasons for discontinuation will be summarised with frequencies and 
percentages. 
8.3.2 
Demographics and Other Baseline Characteristics 
Continuous demographic and baseline parameters will be summarised by the number of 
non-missing observations, mean, standard error, median, minimum, and maximum. Categorical 
parameters will be summarised by frequencies and percentages. 


 
 
 
 
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8.3.3 
Exposure and Treatment Compliance 
 Exposure 
Treatment exposure will be summarised by mean number of days exposed, mean daily dose, and 
standard errors. 
 Treatment Compliance 
Compliance data will be summarised for each subject by overall and by trial visit.  
8.3.4 
Analysis of Efficacy 
As secondary objectives of the trial, efficacy variables will be explored through descriptive 
statistics at each scheduled visit of the current trial. Formal statistical testing is not planned, and 
alpha adjustments not needed. When applicable, 95% confidence intervals (CIs) will be provided 
for absolute and percent changes from Baseline (of the present trial). 
8.3.5 
Analysis of Safety 
 Adverse Events 
AEs will be coded by system organ class and preferred term from the current version of Medical 
Dictionary for Regulatory Activities. 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, and AEs causing premature treatment discontinuation will be listed 
by subject. 
 Other Safety Parameters 
Safety analysis (AEs, laboratory, and vital signs) will be descriptive, based on the safety 
population. The safety analysis will focus on the TEAEs period defined as the time from the first 
dose of the current trial to the last dose of arimoclomol + 2 weeks. 
For analyses of changes from Baseline for laboratory and vital signs parameters, Baseline of the 
present trial will be used. 
The incidence of potentially clinically significant abnormal values for vital signs and safety 
laboratory values will be summarised. 
The C-SSRS will be summarised at each visit and overall using descriptive statistics. 


 
 
 
 
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8.3.6 
Exploratory Analysis 
 Health-related Quality of Life 
The EQ-5D-5L will be summarised at each visit using descriptive statistics.  
 Pharmacokinetics 
Plasma concentrations of arimoclomol will be listed. The pharmacokinetic results will be used for 
population PK analyses and reported separately. 
8.3.7 
General Principles 
Summary statistics will be done by various sub-groups and overall. Sub-groups will include the 
randomized treatment group from the ORARIALS-01, subjects on edaravone, and other entry 
criteria sub-groups. 
No formal hypothesis testing will be done. When applicable, unless otherwise stated, all 
significance tests will be two-sided using the 5% significance level. All 95 % 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. 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 prior to enrolment of the first subject 
under this protocol.  
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 
Missing data will not be imputed. All summaries will be based on observed data. 


 
 
 
 
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9 
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33. European Medicines Agency (EMA). Committee for Medicinal Products for Human Use 
(CHMP). Guideline on Bioanalytical Method Validation. 
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10 APPENDICES 
10.1 
Protocol Summary 
Title 
Arimoclomol in ALS – Open-Label Extension Trial 
 
Open-label, Non-randomised Extension Trial to Assess the 
Long-Term Safety and Efficacy of 1200 mg/day Arimoclomol 
citrate 400 mg Three Times a Day (t.i.d.) in Subjects with 
Amyotrophic Lateral Sclerosis (ALS) who have Completed the 
ORARIALS-01 Trial 
 
ICI 
, MD, PhD 
 
Phase 
3b 
 
Indication 
ALS 
 
Design 
This is a multicentre, non-randomised, open-label, uncontrolled, 
trial to evaluate the safety and efficacy of long-term treatment of 
1200 mg/day arimoclomol citrate (400 mg t.i.d.).  
 
Subjects diagnosed with ALS according to the revised 
EL Escorial criteria must have completed the double-blind 
ORARIALS-01 trial. They will either have met the survival 
endpoint (tracheostomy or PAV) or they will have completed the 
76 weeks randomised treatment period. The end-of-treatment 
visit of the double-blinded ORARIALS-01 trial corresponds to 
the Visit 1 of the OLE trial. All subjects will receive open-label 
arimoclomol treatment. 
 
Treatment Period 
Subjects will attend the investigator site for an in-person visit on 
a 4-weekly basis for the initial 6 months of treatment (on Day 1, 
Weeks 4, 8, 12, 16, 20, 24, 28). Following Week 28, in-person 
visits will be conducted on a 12-weekly basis until Week 76 (i.e., 
weeks 40, 52, 64 and 76). Throughout the treatment period 
subjects will also have remote visits (conducted by telephone) 
every 4 weeks (Table 1-1). All visits should be scheduled within 
the visit window of ± 7 days. 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. 
 


 
 
 
 
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In the event that a subject is no longer able to attend the trial site, 
an in-person visit may be conducted in the subject’s 
home/residency.  
 
Safety Follow Up 
Subjects who discontinue treatment will be encouraged to attend 
all planned visits as per protocol after drug discontinuation. 
Additionally, these subjects will have a remote (telephone) visit 
2 weeks after the premature IMP discontinuation. 
 
End of Trial 
All subjects will attend an end of trial visit. 
 
IMP 
Two arimoclomol capsules of 200 mg t.i.d. (1200 mg/day) will 
be taken orally. 
 
Primary objective 
To assess the long-term safety of arimoclomol treatment of ALS. 
 
Primary endpoints 
• Incidence and severity of TEAEs over a treatment period 
of 76 weeks 
• Mean and change from Baseline (of the present trial) to 
Week 76 (or end of trial) in clinical safety laboratory tests 
and vital signs 
• Incidence of potentially clinically significant 
abnormalities in clinical safety laboratory tests and vital 
signs over a treatment period of 76 weeks 
• 
C-SSRS over a treatment period of 76 weeks 
Secondary 
objective 
To evaluate the long-term efficacy of arimoclomol treatment of 
ALS. 
Secondary 
endpoints 
• Time to PAV/tracheostomy/death (for subjects entering 
this trial having completed 76 weeks of randomised 
treatment in ORARIALS-01) 
• Change in ALSFRS-R from Baseline (of the present trial) 
to the end of the trial 
• 
Change in SVC from Baseline (of the present trial) to the 
end of the trial (for subjects who did not meet the survival 
endpoint in the ORARIALS-01 trial) 
Exploratory 
objectives 
Health-related quality of life 


 
 
 
 
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• To evaluate the effect of arimoclomol on health-related 
quality of life. 
Population pharmacokinetics 
• 
To investigate plasma levels of arimoclomol following 
administration of 1200 mg/day arimoclomol citrate 
(400 mg t.i.d.) 
Exploratory 
endpoints 
Health-related quality of life 
• EQ-5D-5L over a treatment period of 76 weeks 
Population pharmacokinetics 
• 
Plasma concentrations of arimoclomol at weeks 20, 52 and 
76 
Sample size 
Theoretically all 231 subjects from ORARIALS-01 trial may 
join the ORARIALS-02 trial, however it is estimated that 
approximately 60% (i.e., 144 subjects) will be available for 
ORARIALS-02. 
 
Within the total number of subjects to participate in 
ORARIALS-02, up to 18 subjects could be on a stable dose of 
edaravone if they had been using edaravone in ORARIALS-01. 
Statistical methods Primary Analysis 
AEs will be coded by system organ class and preferred term 
from the current version of Medical Dictionary for Regulatory 
Activities. 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, and AEs causing premature 
treatment discontinuation will be listed by subject. 
 
Analysis for other safety parameters (AEs, laboratory, and vital 
signs) will be descriptive, based on the safety population. The 
safety analysis will focus on the TEAEs period defined as the 
time from the first dose of the current trial to the last dose of 
arimoclomol + 2 weeks. 
 
For analyses of changes from Baseline for laboratory and vital 
signs parameters, Baseline of the present trial will be used. 


 
 
 
 
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The incidence of potentially clinically significant abnormal 
values for vital signs and safety laboratory values will be 
summarised. 
 
The C-SSRS will be summarised at each visit and overall using 
descriptive statistics. 
 
Secondary analysis 
As secondary objectives of the trial, efficacy variables will be 
explored through descriptive statistics at each scheduled visit of 
the current trial. Formal statistical testing is not planned, and 
alpha adjustments not needed. When applicable, 95% 
confidence intervals (CIs) will be provided for absolute and 
percent changes from Baseline. 
 
Eligibility criteria 
Inclusion Criteria 
1. Subject is able to comprehend and is willing to provide 
written informed consent and is capable and willing to 
comply with trial procedures or in the circumstance that 
the subject is incompetent, informed consent/assent is 
provided in accordance with local regulation and/or 
procedures. 
2. Subject has completed the ORARIALS-01 trial (i.e., met 
one of the surrogate survival endpoints of tracheostomy 
or PAV or has completed the 76 weeks randomised 
treatment period). 
3. Subject completed ORARIALS-01 while on treatment, 
where on treatment is defined as having taken the last dose 
of IMP within 2 weeks of the End of Trial visit (whether at 
week 76 or prior). 
Exclusion Criteria 
1. Known or suspected allergy or intolerance to the IMP 
(arimoclomol or constituents). 
2. Exposure to any other investigational treatment, advanced 
therapy medicinal product (ATMP) or use of any other 
prohibited concomitant medications (see Section 6.8) 
3. Women who are lactating or pregnant, or men or women 
unwilling to use a highly effective method of birth control 
if not surgically sterile (defined as bilateral tubal ligation, 
bilateral oophorectomy, or hysterectomy for women; 
vasectomy for men) for female participants until 4 weeks 
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after last dose. Pre-menopausal women must have a 
negative pregnancy test prior to dosing with trial 
medication. Acceptable methods of birth control are: 
a. Hormonal methods associated with inhibition of 
ovulation such as oral, implantable, injectable, or 
transdermal contraceptives for a minimum of 
1 full cycle (based on the subject’s usual 
menstrual cycle period) before IMP 
administration. 
b. Total abstinence from sexual intercourse since the 
last menses before IMP administration. (The 
reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical 
trial and the preferred and usual lifestyle of the 
subject. Periodic abstinence methods [calendar, 
symptothermal, post-ovulation methods] are not 
acceptable methods of contraception). 
c. IUD or IUS. 
4. Any of the following medically significant conditions: 
a. Clinically significant renal or hepatic disease OR 
clinical laboratory assessment (results ≥ 3 times 
the upper limit of normal [ULN] for aspartate 
aminotransferase and/or alanine aminotransferase, 
bilirubin ≥ 2 times the ULN, or creatinine 
≥ 1.5 times the ULN). 
b. Any new condition or worsening of existing 
condition which, in the opinion of the investigator 
would put the subject at undue risk. 
5. Any serious adverse event or moderate/severe adverse 
event from the ORARIALS-01 trial which is ongoing at 
the time of transitioning to ORARIALS-02 and assessed 
as probably related to IMP. 
 
Anticipated trial 
period 
First Subject First Visit: approximately April 2019  
Last Subject First Visit: approximately December 2022  
Last Subject Last Visit: approximately July 2024 
 
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 International Ethical Guidelines. 
• Current version of applicable ICH 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 
GCP (4.8) and all applicable laws and regulations. The authorised person obtaining the informed 
consent must also sign the ICF. 


 
 
 
 
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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, and subjects may be up to 36 months 
from first symptom onset (signs of weakness) due to their involvement in ORARIALS-01 trial, it 
is possible that some subjects may be incapable of providing informed consent at the point of 
entry to the present trial the ability of a trial subject to confirm ongoing or provide new consent 
may be diminished (i.e., the trial subject may have significantly declined, including signs of 
fronto-temporal dementia, to a legal status of an incapacitated adult). Other subjects that are 
competent at the time of trial entry may also face significant decline. 
Since there is the possibility of needing to re consent 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. Where permitted, a legal representative will be 
nominated by the time of the Baseline visit to ensure that this occurs while the subject is 
competent. 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). 
For subjects unable to attend a clinic visit, informed consent may be done remotely (if permitted 
by local regulations). 
10.2.3 
Subject Card 
At or prior to the Baseline visit, 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 


 
 
 
 
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card should medical information be required by the non-investigator physician. These contact 
details are not provided for use by the subject. 
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, 
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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. 
10.2.6 
Record Keeping, Quality Control and Data Handling 
 Investigator Logs 
The investigator must keep a subject ID code list and a subject enrolment log. 
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. 
 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. 
 Principles for Data Entry 
If an abnormal finding (vital signs, physical examination, laboratory tests, ECG) at visit 
(including the Baseline visit) it is considered by the investigator to be clinically significant, it will 
be reported as an AE in accordance with Section 7.4.6. 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 7.4.6. 


 
 
 
 
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 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 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. 
 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 schedule of subject visit attendance as well as 
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 
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 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. 
 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. 
 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 Figure 10-1. 


 
 
 
 
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Figure 10-1: Transmission of Electronic Data 
 
  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). 
Investigator/ Site 
Contract Research  
Organisation 
Central Laboratory  
Vendor 
Spirometry Vendor 
Clinical 
Assessments 
eCRF / IRT 
Clinical 
Database 
Clinical Trial 
Report 
Laboratory 
Analysis Data 
FlowScreen™ 
Spirometry 
Data 
PopPK / 
Bioanalysis 
Reports 
Laboratory 
Dataset 
Spirometry 
Dataset 
SpiroSphere™ 
Spirometry 
Data 
Local 
Laboratory 
data 


 
 
 
 
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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 
multi-centre publication. 
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: 


 
 
 
 
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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 
Trial and Site Disclosure 
 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 


 
 
 
 
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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. 
• No inclusion of subjects by the investigator. 
• Discontinuation of further IMP development. 
 
 Completion of Trial 
Only subjects that have completed the ORARIALS-01 trial (i.e., met one of the surrogate 
survival endpoints of tracheostomy or PAV or has completed the 76 weeks randomised treatment 
period) may enroll into the present trial. 
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. 
10.2.11 
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. 


 
 
 
 
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10.2.12 
International Coordinating Investigator 
, MD, PhD, Professor of Neurology, Walter Bradley Chair in ALS Research, 
Chief, Neuromuscular Division, Chief, Neuromuscular Division, University of Miami, 1120 NW 
14th St CRB1318, Miami FL 33136 USA, Phone: 
 email: 
@med.miami.edu 
10.2.13 
National Coordinating Investigator 
A national coordinating investigator may be appointed as required by local regulation. 
10.2.14 
Investigators 
The list of investigators is maintained outside of the protocol. 
10.2.15 
Sponsor 
Sponsor 
Orphazyme A/S, Ole Maaløes Vej 3, DK-2200, Copenhagen N, Denmark, 
, 
contact@orphazyme.com, www.orphazyme.com 
The following individuals have been appointed to act on behalf of the sponsor in the conduct of 
this clinical trial: 
Medical Expert 
, MD, Medical Director, Orphazyme A/S, Copenhagen, Phone: 
, 
email: 
@orphazyme.com 
Biostatistician (consultant representative of Sponsor) 
, PhD, Statistician, President ProSoft Clinical, Phone: 
, email: 
@prosoftclinical.com  
Data Manager 
, Senior Data Manager, Orphazyme A/S, Copenhagen, Phone: 
 
, email: 
@orphazyme.com 
Clinical Safety 
, Clinical Safety Operations Manager, Orphazyme A/S, Copenhagen, 
Phone: 
, email: 
@orphazyme.com 
Clinical Trial Supply 
, Senior Clinical Trial Supply Coordinator, Orphazyme A/S, Copenhagen, Phone 
, email:
@orphazyme.com 


 
 
 
 
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Clinical Trial Manager 
, Senior Clinical Trial Manager, Orphazyme A/S, Copenhagen, Phone: 
 
, email:
@orphazyme.com 
10.2.16 
Service Providers 
The following service providers have been appointed to collaborate with the sponsor in the 
conduct of this clinical trial: 
 Contract Research Organisations 
Worldwide Clinical Trials 
1st Floor Waterfront House, Beeston Business Park, Beeston, Nottingham, NG9 1LA, UK 
Responsible for project management, site feasibility, clinical assessment technologies, clinical 
monitoring, data management, statistical analysis and reporting as agreed in a contract 
ERT 
eResearchTechnology Limited, Peterborough Business Park Lynch Wood, Peterborough PE2 
6FZ UK 
Responsible for centralised spirometry assessment as a third-party provider to Worldwide 
Clinical Trials 
(Safety Vendor) 
Responsible for pharmacovigilance services including safety database management and safety 
reporting as agreed in a contract. Please refer to the SAE Reporting Contact Details document. 
 Contract Manufacturing Organisations 
Catalent Pharma Solutions  
Responsible for secondary packaging and labelling, import, distribution and destruction as agreed 
in a contract. 
Packaging, Distribution and Returns, EU: 
Catalent Germany Schorndorf GmbH, Steinbeisstraße 1-2, 73614 Schorndorf, Germany 
Depot and distribution, North America: 
Catalent Pharma Solutions, 10381 Decatur Road, Philadelphia, Pa 19154 
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 


 
 
 
 
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World Courier 
Responsible for DtP distribution and logistics as agreed in a contract. 
World Courier Denmark A/S, Avedøreholmen 96-98, Hvidovre, DK-2650, Denmark 
 Contract laboratory services 
Covance Laboratories 
Responsible for centralised bioanalysis of safety laboratory parameters (biochemistry, 
haematology and urinalysis) as agreed in a contract. 
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 
10.3 
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. The specific sections of the 
protocol are referenced requiring change for a given country are noted in following sections.  
10.3.1 
Canada 
7.4.6.6 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. 
10.2.6.9 
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 ICF. 


 
 
 
 
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10.3.2 
France 
 Inclusion Criteria 5 
An additional inclusion criterion for subjects recruited in France is mandatory under this 
protocol. Criterion number five as described below is required to ensure compliance with this 
additional national requirement.  
5. 
Affiliated to a social security system (requirement for France only) 
 Neurological Examination 
As part of the Safety assessments per Table 1-1, a neurological examination should also be 
conducted by a neurologist in all subjects who have in clinic visit at Visits 6, 14 and 20 (Weeks 
20, 52 and 76, respectively). 
 
A neurological examination including general, cranial nerves, reflexes, motor system, 
coordination/cerebellar function and sensation will be carried out and only for subjects who are 
able to attend the trial site (see Table 10-1 for the parameters of the neurological examination). 
 
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 7.4.6). 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. 
 
 
 


 
 
 
 
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Table 10-1 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 
Vibration 
 


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 Temporary Halt of IMP 
The below text will replace the text in Section 6.4.2 Temporary Halt of IMP: 
A temporary halt of IMP treatment can be implemented only once for intolerable AEs within a 
given organ/body system. If the subject experiences a different intolerable AE within a different 
organ/body system, the IMP should be discontinued permanently. 
 ECG Assessments 
For subjects in France, the ECG examinations should be conducted in all subjects for visits at 
Day 1, Weeks 20, 52 and 76 regardless of whether the visit is conducted at the trial site or in the 
subject’s home. Section 7.4.4 statement regarding “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” will therefore not be applicable. 
Day 1 coincides with the End of Trial / Week 76 visit of the ORARIALS-01 trial and therefore, 
results will be transferred over from the ORARIALS-01 database. 
10.4 
Coronavirus (COVID) operational changes 
The document ORARIALS-02 (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-02 
Date: 24-Mar-2020 
Version: Final 1.0 
(COVID-19) Addendum 1.0 to 
Clinical Trial Protocol v5.0 dated 28-Feb-2020 
Orphazyme A/S - Strictly Confidential 
(COVID-19) Addendum 1.0, dated 24-Mar-2020 
Page 1 of 11 
Open-label, Non-randomised Extension Trial to Assess 
the Long-Term Safety and Efficacy of 1200 mg/day 
Arimoclomol 400 mg Three Times a Day (t.i.d.) in 
Subjects with Amyotrophic Lateral Sclerosis (ALS) who 
have Completed the ORARIALS-01 Trial 
Sponsor: Orphazyme A/S, Ole Maaløes Vej 3, DK-2200 Copenhagen N, Denmark 
Coordinating investigator: 
, MD PhD 
Protocol number: ORARIALS-02 
EudraCT No.: 2019-000374-39  
Trial product name: Arimoclomol Capsules 
Date of Addendum: 24-Mar-2020 
Clinicaltrials.gov ID: NCT03836716
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.
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 


 
 
 
 
Protocol number: ORARIALS-02 
Date: 24-Mar-2020 
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Page 2 of 11 
 
Approval Statement, Orphazyme A/S 
This trial protocol was subjected to critical review by Orphazyme. 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 and the guidelines on Good Clinical Practice (GCP). 
 
Acknowledgement Statement Investigators 
Each participating investigator must agree to the approved clinical trial protocol Addendum and 
consolidated clinical trial protocol(s) (including any protocol amendments) by signing a clinical trial 
protocol acknowledgement form. 
 
 
 
 
 


 
 
 
 
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Contents 
 
Approval Statement, Orphazyme A/S ............................................................................................................... 2 
Acknowledgement Statement Investigators ...................................................................................................... 2 
Justification for Addendum ............................................................................................................................ 4 
Modification to the Clinical Trial Protocol due to COVID-19 .................................................................... 5 
 
 
 


 
 
 
 
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Justification for Addendum 
 
The international outbreak of a novel respiratory disease named Coronavirus Disease 2019 (COVID-19) is 
currently an ongoing threat to our global health. Characterized as a respiratory virus, those infected present 
symptoms that underlie mild respiratory tract syndrome, severe pneumonia, and organ failure, which in several 
cases have led to fatality. The unprecedented transmission of the disease has meant that the World Health 
Organization have identified this outbreak as a pandemic. 
As a result of the scale and severity of COVID-19, governments have intervened to curtail the spread of the 
virus. Such mitigation strategies include, travel bans, quarantine of persons who have been exposed to the 
disease, isolation of infected persons, closure of public and private sectors, and a general limitation on the 
movement/mobilization of individuals to reduce social interaction and thus contamination.  
In line with the newly imposed restrictions, changes in clinical trial logistics/operations or logistics within a 
hospital may also be required to enforce similar measures to safeguard individuals at risk of severe disease and 
try to contain the spread of the virus. Namely, this will concern situations where subjects may be unable to 
attend scheduled clinic visits to undergo protocol assessments, and where deliveries of clinical trial supplies 
to subjects may not be permitted.  
This 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 their currently approved Clinical Trial 
Protocol. 
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 changes introduced in this Addendum qualify for classification as a Non-Substantial 
Amendment, and is applicable globally. 
 


 
 
 
 
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Modification to the Clinical Trial Protocol due to COVID-19 
 
The following changes shall be made to the respective sections of the Clinical Trial Protocol version 5.0. In countries where version 5.0 is not yet fully in 
effect, the same principles will apply based on the site’s currently approved version. 
Section 
Modification 
 
Rationale (including risk/benefit justification) 
6.4.2 
Temporary Halt 
of IMP and Dose 
Modification 
Potential postponement of laboratory testing, Temporary halt of IMP 
and re-challenge due to missed clinical safety laboratory assessments: 
 
In case a clinical safety laboratory sample cannot be acquired at a planned 
visit (see Schedule of Procedures), the Sponsor must be informed. 
 
An individual subject safety review will be performed by the Investigator. 
Reviews should include laboratory results and clinical assessments since 
baseline and reported adverse events. This evaluation must be 
documented in the subject’s medical records and shared with Medical 
Monitor. The IMP should be halted immediately in any subject where 
safety concerns have been identified. 
 
For subjects with no safety findings, IMP may be continued to be taken, 
on the condition that a clinical safety laboratory sample will be acquired 
as soon as possible based on the below timelines: 
 
For subjects who have not passed week 28 (visit 8): a clinical safety 
laboratory assessment must occur within the visit window as per the 
Clinical Trial Protocol, with the visit windows being extended from -7/+7 
days to -14/+14 days. If a clinical safety laboratory sample (central or 
There needs to be a differentiation between subjects who have been 
dosed for less than 6 months, and those that have been dosed for more 
than 6 months. 
 
Subjects who have been on IMP for less than 6 months will require 
continued review of clinical safety laboratory assessments in a timely 
manner according to the protocol to ensure an adequate safety profile. 
 
The risk to the subjects who have been on IMP for more than 6 months 
is lower, where most IMP related adverse events is expected to have 
emerged.  
 
Subjects are only allowed to postpone safety laboratory testing if it is 
considered to have no added risk, set by the criteria of the Addendum. 
The Investigator should assess if it is in the best interest of the subjects 
to continue with IMP. 
 


 
 
 
 
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Section 
Modification 
 
Rationale (including risk/benefit justification) 
local) cannot be acquired within the visit window, IMP must be 
interrupted. 
 
For subjects who have passed week 28 (visit 8): the maximum permitted 
time between two clinical safety laboratory sample is defined by the per 
protocol visit interval (time between two in-person visits), plus an 
additional 30 days. Subjects should return to the planned schedule and 
resume normal blood draws as per the planned Scheduled of Procedures 
when possible. 
 
Subjects in need of close monitoring where appropriate follow-up cannot 
be performed are required to halt IMP. 
 
IMP re-challenge after a temporary halt: 
 
 
In subjects where a temporary halt does not exceed 4 weeks, IMP may be 
re-challenged once laboratory testing is available, and the subject is 
deemed safe to continue in the trial. 
 
For subjects who have halted IMP for greater than 4 weeks, a clinical 
safety laboratory sample should be acquired at the earliest opportunity. 
The Sponsor will assess whether the subject can be re-challenged with 
IMP. If it is deemed appropriate that IMP can be reinitiated, additional 
subject-specific monitoring may be required (e.g. increased frequency of 
the clinical safety laboratory samples). 
 
Temporary halts due to an adverse event should follow the guidance in the 
existing Clinical Trial Protocol (section 6.4.2).   


 
 
 
 
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Section 
Modification 
 
Rationale (including risk/benefit justification) 
6.5.3 
Drug 
Distribution and 
Dispensation 
Drug distribution: 
 
IMP shall be shipped to the subjects via the following routes, as permitted 
per local legislation: 
1) Subject to collect directly from the site, as per protocol 
2) Direct to subject shipment from site 
3) Direct to subject shipment from depot 
4) In extenuating circumstances where a site may be blocked (for 
example, due to quarantine), and no shipment from the depot may 
be possible, a subject transfer to another open site may be 
considered. 
 
In cases of direct to subject shipment, the shipment of IMP to the subjects 
will be done in a manner that does not compromise the treatment blinding.  
 
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 
through the chain of custody. The service should be used for reverse 
logistics to ensure that used and unused IMP 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. 
 
The overriding objective of all changes in distribution is to provide the 
participating patients with the IMP as needed according to the trial 
protocol to ensure the right, safety and well-being of trial participants 
as well as the integrity of the clinical trial. 


 
 
 
 
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Section 
Modification 
 
Rationale (including risk/benefit justification) 
6.5.3 
Drug 
Distribution and 
Dispensation 
Collection of IMP: 
 
The drug distribution logistics can be found in section 6.5.3 Drug 
Distribution and Dispensation above. 
 
If collecting IMP from the site, arrangements for a nominated person to 
collect IMP may be implemented with the subject’s verbal consent if 
subjects are self-isolating or in quarantine. This should be documented in 
the source notes. 
 
The overriding objective of all changes in distribution is to provide the 
participating patients with the IMP as needed according to the trial 
protocol to ensure the right, safety and well-being of trial participants 
as well as the integrity of the clinical trial. 
6.5.3 
Drug 
Distribution and 
Dispensation 
Additional dispensation of 4-month IMP buffer: 
 
Subjects are normally dispensed enough IMP to last until the next clinic 
visit. An additional dispensation of 4 months’ worth of IMP will be 
shipped to all Subjects. Subjects who are close to End of Trial (EOT) will 
only have IMP shipped to cover the remaining time in the trial. This 
should be documented in the accountability log as per the Clinical Trial 
Protocol. 
 
Individual safety assessments will be made to determine whether the 
subjects can continue on the IMP provided also in this Addendum (see 
section 6.4.2 Temporary Halt of IMP and Dose Modification).   
 
This change is done with the overall objective to provide subjects with 
IMP as needed according to the protocol to ensure the right, safety and 
well-being of the subjects and the integrity of the clinical trial. The 
additional IMP will be dispensed to ensure that patients have enough 
IMP in case the site pharmacy closes and direct to patient IMP 
shipment is not possible.  
 
The additional 4-month dispensation of IMP buffer is considered 
acceptable as the IMP is appropriate for administration and general 
storage at the trial participant’s home.  The IMP has a long shelf-life, 
with the earliest expiration date noted as 31-March-2021 for the 
current batches. The product has a very strong temperature stability 
range – the recommended storage temperature is between 15-25oC, but 
the stability data supports excursions of 0-2oC and 25-40oC for up to 
72 hours.  
 
This action ensures subjects who can have home visits/local laboratory 
testing, also have sufficient IMP to allow their continuation in the trial. 


 
 
 
 
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Page 9 of 11 
 
Section 
Modification 
 
Rationale (including risk/benefit justification) 
 
Management of subject safety shall continue as planned, with 
additional requirements in case a clinical safety laboratory test cannot 
be drawn for any reason. See Addendum to section 6.4.2 Temporary 
Halt of IMP and Dose Modification. 
 
7.4.8 
Clinical Safety 
Laboratory 
Assessments 
Use of home visits and remote visit / local laboratory: 
 
Use of home visit: 
If a subject cannot attend a clinic visit at site, a home visit may be 
conducted – refer to Table 7-1: Clinical Assessments for when an in-
person visit is conducted at the subject’s home/residency) for the task split 
between the site staff and the home nursing vendor. 
 
Subjects whom, per the Investigator’s opinion, should not come to clinic 
due to the increased infection risk (e.g. self-isolation) may also utilise the 
home visit. 
 
Use of local laboratory: 
Site staff should continue with the phone assessments, if an in-person visit 
cannot be conducted. A local local laboratory sample should be requested 
for continued safety review. 
 
Subjects should be instructed to provide their local laboratory results to 
the site as soon as possible. All local laboratory assessments in lieu of 
central laboratory tests must be filed as part of the site’s source data for 
update to the eCRF. 
 
To ensure patient safety, this flexibility will allow the continuation of 
safety assessments, enabling patients to remain in the trial whilst 
reducing the risk of contamination. 
 
In the event where in-clinic visits may enhance the risk of 
contamination for a given patient, the Investigator can suggest the use 
of home nursing to acquire safety laboratory samples limiting patient 
exposure to the virus.  
 
In extenuating circumstances where both in-clinic and home visits are 
not possible, a local laboratory may be used to ensure continued safety 
review, alongside a remote telephone visit. 
 
Alternative methods for safety blood analysis may be utilized in these 
times to reduce the risk of infection, such as dry blood spot testing. 
Sponsor will ensure first that these methods must be validated, and data 
made available for Medical Monitor reviews, prior to approval. The 
purpose of allowing such methods is to ensure subject safety is 
maintained so that they can continue on IMP. 


 
 
 
 
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Page 10 of 11 
 
Section 
Modification 
 
Rationale (including risk/benefit justification) 
If full clinical safety laboratory assessments cannot be performed, the 
following should be prioritized: 
1) Liver and kidney 
2) Haematology 
 
Site staff must inform the trial Medical Monitor of the results as soon as 
it is available. 
 
Use of alternative laboratory methods for safety review: 
Alternative methods of safety blood analysis, such as dry blood spot 
testing, may be applied following Sponsor review and approval. 
 
Site staff should continue with the phone assessments, if an in-person visit 
cannot be conducted. 
 
10.2.2 
Informed 
consent process 
Informed Consent Process: 
 
The site staff should inform the subject of the changes remotely (for 
example: telephone, skype) and document this conversation in the source 
notes. 
 
The verbal consent will be supplemented with e-mail confirmation and 
confirmed by way of normal consent procedures at the earliest opportunity 
when the trial participants will be back at the regular sites. 
 
A verbal consent is appropriate to reduce the risk of having subjects 
being exposed to the virus in-clinic. 
 
This is to facilitate subject continuation in the trial without having the 
need to come back to the clinic for minor logistical amendments to the 
protocol. 
10.2.6.5 
Trial monitoring 
Remote Monitoring: 
 
Oversight of the trial must be maintained as per ICH-GCP. In case the 
CRA can no longer visit the site, remote monitoring will allow 


 
 
 
 
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Page 11 of 11 
 
Section 
Modification 
 
Rationale (including risk/benefit justification) 
Remote monitoring refers to verification of the source by the CRA, while 
not on site. 
 
Remote monitoring shall be utilized where possible to allow continuation 
of trial review to ensure subject safety and compliance with the protocol. 
Methods for remote monitoring, such as direct access to electronic 
medical records for the CRA, teleconferencing/videoconferencing or 
sending on anonymized data via email for verification, should be in 
accordance with local legislation and ICH-GCP.  
 
continuation of trial review to ensure subject safety and protocol 
compliance. 
10.2.6.6 
Protocol 
compliance 
Missed protocol assessments due to local guidance: 
 
There may be assessments deemed as risk factors for spreading the virus 
during this time, and local authorities issue guidance on reduced 
assessments in clinic. Site staff should adhere to the local guidance and 
note in the source notes that such assessments could not be performed. 
Rules applied at the hospital should also be applied at the home visits. 
 
This should also be captured as a reason in the eCRF.  
 
Local guidance should be adhered. 
NA 
Site staff location: 
 
In case a hospital is closed, site staff may conduct telephone assessments 
from home, if possible. The phone assessments should be conducted as 
per the Clinical Trial Protocol.  Site staff should continue to document all 
assessments as appropriate in the source notes. 
Hospital quarantine may result in site staff being asked to work from 
home. If permitted, site staff can easily administer certain assessments 
remotely, as planned, per the Clinical Trial Protocol. 
 

SAP_001.pdf: 
Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Orphazyme A/S 
Protocol Number: 
ORARIALS-02 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
REF: Worldwide-TMP-QA-001f-1.3 
Page 1 of 37
Statistical Analysis Plan 
Title: Arimoclomol in ALS – Open-Label Extension Trial/Open-label, Non-
randomised Extension Trial to Assess the Long-Term Safety and Efficacy of 1200 
mg/day Arimoclomol 400 mg Three Times a Day (t.i.d.) in Subjects with 
Amyotrophic Lateral Sclerosis (ALS) who have Completed the ORARIALS-01 
Trial  
Protocol Number: ORARIALS-02
Protocol Version: 6.0/08-JUN-2020
SAP Version 1.0  
SAP Issue Date: 30-AUG-2021 
SAP Author: 
, MS
Clinicaltrials.gov ID: NCT03836716
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.
Confidential


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Orphazyme A/S 
Protocol Number: 
ORARIALS-02 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
REF: Worldwide-TMP-QA-001f-1.3 
Page 2 of 37
Table of Contents 
1 
INTRODUCTION ............................................................................................... 4
2 
STUDY OBJECTIVES ....................................................................................... 4
2.1 
Primary objective ............................................................................................................ 4 
2.2 
Secondary objectives ...................................................................................................... 4 
2.3 
Exploratory Objectives ................................................................................................... 4 
3 
ENDPOINTS ....................................................................................................... 5
3.1 
Primary Endpoints .......................................................................................................... 5 
3.2 
Secondary Endpoints ...................................................................................................... 5 
3.3 
Exploratory Endpoints .................................................................................................... 5 
4 
SAMPLE SIZE .................................................................................................... 5
5 
RANDOMIZATION ........................................................................................... 5
6 
PLANNED ANALYSES ..................................................................................... 5
6.1 
Analysis Population ........................................................................................................ 6 
6.1.1 
Enrolled Population .................................................................................................. 6 
6.1.2 
Safety Analysis Population ....................................................................................... 6 
6.2 
Observation Periods ........................................................................................................ 6 
6.2.1 
In-trial ....................................................................................................................... 6 
6.2.2 
On-Treatment ............................................................................................................ 7 
6.3 
Imported Data from Orarials-01 ..................................................................................... 7 
6.4 
Derived Data ................................................................................................................... 8 
6.4.1 
Age ............................................................................................................................ 8 
6.4.2 
Race........................................................................................................................... 8 
6.4.3 
Baseline ..................................................................................................................... 8 
6.4.4 
Duration / Study Day / Time ..................................................................................... 8 
6.4.5 
Conventions for Missing and Partial Dates .............................................................. 8 
6.4.6 
Exposure to Study Drug .......................................................................................... 10 
6.4.7 
Inexact Values ......................................................................................................... 11 
6.4.8 
Columbia-Suicide Severity Rating Scale (C-SSRS) ............................................... 11 
6.4.9 
Visit Windowing ..................................................................................................... 12 
6.4.10 
Protocol deviation Categories ................................................................................. 14 
6.5 
Conventions .................................................................................................................. 14 
6.5.1 
Decimal Places ........................................................................................................ 15 
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6.6 
Subject Disposition ....................................................................................................... 15 
6.7 
Protocol Deviations ....................................................................................................... 16 
6.8 
Demographics and baseline characteristics .................................................................. 16 
6.9 
Medical History ............................................................................................................ 16 
6.10 
Prior and Concomitant Medications ............................................................................. 16 
6.11 
Exposure to Study IMP ................................................................................................. 16 
6.12 
Treatment Compliance .................................................................................................. 17 
6.13 
Efficacy Analyses ......................................................................................................... 17 
6.13.1 
Secondary Endpoints and analyses ......................................................................... 17 
6.13.2 
Exploratory Endpoints ............................................................................................ 18 
6.13.3 
Multiplicity ............................................................................................................. 18 
6.14 
Safety Analyses ............................................................................................................. 18 
6.14.1 
Adverse Events ....................................................................................................... 18 
6.14.2 
Laboratory Data ...................................................................................................... 20 
6.14.3 
Vital Signs ............................................................................................................... 22 
6.14.4 
Electrocardiogram Data .......................................................................................... 23 
6.14.5 
C-SSRS ................................................................................................................... 23
7 
CHANGES TO PLANNED PROTOCOL ANALYSIS ...................................23
8 
REFERENCES ..................................................................................................25
9 
LIST OF TABLES, FIGURES AND LISTINGS .............................................26
10 APPENDICES ...................................................................................................34
10.1 
Appendix 1 .................................................................................................................... 34 
10.2 
Appendix 2 .................................................................................................................... 34 
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1 INTRODUCTION 
This document details the planned statistical analyses for Orphazyme A/S, protocol “ORARIALS-
02” study titled “Arimoclomol in ALS – Open-Label Extension Trial/Open-label, Non-randomised 
Extension Trial to Assess the Long-Term Safety and Efficacy of 1200 mg/day Arimoclomol 400 
mg Three Times a Day (t.i.d.) in Subjects with Amyotrophic Lateral Sclerosis (ALS) who have 
Completed the ORARIALS-01 Trial”. 
ORARIALS-02 study was terminated by the sponsor on 11-May-2021.  Although, there is a 
version 7 of the protocol (dated 25JAN2021), it had not been officially implemented before 
termination of the study.  The protocol enforced at the time was version 6 (dated 08-JUN-2020). 
Hence, the study description in this document is based on the content of the protocol version 6. 
This is a multicentre, non-randomized, open-label, uncontrolled trial to evaluate the safety and 
efficacy of long-term treatment with 744 mg/day arimoclomol (248 mg t.i.d.) over a 76 week 
treatment period, consisting of a combination of in-person visits and remote visits (telephone 
calls).  It is an open-label extension (OLE) for subjects that participated in the ORARIALS-01 
study that was designed to assess the efficacy and safety of arimoclomol compared to placebo 
amongst patients with Amyotrophic Lateral Sclerosis (ALS).  Protocol version 6 presents strengths 
of arimoclomol by weight of citrate salt.  However, strengths of arimoclomol are presented 
throughout this document by base weight (e.g., excluding citrate salt).  
Due to the termination of this study, abbreviated analyses will be conducted.  Objectives and 
endpoints have changed.  For details regarding change from protocol please see Section 7. 
2 STUDY OBJECTIVES 
2.1 Primary objective  
To assess the long-term safety of arimoclomol treatment of ALS. 
2.2 Secondary objectives 
“To evaluate the long-term efficacy of arimoclomol treatment of ALS, using disease progression 
and progression of respiratory dysfunction.”    
2.3 Exploratory Objectives 
To evaluate the effect of arimoclomol on health-related quality of life. 
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3 ENDPOINTS 
3.1 Primary Endpoints 
•
Incidence and severity of TEAEs over a treatment period of 76 weeks
•
Mean and change from baseline (of the present trial) to Week 76 (or end-of-trial) in
clinical safety laboratory tests and vital signs
•
Incidence of potentially 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
3.2 Secondary Endpoints 
•
Change from baseline during 76 weeks in the ALS Functional Rating Scale - Revised
(ALSFRS-R)
•
Change from baseline during 76 weeks in  percent (%) predicted slow vital capacity
(PPSVC)
3.3 Exploratory Endpoints 
•
Change from baseline in EQ-5D-5L VAS score over a treatment period of 76 weeks
•
Number (Percent) of patient’s responses to EQ-5D-5L dimensions[*] over a treatment
period of 76 weeks
4 SAMPLE SIZE 
A maximum of 231 subjects might be eligible to be enrolled in this trial, however it is estimated 
that approximately 60% (i.e. 144 subjects) will be available from ORARIALS-01 for the OLE. 
As this trial is an OLE restricted to subjects participating in the previous trial, no additional 
calculation for sample size was performed.
5 RANDOMIZATION 
There is no randomization in this trial as it is an OLE wherein all subjects receive active therapy 
with the same investigational medicinal product (IMP).
6 PLANNED ANALYSES 
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No statistical analysis plan (SAP) prepared in advance of the data can be absolutely definitive and 
the final Clinical Study Report  may contain additional tables or statistical tests if warranted by the 
data obtained. The justification for any such additional analyses will be fully documented in the 
final CSR. 
6.1 Analysis Population 
6.1.1 
Enrolled Population 
The Enrolled Population will include all patients who give informed consent to participate in the 
OLE trial.   
6.1.2 
Safety Analysis Population 
The safety population will include all enrolled patients that receive at least one dose of 
arimoclomol in the OLE trial.  This will be the primary population used for all safety and 
efficacy displays unless otherwise specified. 
6.2 Observation Periods 
Patients and the data to be used in an analysis will be selected in a two-step manner. 
Firstly, patients will be selected based on the specified analysis populations. 
Secondly, data points from the selected patients from the first step will be selected based on the 
specified observation period. 
Information collected with onset date outside the observation period will be excluded from the 
corresponding analysis.   
Two observation periods are defined 
6.2.1 
In-trial 
This observation period represents the time period where patients are considered to be enrolled in 
the trial and as such under systematic follow-up. The in-trial period starts at baseline visit (which 
per protocol is conducted on the same date as the end of trial visit of ORARIALS-01). End of the 
in-trial period will be defined as the end date of the below 
1. Patient recorded as dead (prior to withdrawing from study): end date is the date of death
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2. Patients withdrawing without being registered as dead: end date is the maximum of
withdraw date and all visit dates where assessments took place[§]
[§]: The protocol stipulates that for withdrawn patients, if allowed by patients or caregiver, follow-up regarding
PAV/tracheostomy/death is allowed. With regard to the definition of the in-trial period, as a time period wherein
patients are “under observation”, the time from date of trial withdrawal to “post withdrawal follow-up
PAV/tracheostomy/death” is not relevant for say AEs, safety lab etc.”  Hence, this post withdraw follow-up will not
be included when defining in-trial period.
6.2.2 
On-Treatment 
This observation period represents the time period where patients are considered treated with IMP. 
The on-treatment period is a subset of the in-trial period and starts at the date of first administration 
of IMP. The protocol allows for patients to temporarily be taken off IMP by the decision of their 
investigator and later reinstated on IMP. As per the protocol such drug holidays ≤ 28 days are
allowed. 
6.2.2.1 Safety 
In order to report safety assessments during IMP interruptions in a consistent manner relative to 
assessments after final termination of IMP, a patient is considered to be on-treatment at any time 
point up to 14 days since the latest preceding administration of IMP or the end-date for the in-trial 
period, whichever comes first. This means that a safety assessment occurring 15 days (or later) 
within a (temporary) IMP interruption period will not be considered to occur on-treatment. 
The definition implies that the on-treatment time for a given patient potentially may be composed 
by several periods separated by interruption intervals. 
6.2.2.2 Efficacy 
The on-treatment period used for efficacy evaluation ends at the first time point where a patient 
has not administered IMP for consecutive 15 days or more, or at or the end-date for the in-trial 
period, whichever comes first. This definition is intended to reflect an effect that can be attributed 
as close as possible to a continuous treatment regimen (i.e. without interruptions that potentially 
can weaken the effect following an interruption).  
6.3 Imported Data from Orarials-01 
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Per protocol, the baseline visit for this study is  the end of trial visit (Visit 21) of the ORARIALS-
01. The electronic case report database was designed to import data from Orarials-01 database
(e.g. medical history at screening , assessments collected from Visit 21) of the orarials-01.  Once
imported into the 02 database, a site is able to change the data.
6.4 Derived Data 
This section describes the derivations required for statistical analysis. Unless otherwise stated, 
variables derived in the source data will not be re-calculated. 
6.4.1 
Age 
Age at time of informed consent for the OLE trial will be used to represent age of subject in the 
study.   
6.4.2 
Race 
Where more than one race category has been selected for a subject, these race categories will be 
combined into a single category labeled “Multiple Race” in the summary tables. The listings will 
reflect the original selected categories.  
6.4.3 
Baseline 
Baseline is defined as the last non-missing value (either scheduled, unscheduled or repeat) before 
the subject receives the first dose of investigational Medicinal Product (IMP).  Per protocol, the 
baseline visit for this study is the end of trial visit (Visit 21) of the ORARIALS-01.   
6.4.4 
Duration / Study Day / Time 
Study day will be calculated as the number of days from first dose of investigational medicinal 
product (IMP).  
•
date of event – date of first dose of IMP + 1, for events on or after first dose
•
date of event – date of first dose of IMP, for events before first dose.
6.4.5 
Conventions for Missing and Partial Dates 
All rules explained below for partial / missing dates will be followed unless contradicted by any 
other data recorded on the electronic Case Report Form (eCRF). 
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6.4.5.1 Missing / Partial Start / Stop Date of Adverse Events (AE) and Concomitant 
Medications 
Missing and partial start and stop date will be imputed for analysis purposes as follows 
Partial or missing stop date will be imputed as follows: 
If the stop date is completely missing and the event has resolved or the patient has stopped taking 
the concomitant medication, the stop date will be imputed as the date of the patient’s last clinic 
visit in the study. 
•
If only the year is known, the stop date will be imputed as “31-Dec” of that year or as the
date of the patient’s last clinic visit in the study if in the same year.
•
If the month and year are known, the stop date will be imputed as the last day of that month
unless the stop date corresponds to the same month as the patient’s last clinic visit in which
case the date of patient’s last clinic visit in the study will be used instead.
Missing start date will be imputed as follows: 
•
If the stop date occurs on or after the start of IMP or the event/concomitant medication is
ongoing, the start date will be imputed as the date of the first dose of IMP.
•
If the stop date occurs before the start of IMP, the start date of the event/concomitant
medication will be imputed as the patient’s screening date or the stop date of the
event/concomitant medication whichever the earlier.
Partial start date (year present, but month and day missing) 
•
If the stop date occurs on or after the start of IMP or the event/concomitant medication is
ongoing, and the year is the same as the year of first dosing the start date will be imputed
as “01-Jan” of the same year or the date of the first dose of IMP whichever is latest. If the
year is different from the year of first dosing “01-Jan” will be used.
•
If the stop date occurs before the start of IMP, the start date of the event/concomitant
medication will be imputed as the “01-Jan” of the same year.
Partial start date (month and year present, but day missing) 
•
If the stop date occurs on or after the start of IMP or the event/concomitant medication is
ongoing, the start date will be imputed as the first day of the same month and year unless
this partial start date is in same month as the first dose of IMP in which case the date of
first dose of IMP will be used.
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•
If the stop date occurs before the start of IMP, the start date will be imputed as the first day
of the month and year of the partial stop date.
If the start time is missing it will only be imputed in the case where the start date of the concomitant 
medication/event corresponds to the date of the first dose of IMP. The time will be imputed as the 
time as the first dose of IMP+ 1 min. In all other cases the time will not be imputed. 
6.4.5.2 Missing Last Dates of Study Drug Dosing 
If the date of last dose of study drug is completely missing, then for analysis purposes, last dose 
date will be imputed as the earliest date among the following dates:  
•
Date patient would run out of study drug assuming full compliance from the date of the
study drug was last dispensed taking into account dose (e.g., was patient de-escalated to
372 mg/day)
•
Date of early withdraw or
•
Date of death
Similarly, if only the month and year of last dose was recorded, then for analysis purposes, day of 
last dose will be imputed as the earliest day among the above dates and last day of the month of 
the recorded last dose.  
6.4.5.3 Missing Diagnosis Dates 
If the month and year are present but the day is missing, the diagnosis date will be set to first day 
of the relevant month. If only the year is recorded the diagnosis date will be set as “01-Jan” for 
that year.  
6.4.6 
Exposure to Study Drug 
Exposure to IMP will be calculated as follows from the date of last dosing minus the first day of 
dosing + 1. The exposure calculation will not take into account breaks in therapy. 
6.4.6.1 Compliance 
Per protocol, subjects rolling over from the original study (Orarials-01) who were on a reduced 
dose of 372 mg/day (124 mg t.i.d.) should maintain the same dose in the Orarials-02.  All other 
subjects will be on 744 mg/day (248 mg t.i.d.).  
Overall treatment compliance will be determined as follows 
Compliance = 100 x (capsules taken/capsules expected to be taken) 
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where, 
capsules taken = number of capsules expected to be taken* – number of missed capsules 
(regardless of reason including investigator instituted temporary halt). 
*Number of capsules expected to be taken should take into account prescribed dose.
6.4.7 
Inexact Values 
In the case where a variable is recorded as “> x”, “≥ x”, “< x” or “≤ x”, a value of x will be taken 
for analysis purposes.  
6.4.8 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The following outcomes are C-SSRS categories and have binary responses (yes / no). The 
categories have been re-ordered from the actual scale to facilitate the definition of composite 
endpoints: 
Category 1 
Wish to be Dead 
Category 2 
Non-specific Active Suicidal Thoughts 
Category 3 
Active Suicidal Ideation with Any Methods (Not Plan) without Intent to 
Act 
Category 4 
Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Category 5 
Active Suicidal Ideation with Specific Plan and Intent 
Category 6 
Preparatory Acts or Behavior 
Category 7 
Aborted Attempt 
Category 8 
Interrupted Attempt 
Category 9 
Actual Attempt (non fatal) 
Category 10 
Completed Suicide 
C-SSRS “Since last visit” version is used in this study.
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Suicidal Ideation – A “yes” answer at any time during  treatment to any one of the 5 suicidal 
ideation questions (categories 1-5) on the C-SSRS. 
Suicidal Behavior – A “yes” answer at any time during treatment to any one of the 5 suicidal 
behavior questions (categories 6-10) on the C-SSRS. 
Suicidal Ideation or Suicidal Behavior- A “yes” answer at any time during treatment to any of 
suicidal ideation/behavior questions (categories 1-10) on the C-SSRS. 
There will be no imputation of missing data for C-SSRS. 
6.4.9 
Visit Windowing 
The summary and analysis of the study endpoints by visit is conditioned on each patient 
contributing no more than one observation per visit.  As some parameters may have assessments 
occurring very close in time and thus may be attributable to the same planned visit, an algorithm 
whereby maximally 1 (one) is being selected for summary analysis is detailed below.  
There are two observation periods (in-trial and on-treatment).  When doing in-trial windowing, all 
visits that occur in the in-trial period are included in the process whereas for on-treatment 
windowing only visits at or before date of last dose+14 (for the latter identify the assessments that 
meet these criteria before windowing; refer to on-treatment period definition).  It should be noted 
that the last eligible assessment (e.g. end of study (EOS)) should flagged as eligible for analysis. 
It may be that if last assessment falls into a window with another assessment, that the last 
assessment would be assigned to the next visit window (see below for rules). 
For purposes of by-visit analysis, the following endpoints assessed  (Vital signs, Clinical safety 
laboratory test, ECG, EQ-5D-5L, SVC, C-SSRS, ALSFRS-R assessments), will be assigned to 
analysis visits based on the below time windows as appropriate.  
For efficacy endpoints, only scheduled visits will be assigned to the defined windows (below). For 
efficacy endpoints, only in-trial windowing will be done.  
For all safety endpoints, all scheduled and unscheduled visits with observations will be assigned 
to the defined windows (below). Only on-treatment windowing will be done for safety endpoints. 
If more than one measurement falls into a visit window, the measurement collected closest to the 
scheduled date will be used in the analysis. In case where measurements were collected an equal 
number of days before and after the scheduled day of the visit window then the later of the two 
measurements will be used for analysis. The exception is the EOS assessment, if this assessment 
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falls into a window with another assessment and based on rules wouldn’t be flagged as eligible 
then EOS takes precedence and will be assigned to the next window visit and mark for analysis.   
Assessments not marked “as eligible” for analysis will not be used in any analysis (descriptive or 
inferential) using visits as a means for organizing data and results. 
All collected data will be listed and eligibility will be flagged. 
Visit Windows  
 Time Window (Days) 
Scheduled 
Assessments 
collected at in-
clinic visit 
(except at 
weeks 
8, 16, 24) 
Assessments 
collected at 
Week 
20, 52 and 76 
post-baseline 
(only) 
ALSFRS-R 
and CSSRS 
Clinical Safety 
Labs 
Weight 
Visit 
 Month 
Day 
1* 
Baseline 
1 
Assigned as collected (if applicable) 
2* 
Week 4 
28 
2 
56 
2 
42 
2 
42 
3r,*v3 
Week 8 
56 
43 
70 
43 
70 
4* 
Week 12 
84 
57 
112 
71 
98 
71 
98 
5r,*v3 
Week 16 
112 
99 
126 
99 
126 
6* 
Week 20 
140 
113 
168 
2 
252 
127 
154 
127 
154 
7r,*v3 
Week 24 
168 
155 
182 
155 
182 
8* 
Week 28 
196 
169 
238 
183 
210 
183 
238 
9r 
Week 32 
224 
211 
238 
10r 
Week 36 
252 
239 
266 
11c 
Week 40 
280 
239 
322 
267 
294 
239 
322 
12r 
Week 44 
308 
295 
322 
13r 
Week 48 
336 
323 
350 
14* 
Week 52 
364 
323 
406 
253 
448 
351 
378 
323 
406 
2 
448 
15r 
Week 56 
392 
379 
406 
16r 
Week 60 
420 
407 
434 
17* 
Week 64 
448 
407 
490 
435 
462 
407 
490 
18r 
Week 68 
476 
463 
490 
19r 
Week 72 
504 
491 
518 
20* 
Week 76 
532 
491 
EOPa 
449 
EOPa 
519 
EOPa 
491 
EOPa 
449 
EOPa 
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* In-clinic/person visit: In the event a patient is no longer able to attend the site, site staff will conduct a home visit and/or by telephone call.  It 
should be noted for home visits, certain questionnaires are collected via phone.  Only a subset of clinical assessments will be conducted; those 
should also be included in the above windowing scheme.  
rRemote Visits  
v3In-person visits per protocol amendment v3 
aEOP=end date (day) of in-trial period    
“Any time, Post-Baseline” visit is derived and should be based on all post-baseline assessments 
(scheduled/unscheduled) [applies to safety endpoints where applicable]. 
6.4.10 
Protocol deviation Categories 
Worldwide PD Categories will be mapped to Sponsor defined categories for presentation purposes 
(see Appendix X).  
6.5 Conventions 
All data listings, summaries, figures and statistical analyses will be generated using SAS version 
9.4 or higher1. 
Continuous (quantitative) variable summaries will include the number of patients (n) with non-
missing values, mean, standard deviation (SD), median, minimum, maximum, quartile 1 and 
quartile 3. 
Categorical (qualitative) variable summaries will include the number of patients (n) with non-
missing values, frequency and percentage of patients who are in the particular category or each 
possible value. In general, the denominator for the percentage calculation will be based upon the 
total number of patients in the trial population for the treatment groups, unless otherwise specified. 
The denominator for by-visit displays will be the number of patients in the relevant trial population 
with non-missing data at each visit.
Percentages will be based on the number of non-missing observations or the patient population 
unless otherwise specified. For each variable, all categories will be shown. Zero frequencies (but 
not the percent) within a category will be presented.
Section 6.4.9 describes rules for deciding which visits/assessments are eligible for (which) 
analysis. Please note that all data will appear in lists and for analysis non-eligible datapoints will 
be highlighted in the lists. 
Treatment group labels will be displayed as follows: »Arimoclomol 744 mg «. 
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6.5.1 
Decimal Places 
The minimum and maximum will be reported with the same degree of precision (i.e., the same 
number of decimal places) as the observed data.
Decimal places for derived data will be determined by the scale of measurement unless otherwise 
stated. No decimal places will be displayed if the smallest calculated value is ≥ 100; 1 decimal 
place will be displayed when the smallest value is within the interval (10, 100), with 10 being 
inclusive; 2 decimal places will be displayed when the smallest value is within (1, 10), with 1 being 
inclusive; and so on for even smaller scales of measurement. 
Derived data where it is known in advance the result will be an integer for example day, month, 
year, number of days and total scores (for rating scales) will be presented with zero decimal places. 
Means, medians and percentiles will be displayed to one more decimal place than the data, 
dispersion statistics (e.g. standard deviation) will have two more decimal places, and the minimum 
and maximum will be displayed to the same number of decimal places as reported in the raw data. 
Percentages will be displayed with one decimal place. 
P-values will be quoted to 3 decimal places. P-values < 0.001 will be presented as p<0.001.
6.6 Subject Disposition 
Patient disposition will be summarized as follows: 
•
The number of patients in each analysis population (enrolled, Safety) will be tabulated by
treatment group.
•
Number (percent) of patients in the Safety Population within country and site will be
tabulated by treatment group.
•
The number of patients in the safety population who completed, withdrew early and
reasons for withdrawal, who met survival endpoint (PAV/Tracheostomy/death), for those
who withdrew early without meeting a survival event, if they consented to be contacted
post-withdraw to determine if they met a survival event by Week 76 and if they did will be
tabulated by treatment group.
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•
The number of patients that discontinued IMP prematurely and primary reason for
withdrawal will be tabulated by treatment group.
6.7 Protocol Deviations 
Number (percent) of patients with Major Deviations will be presented by treatment group. 
Important Deviations are defined as deviations classified as critical or major.   
Listing of protocol deviations will be presented. 
6.8 Demographics and baseline characteristics 
Demographic data and baseline characteristics will be summarized for the Safety Population. 
Standard continuous or categorical variable summaries will be presented where appropriate. 
Demographic data (e.g., age in years at Informed Consent, gender, race, as well as weight in kg, 
body mass index (BMI) in kg/m2) will be summarized. 
6.9 Medical History 
Medical history will be listed only.   
6.10 Prior and Concomitant Medications 
Prior medications are defined as all medications starting before the date of first dose of IMP. 
Concomitant medications are defined as medications taken on or after the date of first dose of IMP. 
Prior and concomitant medications will be coded using B3 WHO Drug Global - Sep 2018 A 
tabulation will be produced for concomitant medications presented by treatment group for Safety 
population. Concomitant medications will be summarized using Anatomic Therapeutic Chemical 
(ATC) Level 2. 
All medication data will be listed. 
6.11 Exposure to Study IMP 
Extent of exposure (number of days of exposure to IMP) will be presented by treatment group for 
the Safety Population.   
The number (percent) of patients that fall into the following “number of interruptions” categories 
(0, 1, 2, >3 interruptions) and duration of longest interruption of IMP will be summarized by 
treatment group for Safety Population.  
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6.12 Treatment Compliance 
Overall compliance will be presented by treatment group and overall for the Safety population 
descriptively (n, mean, standard deviation, median, minimum and maximum) and number 
(percent) of patients in the following compliance categories (<50%, 50 to <80%, 80 to 100%, 
>100%).
6.13  Efficacy Analyses 
Due to the termination of this study, only certain efficacy and GHO endpoints will be 
summarized.  
6.13.1 
Secondary Endpoints and analyses 
6.13.1.1 ALSFRS-R 
The ALSFRS-R is a short ordinal rating scale used to determine patients’ patientive 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’, ‘climbing stairs’, ‘dyspnea’, ‘orthopnea’ and 
‘respiratory insufficiency’). Each activity/item is rated on a 5-point scale (from 0 to 4), giving a 
maximum ALSFRS-R score of 48 (sum of all 12 items). The higher the score the better 
functioning. 
Absolute and change from baseline  in ALSFRS-R will be summarized by visit for the in-trial 
period by treatment group.  
6.13.1.2 % predicted SVC 
SVC measures the volume that can be exhaled from a full inhalation after exhaling to a maximum 
as slowly as possible. SVC is collected at in-clinic and at home visits. Several attempts at the SVC 
are conducted and the highest SVC result from the acceptable attempts is considered the best 
attempt/result and used for analysis.  The spirometer used in-clinic for assessments is different 
from the one that will be used for an at home visit. Additionally, in-clinic visit spirometry results 
were subject to centralized over-read analysis whereas the home visit results were not.  PPSVC 
will be derived as follows for SVC assessments: 
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PPSVC = (SVC ÷ predicted SVC (PSVC)) * 100 
where PSVC is derived per European Community of Coal and Steel (ECCS) reference equations: 
•
If male: PSVC = 0.061 x height – 0.028 x age – 4.65
•
If female: 0.0466 x height – 0.024 x age – 3.28,  where [height units (cm); age units (year)]
 The quality of the spirometry results could impact interpretation of the results. Hence, data of 
“unacceptable” quality will be excluded from analysis.  For in-clinic assessments, if a spirometry 
assessment is assigned a best test review (BTR) grade of unacceptable, then this means the data 
does not meet ATS criteria for data quality and hence will be excluded from analysis. Although, 
spirometry results from home visits are not overread and an BTR grade isn’t assigned, the 
spirometric device will provide “error codes” for the attempts that are used to determine the best 
measurement.  These “error codes” represent specific issues with the measurement (e.g. error code 
Q means No stable baseline) which may lead to excluding the best attempt from analysis. This will 
depend on the error code(s) provided by the device (e.g., any attempt with error code of Q, an 
assessment with combination of  O (no plateau) or  (expiration of less than 6 sec) with error code 
N (no repeatability)).    
Absolute and change from baseline  in PPSVC will be summarized by visit for the in-trial period 
by treatment group.  
6.13.2 
Exploratory Endpoints 
•
Change from baseline in EQ-5D-5L VAS score over a treatment period of 76 weeks
•
Number (Percent) of patient’s responses to EQ-5D-5L dimensions[*] over a treatment
period of 76 weeks
6.13.3 
Multiplicity 
Not applicable.  No inferential analyses are plan. 
6.14 Safety Analyses 
Unless otherwise stated, safety summaries are based on the on-treatment period, however, all data 
will be listed in the appropriate listings.  
6.14.1 
Adverse Events 
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A »pre-treatment AE« is defined as any AE that has an onset prior to the first dose of IMP. This
may include AEs with an onset date in original study, ORARIALS-01 (imported data). This data 
will be listed.   
A »treatment emergent adverse event« (TEAE) is defined as
•
Any AE that has an onset on or after the date of first dose of IMP or
•
Any pre-existing AE that has worsened in severity after the first dose of IMP.
A treatment-related AE is defined as an AE that is being assessed as probably or possibly related 
to the IMP. If an AE has missing relationship it is assumed to be related to the IMP and assigned 
as “probably related” to the IMP for analysis purposes. 
Maximum severity will be assumed for an AE with missing severity. 
An on-treatment period TEAE is defined as  
•
Any TEAE that has an onset in the on-treatment period as defined for safety (see section
6.2.2.1).
An in-trial period TEAE is defined as 
•
Any TEAE that has an onset during the in-trial period (see Section 6.2.1)
Maximum severity will be assumed for an AE with missing severity. 
The following tables will be presented for AEs: 
•
Overall incidence and the number of TEAEs (on-treatment and in-trial period), Serious
TEAE (SAEs; on-treatment and in-trial period), on-treatment period treatment related
TEAEs, on-treatment period treatment related SAEs, on-treatment period TEAEs leading
to IMP withdrawal, and on-treatment period TEAEs leading to IMP interruption.
•
TEAE by system organ class and preferred term, incidence and number of events
•
Treatment related TEAE by system organ class and preferred term, incidence and number
of events
•
Serious TEAE by system organ class and preferred term, incidence and number of events
•
Treatment related Serious TEAE by system organ class and preferred term, incidence and
number of events
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•
TEAE by system organ class, preferred term and maximum severity, incidence
•
TEAE by system organ class, preferred term and relationship, incidence
•
TEAEs leading to IMP withdrawal by system organ class and preferred term, incidence
and number of events
•
TEAEs leading to IMP Interruption by system organ class and preferred term, incidence
and number of events
•
Liver-Related Investigations, Signs and Symptoms (SMQ) , incidence and number of
events
•
Drug Related Hepatic Disorders, Severe Events only (SMQ), incidence and number of
events
•
In-trial period
o
TEAE by system organ class and preferred term, incidence and number of events
o
Serious TEAE by system organ class and preferred term, incidence and number of
events
•
Listing of (all) AEs
•
Listing of Serious AEs
Overall incidence of deaths and a listing of all deaths will be presented. Deaths are AEs with 
reported outcome of Fatal or a reported death due to disease progression (latter would not be 
captured as an AE).  
6.14.2 
Laboratory Data 
Individual lab parameters will be summarized descriptively by treatment and visit. Descriptive 
statistics will be presented for each hematology and serum chemistry parameter. In addition to the 
summaries detailed previously, geometric mean and associated CV[§] of the ratio-to-baseline and 
observed value of each lab parameter for post-baseline will be output. 
[§]: The geometric mean is calculated as the exponentiated mean of the log-transformed parameter where
parameter is either observed value or ratio to baseline. The associated CV is calculated as 100exp 1 where
 is the variance of the log transformed parameter of interest.
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Each measurement (continuous data) will be classed as below (low), within (normal), or above 
(high) normal range, based on ranges supplied by the laboratory used. Number (%) of patients that 
fall out-side and within range will be reported by visit.  
Listings of patients with parameter results considered to be clinically significantly abnormal by 
investigator will be presented. The listings will list all lab parameter results where at least one 
value is considered clinically significantly abnormal.   
Furthermore, 
•
a list of all (in-trial) AEs in patients with ALAT or ASAT ≥ 3 × ULN (in-trial).
•
a list of all (in-trial) AEs in patients fulfilling criteria {ALAT ≥ 3 × ULN and eosinophilia[*]
> 5%} or {ASAT ≥ 3 × ULN and eosinophilia > 5%} (in-trial).
[*]: SDTM.LB$LBTEST=”Eosinophils/Leukocytes” 
All clinical safety lab parameters captured for this study with defined PCS values (Appendix 2) 
will be summarized descriptively by visit and overall, respectively.  
Liver Parameter Categories of Potentially Clinical Significance[*] 
•
ALAT (Alanine Aminotransferase) or ASAT (Aspartate Aminotransferase) ≥ 3 × ULN
•
ALAT or ASAT ≥ 5 × ULN
•
ALAT or ASAT ≥ 8 × ULN
•
ALAT or ASAT ≥ 20 × ULN
•
Total Bilirubin ≥ 2 × ULN
•
ALP ≥ 2 × ULN
•
ALP ≥ 3 × ULN
•
(ALAT or ASAT ≥ 3 × ULN) & Total Bilirubin ≥ 2 × ULN & ALP ≤ 1.5 × ULN
•
ALAT ≥ 3 × ULN
•
ALAT ≥ 5 × ULN
•
ALAT ≥ 8 × ULN
•
ALAT ≥ 20 × ULN
•
ALAT ≥ 3 × ULN & Total Bilirubin ≥ 2 × ULN & ALP ≤ 1.5 × ULN
•
ASAT ≥ 3 × ULN
•
ASAT ≥ 5 × ULN
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•
ASAT ≥ 8 × ULN
•
ASAT ≥ 20 × ULN
•
ASAT ≥ 3 × ULN & Total Bilirubin ≥ 2 × ULN & ALP ≤ 1.5 × ULN
[*]: The single-parameter categories, like e.g. “ALAT ≥ 3 × ULN” is simply a categorization of the individual recorded 
value (AVAL in CDISC terminology). For “by visits” summaries, the data will be “in-windowed” records, whereas 
for “overall” summaries also “not in-windowed” records are eligible for summary. 
For multi-parameters categories like e.g. “ALAT or ASAT ≥ 3.0 × ULN & Total Bilirubin ≥ 2 × ULN & ALP ≤ 
1.5 × ULN”, because of windowing being parameter specific, it is important that parameters get compared/merged 
not by visits (after relocation/windowing) but based on the original sample dates (in CDISC terminology either
“VISITNUM” or “ADT”). 
The above categorical parameters are to be presented in one table for “by visit” and one table for 
“overall” summaries, respectively. 
Furthermore, the following categorical summaries will be summarized descriptively overall: 
•
ALAT or ASAT ≥ 5 × ULN for more than 14 days[§]
•
(ALAT or ASAT ≥ 3 × ULN) & (Total Bilirubin ≥ 2 × ULN)
•
(ALAT or ASAT ≥ 3 × ULN) and with ongoing eosinophilia > 5% (in SDTM.LB$LBTEST
= ”Eosinophils/Leukocytes”)
[§]: either or both “ALAT ≥ 5 × ULN for 14 days” and/or “ASAT ≥ 5 × ULN for 14 days”.
The above categorical parameters are to be presented in one table for “overall” summary. 
The following creatinine related categorical summaries will be summarized both by visit and 
overall, respectively: 
(Creatinine) Categories of Potentially Clinical Significance 
•
Post baseline value ≥ 1.5 × baseline value
•
Post-baseline value ≥ 2 × baseline value
•
Post-baseline value ≥ 3 × baseline value
The above categorical creatinine parameters are to be presented in one table for “by visit” and one 
table for “overall” summaries, respectively. 
6.14.3 
Vital Signs 
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Descriptive statistics for observed values and changes from baseline in the following vital signs 
will be presented by treatment group and visit: 
•
Systolic blood pressure (mmHg)
•
Diastolic blood pressure (mmHg)
•
Pulse rate (bpm)
•
Respiration rate (breath / min)
•
Body temperature (degrees Celsius)
•
Body weight (kg)
In addition, the Number (%) of patients that have potentially clinically significant vital sign 
values overall and by visit will be presented: 
Vital Sign Parameters Potentially Clinically Significant Values 
Parameters 
Unit 
Reference 
Range 
PCS LOW 
PCS HIGH 
Pulse rate 
Beats/min 
60-100
< 50 and decrease of ≥ 15 
>120 and increase of ≥ 15
Diastolic Blood Pressure 
mmHg 
60-90
≤ 50 and decrease of ≥ 15 
> 105 and increase of ≥ 15
Systolic Blood Pressure 
mmHg 
100-140
≤ 90 and decrease of ≥ 20 
> 180 and increase of ≥ 20
Weight 
Kg 
decrease of ≥ 7% 
increase of ≥ 7% 
6.14.4 
Electrocardiogram Data 
Summary tables in relation to the overall interpretation (Normal, Abnormal NCS, and Abnormal 
CS) by visit and any time, post-baseline will be presented. 
6.14.5 
C-SSRS 
Number (percent) of patients with Suicidal Ideation, Suicidal Behavior, and Self-Injurious 
Behavior without Suicidal Intent Based on the C-SSRS will be summarized for baseline and any 
Time, Post-baseline separately. 
7 CHANGES TO PLANNED PROTOCOL ANALYSIS 
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Due to termination of the study, 
•
Objective 2 was changed (highlighted text removed)
To evaluate the long-term efficacy of arimoclomol treatment of ALS, using intervention-
free survival, disease progression and progression of respiratory dysfunction
•
Objective 3 had the following objective removed:
To investigate plasma levels of arimoclomol following administration of 744 mg/day (to
be described in a separate PK analysis plan and report).
•
Trial analysis sets -  Change in Analysis sets.
Protocol specified that “Efficacy analyses will be performed on subjects receiving at least 
one dose of IMP in the in the OLE trial, with a Baseline (of the present trial) and at least one 
post-baseline value of ALSFRS-R and SVC if applicable.”   However, now efficacy analyses 
will be performed on the safety population which consists of all enrolled subjects receiving 
at least one dose of arimoclomol in the OLE trial. 
•
Time to PAV/Tracheostomy/Death was removed as an efficacy endpoint.
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8 REFERENCES 
1. SAS Institute Inc., Cary, NC, 27513, USA
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9 LIST OF TABLES, FIGURES AND LISTINGS 
The following table includes details of the tables, figures and listings to be included within each 
section of the eCTD. The eCTD section is shown in bold. The following validation methods maybe 
used:  
•
Independent programming of numbers and manual review of format (IP)
•
Independent programming by statistician of numbers and manual review of format (Stat
IP)
•
Manual review (MR)
•
Code review (CR)
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number 
(if repeat)
Items in bold are not table titles but references to the section headings within eCTD. 
14.1 
Demographics Data
14.1.1 
Disposition
14.1.1.1 
Patient Disposition, Analysis Populations Enrolled 
Population In-trial period
IP 
14.1.1.2 
Patient Disposition,  Early Withdrawals Safety 
Population In-trial Period
IP 
14.1.1.3 
Patient Disposition,  Premature Discontinuation of IMP 
Safety Population In-trial Period
IP 
14.1.1.4 
Patient Disposition, Safety population by Country and 
site Safety Population In-trial Period
IP 
14.1.1.5 
Patient Disposition, Major Protocol Deviations 
Safety Population In-trial Period
IP 
14.1.2 
Demographics 
14.1.2
Demographics Safety Population In-trial Period
IP
14.1.3 
Baseline Characteristics 
14.2 
Efficacy Data
14.2.1 
Primary Efficacy Endpoint 
14.2.2 
Secondary Efficacy Endpoints 
14.2.2.1 
ALSFRS-R, Descriptive Summary by Visit Safety 
Population In-trial Period
IP 
14.2.2.2 
% Predicted SVC, Descriptive Summary by Visit Safety 
Population In-trial Period
IP 
14.2.3 
Exploratory Endpoints 
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Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number 
(if repeat)
14.2.3.1 
EQ-5D-5L, Categorical Summary of Dimensions by 
Visit Safety Population In-trial Period
IP 
14.2.3.2 
EQ-5D-5L, Descriptive Summary of VAS Score by Visit 
Safety Population In-trial Period
IP 
14.3 
Safety Data
14.3.1 
Displays of Adverse Events
14.3.1.1 
Adverse Events, Overall Summary of Adverse Events 
Safety Population In-trial Period
IP 
14.3.1.2 
Adverse Events,  TEAEs by Primary System Organ Class 
and Preferred Term Safety Population On-treatment 
Period
IP 
14.3.1.3 
Adverse Events, Treatment Related TEAEs by Primary 
System Organ Class and Preferred Term Safety 
Population On-treatment Period
IP 
14.3.1.4 
Adverse Events,  Serious TEAEs by Primary System 
Organ Class and Preferred Term Safety Population 
On-treatment Period
IP 
14.3.1.5 
Adverse Events,  Treatment Related Serious TEAEs by 
Primary System Organ Class and Preferred Term 
Safety Population On-treatment Period
IP 
14.3.1.6 
Adverse Events,  TEAEs Leading to IMP Withdrawal by 
Primary System Organ Class and Preferred Term 
Safety Population On-treatment Period
IP 
14.3.1.7 
Adverse Events,  TEAEs Leading to IMP Interruption by 
Primary System Organ Class and Preferred Term 
Safety Population On-treatment Period
IP 
14.3.1.8 
Adverse Events,  TEAEs by Primary System Organ Class, 
Preferred Term and Severity Safety Population 
On-treatment Period
IP 
14.3.1.9 
Adverse Events,  TEAEs by Primary System Organ Class, 
Preferred Term and Relationship Safety Population 
On-treatment Period
IP 
14.3.1.10 
Adverse Events,  TEAEs by Primary System Organ Class 
and Preferred Term Safety Population In-trial Period
IP 
14.3.1.11 
Adverse Events,  Serious TEAEs by Primary System 
Organ Class and Preferred Term Safety Population
IP 
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Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number 
(if repeat)
In-trial Period
14.3.1.12 
Adverse Events,  TEAEs - Liver-Related Investigations, 
Signs and Symptoms  (SMQ) Safety Population 
On-treatment Period
IP 
14.3.1.13 
Adverse Events,  TEAEs -  Drug Related Hepatic 
Disorders, Severe Events only (SMQ) Safety Population 
On-treatment Period
IP 
14.3.2 
Listings of Deaths, Other Serious and Significant 
Adverse Events
14.3.2.1
Deaths, Listing – Safety Analysis Population
IP
14.3.2.2
SAE Listing – Safety Analysis Population
IP
14.3.3 
Narratives of Deaths, Other Serious and Certain Other 
Significant Adverse Events 
14.3.4 
Abnormal Laboratory Values
14.3.4.1 
Hematology, Descriptive Summary of Parameters by 
Visit-Safety Population-On-treatment Period
IP 
14.3.4.2
Hematology, Categorical Summary of Potentially 
Clinically Significant Values at Any Time, Post-
Baseline-Safety Population-On-treatment Period
IP 
14.3.4.3
Hematology, Categorical Summary of Potentially 
Clinically Significant Values at by Visit-Safety 
Population-On-treatment Period
IP 
14.3.4.4 
Hematology, Categorical Summary of In/Out of Normal 
Range Values by Visit Safety Population 
On-treatment Period
IP 
14.3.4.5
Chemistry, Descriptive Summary of Parameters by Visit-
Safety Population-On-treatment Period
IP 
14.3.4.6
Chemistry, Categorical Summary of Potentially 
Clinically Significant Values at Any Time, Post-
Baseline-Safety Population-On-treatment Period
IP 
14.3.4.7
Chemistry, Categorical Summary of Potentially 
Clinically Significant Values at by Visit-Safety 
Population-On-treatment Period
IP 
14.3.4.8
Chemistry, Categorical Summary of In/Out of Normal 
Range Values at by Visit-Safety Population-On-
treatment Period
IP 
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Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number 
(if repeat)
14.3.4.9
Lab Parameters, Categorical Summary of Potentially 
Clinically Significant Categories by Post-Baseline Visit-
Safety Population-On-treatment Period
IP 
14.3.4.10 
Lab Parameters, Categorical Summary of Potentially 
Clinically Significant Categories by at Any Time, Post-
Baseline-Safety Population-On-treatment Period
IP 
14.3.4.11 
All Adverse Events in patients with ALAT or ASAT ≥ 
3x ULN during the in-trial period, Listing 
Safety Population In-trial Period
IP 
14.3.4.12 
All Adverse Events in patients with ALAT or ASAT ≥ 
3x ULN in combination with eosinophils > 5% during 
the in-trial period, Listing Safety Population In-trial 
Period
IP 
14.3.4.13 
Lab parameters,  listing of patients with ALAT or ASAT 
≥  3x ULN in combination with eosinophils > 5%, 
Listing 
Safety Population In-trial Period
IP 
14.3.4.14 
Hematology Lab Parameter Results where at least one 
value is Abnormal Clinically Significant, Listing 
Safety Population In-trial Period
IP 
14.3.4.15 
Chemistry Lab Parameter Results where at least one 
value is Abnormal Clinically Significant, Listing-Safety 
Population-In-trial Period
IP 
14.3.4.16 
Hematology Lab Parameter Results where at least one 
value is Potentially Clinically Significant, Listing-Safety 
Population-In-trial Period
IP 
14.3.4.17 
Chemistry Lab Parameter Results where at least one 
value is Potentially Clinically Significant, Listing-Safety 
Population-In-trial Period
IP 
14.3.5 
Extent of Exposure, Dosage Information, And 
Compliance
14.3.5.1
Extent of Exposure Safety Population In-trial Period
IP
14.3.5.2
Investigational Medicinal Product Interruptions
IP
14.3.5.3
Overall Treatment Compliance
14.3.6 
Vital Signs and Physical Examination
14.3.6.1
Vital Signs, Descriptive Summary of Parameters by Visit
IP
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Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number 
(if repeat)
Safety Population On-treatment Period
14.3.6.2.1 
Vital Signs, Categorical Summary of Potentially 
Clinically Significant Categories by Post-Baseline Visit 
Safety Population On-treatment Period
IP 
14.3.6.2.2 
Weight, Categorical Summary of Potentially Clinically 
Significant Categories by Post-Baseline Visit 
Safety Population On-treatment Period
IP 
14.3.7 
Other Safety
14.3.7.1 
ECG, Categorical Summary of Overall Interpretation of 
findings by Visit Safety Population On-treatment Period
IP 
14.3.7.2 
C-SSRS, Number and Percentage of patients with
Suicidal ideation, Suicidal Behavior and Self-Injurious
Behavior without Suicidal Intent at baseline Safety
Population On-treatment Period
IP 
14.3.7.3 
C-SSRS, Number and Percentage of patients with
Suicidal ideation, Suicidal Behavior and Self-Injurious
Behavior without Suicidal Intent at Any Time Post-
Baseline Safety Population On-treatment Period
IP 
14.3.8 
Concomitant Medication
14.3.8.1 
Concomitant Medications -Safety Population In-trial 
Period
IP 
14.4 
PK Tables
14.5 
PD Tables
14.6 
Other Data
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Page 31 of 37
Figure 
Number 
Figure Title 
Validation 
Method 
Shell 
Number (if 
repeat)
14.2.1.1
ALSFRS-R Total Score by Visit Safety Population In-trial Period
IP
14.2.1.2
% Predicted SVC by Visit  Safety Population In-trial Period
IP
14.2.1.3 
Hematology, Mean by Visit – Safety population On-treatment 
period
IP 
14.2.1.4
Chemistry, Mean by Visit – Safety population On-treatment period 
IP
Confidential


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Orphazyme A/S 
Protocol Number: 
ORARIALS-02 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
REF: Worldwide-TMP-QA-001f-1.3 
Page 32 of 37
Listing 
Number 
Listing Title 
Validation 
Method 
Shell 
Number 
(if repeat)
16.2 
Subject Data Listings
16.2.1 
Discontinued Subjects 
16.2.1.1 
Subject Disposition and Reasons for Discontinuation 
from Study- Safety Population-In-trial Period
IP 
16.2.1.2
Early Discontinuation From Study Drug Safety 
Population-In-trial Period
IP 
16.2.1.3
Analysis Population Enrolled Population In-trial Period
IP
16.2.2 
Protocol Deviations 
16.2.2.1
Protocol Deviations-Safety Population-In-trial Period
IP
16.2.2.2
Site-Level Subject Related Protocol Deviations Safety 
Population-In-trial Period
IP 
16.2.3
Subjects Excluded from The Efficacy Analyses
16.2.4 
Demographic Data
16.2.4.1 
Demographic Data Safety Population In-trial period
IP
16.2.4.2
Medical History Safety Population In-trial period
IP
16.2.5 
Compliance and / or Drug Concentration Data
16.2.5.1
Prior/Concomitant Medication-ITT Population-In-trial 
Period
IP 
16.1.5.2 
Investigation Medicinal Product Administration: Missed 
Doses, Extra Doses and/or Temporary IMP 
interruptions-ITT Population
IP 
16.1.5.3 
Investigation Medicinal Product Administration: Overall 
Compliance and Extent of exposure-ITT Population
IP 
16.2.6 
Individual Efficacy Response Data 
16.2.6.1 
ALSFRS-R total Score - Safety Population-In-trial 
Period
IP 
16.2.6.2
SVC  Safety Population In-trial period
IP
16.2.6.3
EQ-5D-5L-Safety Population In-trial Period
16.2.7 
Adverse Event Listings 
16.2.7.1
Adverse Events Safety population in-trial Period
IP
16.2.8 
Individual Laboratory Measurements and Other 
Safety 
16.2.8.1
Hematology Safety population-in-trial Period
IP
16.2.8.2
Chemistry Safety population-in-trial Period
IP
16.2.8.3
Vital Signs Safety population-in-trial Period
IP
Confidential


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Orphazyme A/S 
Protocol Number: 
ORARIALS-02 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
REF: Worldwide-TMP-QA-001f-1.3 
Page 33 of 37
Listing 
Number 
Listing Title 
Validation 
Method 
Shell 
Number 
(if repeat)
16.2.8.4
ECG Findings Safety population-in-trial Period
IP
16.2.8.5
C-SSRS Safety population-in-trial Period
IP
Confidential


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Orphazyme A/S 
Protocol Number: 
ORARIALS-02 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
REF: Worldwide-TMP-QA-001f-1.3 
Page 34 of 37
10 APPENDICES 
10.1 Appendix 1 
Mapping WorldWide protocol deviation categories to Orphazyme defined categories 
Orphazyme Category
WW categories
INCLUSION / EXCLUSION CRITERIA
Eligibility Criteria
WITHDRAWAL CRITERIA
Other: Withdrawal
IMP COMPLIANCE
Investigational Product
DISALLOWED CONCOMITANT MEDICATION
Prohibited Medications
OTHER 
Informed Consent 
Other: Subject Trial ID Card 
Study Procedures 
Safety 
Other: Miscellaneous
10.2 Appendix 2 
Laboratory Test 
CDISC 
Unit 
PCS LOW 
PCS HIGH 
Haematology / Coagulation 
B-haemoglobin
HGB 
g/dL 
≤ 9.5 (women); 
≤ 11.5 (men) 
≥ 16.5 (women); 
≥ 18.5 (men) 
B-erythrocytes (red cell count)
RBC 
X 10E12/L 
≤ 3.5 (women); 
≤ 3.8 (men) 
≥ 6.0 (women); 
≥ 7.0 (men) 
B-haematocrit 
(packed 
cell
volume)
HCT 
V/V 
≤ 0.32 (women); 
≤ 0.37 (men) 
≥ 0.50 (women); 
≥ 0.55 (men) 
B-total leucocyte (white cell
count)
WBC 
X 10E9/L 
≤ 2.8 
≥ 16 
B-neutrophils/leucocytes
NEUTLE 
% 
≤ 20 
≥ 85 
B-eosinophils/leucocytes
EOSLE 
% 
- 
≥ 10 
B-basophils/leucocytes
BASOLE 
% 
- 
≥ 10 
B-lymphocytes/leucocytes
LYMLE 
% 
≤ 10 
≥ 75 
Confidential


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Orphazyme A/S 
Protocol Number: 
ORARIALS-02 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
REF: Worldwide-TMP-QA-001f-1.3 
Page 35 of 37
Laboratory Test 
CDISC 
Unit 
PCS LOW 
PCS HIGH 
B-monocytes/leucocytes
MONOLE 
% 
- 
≥ 15 
B-thrombocytes
(platelet 
count)
PLAT 
X 10E9/L 
≤ 75 
≥ 600 
P-INR (prothrombin ratio)
INR 
Ratio 
- 
≥ 2.0 
B-prothrombin time
PT 
Sec 
- 
≥ 18 
Liver 
S-aspartate aminotransferase
AST 
IU/L 
- 
≥ 3 x ULN 
S-alanine aminotransferase
ALT 
IU/L 
- 
≥ 3 x ULN 
S-bilirubin
BILI 
µmol/L 
- 
≥ 34 
S-bilirubin, direct
BILDIR 
µmol/L 
- 
≥ 12 
S-bilirubin, indirect
BILIND 
µmol/L 
- 
≥ 22 
S-alkaline phosphatase
ALP 
IU/L 
- 
≥ 3 x ULN 
S-gamma glutamyl transferase
GGT 
IU/L 
- 
≥ 200 
S-alpha-glutathione
S-
transferase (alpha-GST)
GSTAL 
µg/L 
- 
≥ 20 
Kidney 
S-creatinine
CREAT 
µmol/L 
- 
≥ 1.5 x ULN 
B-urea nitrogen (BUN)
BUN 
mmol/L 
- 
≥ 11 
Electrolytes 
S-sodium (natrium)
SODIUM 
mmol/L 
≤ 125 
≥ 155 
S-potassium (kalium)
K 
mmol/L 
≤ 3.0 
≥ 6.0 
S-calcium
CA 
mmol/L 
≤ 1.8 
≥ 3.0 
S-chloride
CL 
mmol/L 
≤ 90 
≥ 117 
Confidential


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Orphazyme A/S 
Protocol Number: 
ORARIALS-02 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
REF: Worldwide-TMP-QA-001f-1.3 
Page 36 of 37
Laboratory Test 
CDISC 
Unit 
PCS LOW 
PCS HIGH 
S-magnesium
MG 
mmol/L 
≤ 0.6 
≥ 1.3 
S-phosphate
(phosphorus, 
(inorganic))
PHOS 
mmol/L 
≤ 0.65 
≥ 1.95 
S-bicarbonate
BICARB 
mmol/L 
≤ 12 
≥ 38 
Endocrine / Metabolic 
B-glucose,
non-
fasting/unknown
GLUC 
mmol/L 
≤ 3.4 
≥ 9.4 
B-glucose, fasting
GLUC 
mmol/L 
≤ 3.0 
≥ 6.0 
S-glucose,
non-
fasting/unknown
GLUC 
mmol/L 
≤ 3.9 
≥ 11.1 
S-glucose, fasting
GLUC 
mmol/L 
≤ 3.5 
≥ 7.0 
B-glycosylated haemoglobin,
fasting
HBA1C 
% 
- 
≥ 6.5 
S-prolactin
PROLCTN 
mIU/L 
- 
≥ 1350 
S-protein (total)
PROT 
g/L 
≤ 45 
≥ 95 
S-albumin
ALB 
g/L 
≤ 27 
- 
Lipids 
S-cholesterol
total, 
non-
fasting/unknown
CHOL 
mmol/L 
- 
≥ 7.8 
S-cholesterol total, fasting
CHOL 
mmol/L
- 
≥ 6.2 
S-triglycerides,
non-
fasting/unknown
TRIG 
mmol/L 
- 
≥ 5.65 
S-triglycerides, fasting
TRIG 
mmol/L 
- 
≥ 4.2 
S-LDL
cholesterol, 
non-
fasting/unknown 
LDL 
mmol/L 
- 
≥ 5.3 
S-LDL cholesterol, fasting
LDL 
mmol/L 
- 
≥ 4.9 
Confidential


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Orphazyme A/S 
Protocol Number: 
ORARIALS-02 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
REF: Worldwide-TMP-QA-001f-1.3 
Page 37 of 37
Laboratory Test 
CDISC 
Unit 
PCS LOW 
PCS HIGH 
S-HDL
cholesterol, 
non-
fasting/unknown
HDL 
mmol/L 
≤ 0.8 
- 
S-HDL cholesterol, fasting
HDL 
mmol/L 
≤ 0.9 
- 
Cardiac / Skeletal / Muscle 
S-creatinine kinase (total)
CK 
IU/L 
- 
≥ 400 (women); 
≥ 750 (men) 
S-lactate dehydrogenase (total)
LDH 
IU/L 
- 
≥ 750 
Infection 
S-C-reactive protein
CRP 
mg/L 
≥ 25 
Urine 
Urinary pH 
PH 
≤ 4 
≥ 9 
Confidential