Clinical trial NCT03491462
Conditions: Amyotrophic Lateral Sclerosis
Keywords: Arimoclomol ALS
Sponsor: ZevraDenmark
Start date: 2018-07-31; Completion date: 2020-12-18
Enrollment: 245 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A multicenter, randomized, double-blind, placebo-controlled, parallel group trial to evaluate the efficacy and safety of arimoclomol in amyotropic lateral sclerosis (ALS)

Detailed description:
Screening up to 4 weeks Treatment up to 76 weeks

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

Protocol documents:
Prot_000.pdf: 
Protocol number: ORARIALS-01 
Date: 08-Jun-2020 
Version: Final 7.0 
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CLINICAL TRIAL PROTOCOL 
A Phase 3, Randomised, Placebo-Controlled Trial of 
Arimoclomol in Amyotrophic Lateral Sclerosis
Sponsor: Orphazyme A/S, Ole Maaløes Vej 3, DK-2200 Copenhagen N, Denmark 
Coordinating investigator: 
, MD PhD 
Protocol number: ORARIALS-01 
EudraCT No.: 2018-000137-13 
ClinicalTrials.gov Identifier: NCT03491462
Trial product name: Arimoclomol Capsules 
Date of Amendment: 08-Jun-2020 
Strengths of arimoclomol are presented throughout this document by weight of the citrate 
salt. 
The trial will be conducted according to the protocol and in compliance with Good Clinical Practice (GCP), 
with the Declaration of Helsinki and with other applicable regulatory requirements 
This document contains information which is the property of Zevra Denmark 
A/S and is provided here as part of the results registration on 
clinicaltrials.gov. It is understood that this information cannot and will not be 
disclosed to others without written approval from Zevra Denmark A/S.


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


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


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


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


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


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


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


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


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


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


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


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








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


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


 
 
 
 
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2. INTRODUCTION AND RATIONALE 
2.1 Amyotrophic Lateral Sclerosis 
Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig's disease, is a progressive, fatal 
neurodegenerative disorder. The loss of motor neurons causes the muscles under their control 
to weaken and waste away, leading to paralysis and death, usually due to respiratory failure, 
within 3-5 years of symptom onset. Symptoms include loss of motor control in hands, arms 
and legs, tripping and falling and bulbar symptoms with difficulty speaking, swallowing 
and/or breathing, persistent fatigue, and twitching and cramping of the muscles. In addition, 
cognitive and behavioural changes are often seen.  
Several mechanisms have been implicated in the pathogenesis of ALS. These include 
excitotoxicity, oxidative stress, neuro-inflammation, mitochondrial dysfunction, disrupted 
nucleocytoplasmic transport and impaired proteostasis characterised by protein misfolding 
and aggregation. Of these, the latter two are increasingly recognised as general molecular 
hallmarks of ALS (3).  
While rare in prevalence, ALS is considered one of the most common neuromuscular diseases 
worldwide. The incidence of ALS is estimated at between 1-3 per 100,000 individuals per 
year globally. The patient population in Europe and the United States is estimated to be 
approximately 50,000 patients and about 10 percent of ALS cases are inherited. While the 
mean age of onset is between 55 and 65 years, symptoms can begin at any adult age. The 
disease occurs more frequently in men than women, whereas prevalence is roughly the same 
throughout the world (4-5.4 per 100,000 individuals) with no ethnic, racial or socioeconomic 
differences.   
Around 10 percent of patients with ALS have ALS associated with pathogenic mutations 
(commonly referred to as ‘familial ALS’) and the remaining 90 percent are isolated or 
sporadic in nature and are denoted ‘sALS’. 
The focus of medical care is to give symptomatic management of patients with mild to 
moderate disease and easing (palliative) intervention in patients with severe or terminal 
disease. The care of ALS patients is often provided in multidisciplinary clinics, with a team 
comprised by respiratory therapist, physiotherapist, occupational therapist, dietician, speech 
consultant and social worker.  
There is significant unmet medical need for further treatment options as current therapies 
convey only modest treatment benefit. The only approved treatment for ALS in EU, riluzole 
(Rilutek®), has been granted a marketing authorisation in the EU in 1996 to extend life or the 
time to mechanical ventilation for patients with ALS. According to the product’s Summary of 
Product Characteristics (Rilutek® SmPC), clinical trials have demonstrated that Rilutek® 
extends survival for patients with ALS. Survival was defined as patients who were alive, not 
intubated for mechanical ventilation and tracheotomy-free. The mode of action of riluzole is 
not fully understood. It may exert its effect via an inhibitory effect on glutamate release, 
inactivation of voltage-dependent sodium channels, and/or ability to interfere with 
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Riluzole has since been approved as a 5 mg/mL oral suspension (Teglutik®, Tiglutik®) with a 
recommended dose of 100mg daily (50 mg every 12 hours). 
In May 2017, the Food and Drug Administration (FDA) approved edaravone (Radicava®, 
Radicut®), which is the first approved ALS treatment option for more than 20 years. 
Edaravone is thought to act as a free-radical scavenger which prevents oxidative stress 
damage to neurones. It is an intravenous infusion treatment for ALS and has been shown to 
reduce functional decline as measured by the ALS Functional Rating Scale-Revised 
(ALSFRS-R) by 33%. As the clinical trials were of short duration (6 months), there is no 
information available on the effect on survival. 
2.2 Arimoclomol 
Orphazyme A/S (hereafter referred to as Orphazyme) is developing arimoclomol for treatment 
of ALS.  
Arimoclomol amplifies the heat shock response under conditions of cellular stress (3). The 
heat shock response promotes natural folding of nascent proteins and refolding of damaged or 
mutated proteins via enhanced heat shock protein expression, a mechanism of action that is 
thought to be highly relevant to an essential and early pathophysiological event that leads to 
neurodegeneration in ALS (4,5). 
Notably, in super oxide dismutase 1 (SOD1) mutant mice that model some of the features of 
human SOD1 ALS, arimoclomol amplifies the production of heat shock proteins, rescues 
motor neurons, improves neuromuscular function and extends lifespan, even when treatment 
is initiated after the emergence of clinical and pathological manifestations of disease (6, 7).   
A major hallmark of sporadic and most forms of familial ALS, is the presence of mis-
localised transactive response (TAR) DNA binding protein 43 (TDP-43) in cytoplasmic 
inclusions in affected areas of the central nervous system (CNS) (9). TDP-43 belongs to a 
group of ribonucleic acid (RNA) binding proteins, several of which have been shown to be 
mutated in different forms of ALS (9), and is involved in regulation of RNA splicing and 
modulation of microRNA biogenesis (11). TDP-43 plays an important role in neuronal 
plasticity by regulating protein synthesis in dendrites (12), and mutated and misfolded forms 
are prone to toxic fibrillization in stress granules (11). Importantly, arimoclomol ameliorates 
TDP-43 pathology in a mouse model for multisystem proteinopathy, a disease that is tightly 
linked to ALS on a genetic level (13). Additional evidence of the relevance of heat shock 
response in ALS comes from preclinical data demonstrating that activation of the heat shock 
response leads to clearance of TDP-43 inclusions (14). Thus, augmentation of the heat shock 
response might remedy the mis-localisation and inclusion of TDP-43 and other ALS related 
proteins, and thereby be a promising target for new treatment (summarised in (15)). 
See the current version of the Investigator’s Brochure for further information (19). 
In conclusion, the mode of action of arimoclomol addresses fundamental pathophysiological 
processes of ALS and by doing so, arimoclomol may potentially slow the progression of the 
disease and the associated symptoms with or without riluzole treatment.  




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


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




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


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


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




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


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


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


 
 
 
 
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Figure 1: 
Trial Design 


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


 
 
 
 
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5. 
TRIAL POPULATION AND WITHDRAWAL 
5.1 
Subject Eligibility 
The investigator should only enrol subjects who meet all inclusion and none of the exclusion 
criteria, are not put at undue risk by participating in the trial and can be expected to comply 
with the protocol.  
The subject’s eligibility for the clinical trial must be checked according to the inclusion and 
exclusion criteria listed in Sections 5.2 and 5.3. 
In addition, section 10.4 should be consulted for any country-specific eligibility criteria. 
Any implementation of national requirements/law for the subject’s participation in the clinical 
trial will be ensured and described in the submission documentation to regulatory 
authorities/ethics committees, as applicable.  
5.2 
Inclusion Criteria 
1. Capable of- and willing to- provide written informed consent and comply with trial 
procedures. 
2. Subject is male or female ≥18 years of age. 
3. Subject meets revised El Escorial criteria for clinically possible, clinically probable / 
clinically probable ALS laboratory-supported, clinically definite ALS or clinically 
definite familial ALS laboratory-supported. 
4. 18 months or less since first appearance of weakness (e.g. limb weakness, dysarthria, 
dysphagia, shortness of breath). 
5. ALSFRS-R ≥35 and erect (seated) SVC % predicted ≥ 70% at Screening. 
6. Able and willing to travel to the site, and in the investigator’s opinion is likely to 
attend visits for at least 24 weeks. 
7. All sexually active female subjects of child-bearing potential (postmenarchal)* must 
agree not to intend to become pregnant and use a highly effective method of 
contraception** during the trial through 1 month after the last dose of trial medication. 
If the subject is a sexually active male with female partners of child-bearing potential 
(postmenarchal) he must use a condom with or without spermicide in addition to the 
birth control used by their partners during the trial until 3 months after the last dose of 
trial medication. 
8. Stable dose of riluzole (50 mg twice daily) for a minimum of 14 days prior to Day 1 
(Baseline) or has not taken it for 14 days prior to Day 1. 


 
 
 
 
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* Non child-bearing potential is defined as post-menopausal (minimum of 12 months with no 
menses and follicle-stimulating hormone in the post-menopausal range) or sterilisation 
(hysterectomy, oophorectomy, or bilateral tubal ligation). 
** Highly effective methods of contraception include combined (oestrogen and progestogen 
containing) hormonal contraception associated with inhibition of ovulation (oral, 
intravaginal, or transdermal); progestogen-only hormonal contraception associated with 
inhibition of ovulation (oral, injectable, or implantable); intrauterine device; intrauterine 
hormone-releasing system; bilateral tubal occlusion; and vasectomised partner. 
According to the recommendations from the Clinical Trial Facilitation Group (CTFG, 2014), 
sexual abstinence is considered a highly effective birth control method only if it is defined as 
refraining from heterosexual intercourse during the trial until 1 week after the last dose of 
trial medication (for female subjects of child-bearing potential) and for 3 months after the last 
dose of trial medication (for male subjects with female partners of child-bearing potential). 
The reliability of sexual abstinence needs to be evaluated by the investigator in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject. 
5.3 
Exclusion Criteria 
1. Tracheostomy or use of non-invasive ventilation for more than 2 hours during waking 
hours at the time of Screening and Baseline visits. 
2. Pregnant or breast-feeding. 
3. Current or anticipated use of diaphragmatic pacing during the trial. 
4. Exposure to any investigational treatment within 4 weeks or <5 half-lives of the 
Screening visit, whichever is longest and/or advanced therapy medicinal product 
(ATMP), i.e. treatments based on genes, cells or tissues and/or participated in any 
prior ALS clinical trial receiving active drug treatment (with the exception described 
in exclusion criterion 5). 
5. Treatment with edaravone within 4 weeks of the Baseline visit. However, up to 18 
subjects on stable (i.e. minimum 6 months’) treatment with edaravone and who 
otherwise fulfil the eligibility criteria are planned for enrolment (limited to countries 
where edaravone has a marketing authorisation for treatment of ALS). 
6. Any of the following medically significant conditions: 
a. Neurological impairment/dysfunction or unstable psychiatric illness that in 
the investigator’s opinion is likely to interfere with assessment of ALS 
disease progression. 
b. Clinically significant unstable medical condition other than ALS, which 
would present a risk to a subject to participate in the trial. 
c. Presence of dementia that impairs the ability of the subject to provide 
informed consent, according to the PI decision. 
d. Known or suspected allergy or intolerance to the IMP (arimoclomol or 
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e. Chronic infection particularly HIV or Hepatitis B or C. 
f. Clinically significant renal or hepatic disease. 
g. Aspartate aminotransferase and/or alanine aminotransferase, and/or lactate 
dehydrogenase ≥3 times the upper limit of normal [ULN], bilirubin≥2 times 
the ULN, or creatinine ≥1.5 times the ULN. Laboratory tests may be repeated 
once at Screening. Reasons to repeat laboratory tests may include that the 
medication causing laboratory abnormality was suspended, any other 
suspected cause may no longer exist, or to rule out laboratory error. 
h. Cancer that is currently under active treatment or is likely to require treatment 
during the trial that may alter the subject´s function and thereby interfere with 
assessment of ALS disease progression. 
i. Any other condition that in the investigator’s opinion would present a risk to 
a subject to participate in the trial, interfere with the assessment of safety or 
has an increased risk of causing death during the trial. 
5.4 
Screening, Screening Failures and Randomisation Procedure  
Trial participation begins once written informed consent is obtained (see Appendix 10.2.2 for 
details on the informed consent process). Once informed consent is obtained, a subject 
identification number (subject ID) will be assigned by a central interactive response 
technology (IRT) and the screening evaluations to assess eligibility criteria may begin. The 
subject ID will be used to identify the subject during the screening process and throughout 
trial participation, if applicable. A master log of all consented subjects will be maintained at 
the trial site.   
Screening may be up to 4 weeks prior to Baseline if a washout period for an investigational 
treatment is required (see exclusion criterion 4). The minimum screening period is set as one 
week for practical reasons (to ensure all results are available to determine eligibility at 
Baseline). If laboratory re-tests are required, these should be completed within the maximal 
4 weeks’ screening period.  
Screening failures are defined as subjects who consent to participate in the trial but are not 
subsequently randomly assigned to trial treatment. A minimal set of screening failure 
information is required to ensure transparent reporting of screening failure subjects to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements (30) 
and to respond to queries from regulatory authorities. Minimal information includes 
demography, screening failure details, eligibility criteria, and any AEs and SAEs. Follow-up 
of SAEs must be carried out according to Section 7.5.7.6. 
In principle subjects may not be rescreened however if the reason for screen failure is deemed 
to be due to acute illness, the subject may be rescreened following recovery. Likewise, screen 
failure due to safety laboratory abnormality may be repeated on one occasion. Subjects who 
have failed to qualify for trial participation due to the requirements for SVC according to 
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eligibility criteria of this protocol (amendment 4.0).  The appointed medical monitor should 
be notified of such occurrence. In the event of rescreening, the subject should be marked as a 
screen failure in IRT, electronic case report form (eCRF) for the first screening attempt and a 
new Subject ID should be generated for the second screening attempt. A cross reference 
between the two Subject IDs will be prompted in the IRT/eCRF. 
Only the assessment of ALSFRS-R and SVC at the Screening visit is used for determination 
of subject eligibility. The result of these assessments at the Baseline visit is used for analysis 
purposes and the value will not exclude the subject from trial participation. 
5.5 
Discontinuation  
A subject may withdraw from trial or from treatment at any time (prior to first dose or during 
treatment period) at his/her own request. A subject may be withdrawn at any time at the 
discretion of the investigator. Discontinued subjects will not be replaced. 
5.5.1 
Discontinuation from Treatment 
Reasons for permanent discontinuation of IMP are given in Section 6.5. 
If a subject discontinues treatment and does not meet any of the survival endpoint definitions 
the subject should be invited to attend the remaining trial visits as per the schedule of 
procedures. Additionally, a remote follow-up (Safety Follow Up) phone call should be 
scheduled for 2 weeks after the last treatment. 
Subjects who remain on the trial and do not take IMP will have telephone calls in place of in-
clinic visits and only the following assessments will be completed: ALSFRS-R, AE and 
concomitant medication (based on patient recall), and survival status.  If the subject has an 
ongoing AE possibly or probably related to an AE requiring clinical safety laboratory tests, 
in-clinic visits may be used to collect a central laboratory sample; samples should be collected 
until resolution or following agreement with the medical monitor. 
For subjects discontinuing treatment, the end of trial form must be completed in the eCRF and 
the final drug accountability must be performed. The reason for discontinuation of trial 
product must be recorded in subject’s medical records and the eCRF. 
5.5.2 
Discontinuation from the Trial 
Subjects who move to another CTIMP shall be withdrawn from this trial. Subjects who enter 
registry trials do not need to be withdrawn from this current trial. 
If a subject withdraws from the trial, the last in-person visit should be conducted as per the 
schedule of assessments for the End of Trial Visit and recorded as this visit in the eCRF. If 
the subject has not already discontinued treatment, the Safety Follow Up visit should also be 
scheduled for 2 weeks after the last treatment. 
If a subject withdraws from the trial, he/she may request the destruction of any samples taken 
and not tested however data and samples collected up to the point of withdrawal may not be 


 
 
 
 
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removed from the clinical database. The investigator must record this in the site’s trial records 
and notify the clinical research associate (CRA) and appointed medical monitor. 
Subjects and/or caregiver may be asked to sign an additional informed consent form prior to 
trial discontinuation to allow follow-up of the survival endpoints (PAV/tracheostomy/death) 
at the scheduled week 76. 
5.6 
Missed Visits and Lost to Follow-Up 
If a visit is missed, every effort should be made to ensure that as much information as 
practically possible is collected at a telephone contact as close to the scheduled visit date as 
possible. If the missed visit was expected to be in person, the assessments and procedures 
scheduled for remote visits should be followed. The subject should be advised to use IMP as 
supplied from the spare bottle and where the subject does not have sufficient IMP for the 
remaining visit interval, site staff should ensure that additional spare IMP is allocated via IRT 
and provided to the subject (by direct to patient shipment, as required). Subjects will be 
invited for the next scheduled visit according to visit schedule (Table 1). 
Subjects will be considered lost to follow-up if they repeatedly fail to return for scheduled in-
person visits and are unable to be contacted by the trial site (including remote visits or other 
appropriate means of follow-up). The threshold for being considered lost-to follow-up is set 
as 3 consecutive missed visits. 
The following actions must be taken if a subject fails to return to the trial site for a required 
visit: 
• The trial site must attempt to contact the subject and reschedule the missed visit as 
soon as possible and counsel the subject on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the subject wishes to and/or 
should continue in the trial. If a subject is no longer able to travel to the trial site an in-
person visit may be conducted in the subject’s home/residency (see section 7.1.7)  
• Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, if 
necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s 
medical record. 
• Should the subject continue to be unreachable, he or she will be considered to have 
withdrawn from the trial with a primary reason of lost to follow-up. 
As the subject has not withdrawn consent, a telephone call will be attempted at the scheduled 
week 76, and the following assessments will be completed: ALSFRS-R, AE, concomitant 
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At any time during the trial, dose de-escalation from 1200 mg/day (400 mg t.i.d.) to 
600 mg/day (200 mg t.i.d.) for tolerability may be considered (see Section 6.5). The subject 
will continue on this decreased dose for the remainder of the trial. 
6.3 
Interactive Web Response System 
A trial-specific IRT will be used for (amongst others); forward logistics of the supply chain, 
inventory management and randomised treatment assignment. A full description of 
functionalities will be included in an IRT user manual which will be provided to each trial 
site. This IRT can be accessed at any time via the internet with a telephone helpdesk back-up 
solution for emergency situations. Access to the IRT must be restricted to and controlled by 
authorised persons.  
6.4 
Treatment Assignment 
6.4.1 
Randomisation 
Subjects found to be eligible will be randomised via the IRT in a 2:1 ratio to one of the 
following treatments: 
a. 
1200 mg/day arimoclomol (400 mg t.i.d.) 
b. 
Placebo (matching) 
 
Treatment assignment will also be stratified by the presence or absence of a background 
treatment with riluzole. 
6.4.2 
Blinding 
This is a double-blinded trial in which arimoclomol and placebo are visually identical and 
matched for taste. 
Neither the subject nor any of the investigator site staff or Orphazyme staff (included Contract 
Research Organisation (CRO) delegated staff) who are involved in the treatment or clinical 
evaluation and monitoring of the subjects will be aware of the treatment received. The 
packaging and labelling of the IMPs will contain no evidence of their identity.  
The DMC may have access to unblinded data. 
6.4.3 
Emergency Unblinding of Individual Subject Treatment  
The randomisation code for an individual subject may be broken if knowledge of the assigned 
treatment would influence the care of the subject in a medical emergency. Facility to unblind 
individual subject is provided for investigators. The circumstances under which an individual 
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immediate management of the subject should take precedence in an emergency situation and 
the final decision to unblind a subject is the sole responsibility of the investigator.  
Emergency unblinding is performed in the IRT. For clinicians outside of the clinical trial who 
do not have access to this system, unblinding will occur by proxy by the investigator. 
Investigator contact details will be provided via the subject trial card. 
Immediately after an unblinding event, the IRT will automatically distribute an unblinding 
notification email. This notification will be unblinded to the requester and will be blinded for 
all other nominated recipients; medical monitor and selected other representatives of the 
sponsor e.g. clinical safety, medical director, trial manager. 
Whenever a code is broken, the investigator must print the unblinding notification email, sign 
and date the document to acknowledge awareness of the event and file in the investigator site 
file. The reason for code break should be documented in the medical record. 
If the code has been broken, the subject must be discontinued from the trial.  
End of trial procedures should be observed, see Section 5.5. 
6.5 
Dose Modification and IMP Discontinuation  
6.5.1 
Permanent Discontinuation of IMP 
In case of a safety concern or unacceptable intolerability, the IMP may be permanently 
discontinued at the investigator’s discretion. In case of pregnancy or intention to become 
pregnant the trial product must be discontinued (see section 7.5.7.7 for reporting of 
pregnancies in the trial). The primary reason for discontinuation of the IMP must be specified 
in the eCRF.  
According to the FDA Guidance for Industry on Drug-Induced Liver Injury (DILI) (39), IMP 
must be permanently discontinued in the case of the following: 
• ALAT or ASAT >8 x ULN 
• ALAT or ASAT >5 x ULN for more than 2 weeks 
• ALAT or ASAT >3 x ULN and bilirubin >2 x ULN or International Normalised Ratio 
(INR) >1.5) 
• ALAT or ASAT >3 x ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
 
If a subject reaches a trial survival endpoint (e.g. tracheostomy or PAV), the IMP will be 
permanently discontinued. The subject will be offered to participate in an open-label 
extension which will be conducted as a separate trial. 
If a subject is no longer able to attend the clinic, nor have the option of a home visit via an 
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monitoring, the IMP will be permanently discontinued. The subject may remain on the trial 
without IMP. 
For procedures related to discontinuation, see Section 5.5. 
6.5.2 
Temporary Halt of IMP and Dose Modification 
A temporary halt of IMP treatment of up to 4 weeks is permitted if a subject experiences an 
intolerable AE. The interruption of IMP should be as short as possible, and the appointed 
medical monitor should be consulted prior to re-initiation of the intended 1200 mg/day (400 
mg t.i.d.) dose.   
If the subject experiences the same intolerable AE after re-challenge with the intended dose, 
dose de-escalation from 1200 mg/day (400 mg t.i.d.) to 600 mg/day (200 mg t.i.d.) may be 
considered following consultation with the appointed medical monitor. The subject will 
continue this decreased dose for the remainder of the trial. If this reduced dose is not 
tolerated, the IMP must be discontinued permanently. 
This sequence of events can be implemented only once for intolerable AEs within a given 
organ/body system. If the subject experiences a different intolerable adverse event within a 
different organ/body system, this sequence of events can be repeated for that AE. 
Likewise, a temporary halt of IMP treatment of up to 4 weeks is permitted in circumstances 
where a concurrent procedure or concomitant treatment for an acute condition requires 
withdrawal of IMP administration. The circumstances under which a temporary halt is 
initiated should be discussed with the appointed medical monitor. 
Re-Challenge in Case of Increased Transaminases  
If in the Investigator’s judgement, a temporary halt in IMP is instituted because of elevated 
transaminases, a re-challenge must not occur if the patient had the following: 
• ALAT or ASAT > 5 x ULN 
• ALAT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
• ALAT or ASAT > 3 x ULN AND TBL >2 x ULN   
 
IMP must also be discontinued for subjects with elevated transaminases where close 
observation (repeated laboratory tests) is not possible, see Section 7.5.10.2.  
The missed doses must be recorded in the eCRF. 
An Safety Follow Up visit should not be conducted when a temporary halt of IMP is initiated. 


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


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


 
 
 
 
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• Trade name or generic name 
• Reason for use (indication) 
• Dates of administration including start and stop dates 
• Dosage information including dose, route and frequency 
 
 
Investigators may prescribe concomitant medications or treatments to provide adequate 
supportive care as deemed necessary, except for medications listed in Section 6.9. The 
appointed medical monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
Concomitant medication for conditions other than ALS may be continued throughout the trial 
without any change in dosage whenever possible. 
Arimoclomol is an in vitro inhibitor of the OCT2, MATE-1, and MATE-2K transporters and 
consequently may inhibit the elimination of cationic drugs that are significantly eliminated by 
tubular secretion. In addition, arimoclomol is an in vitro substrate of the MATE-1 and 
MATE-2K transporters. Arimoclomol undergoes renal tubular secretion and concomitant 
treatment with drugs that are MATE1 or MATE-2K inhibitors may therefore lead to increased 
exposure of arimoclomol. Consequently, the concomitant use cationic drugs that are 
significantly eliminated by tubular secretion as well as drugs which are MATE1 or MATE-2K 
inhibitors should be administered with caution. These include but are not limited to: 
amantadine, amiloride, cimetidine, dopamine, famotidine, memantine, metformin, pindolol, 
procainamide, ranitidine, varenicline, oxaliplatin, dofetelide, trimetroprim, verapamil, 
levofloxacin, ciprofloxacin, moxifloxacin, pyrimethamine, ondansetron and quinidine. 
Additionally, in vitro studies show that arimoclomol is a direct inhibitor of CYP2D6 and may 
potentially cause increase in exposure of co-administered medications that are substrates of 
CYP2D6 when arimoclomol is dosed at 400 mg t.i.d (40). 
Since the magnitude of the potential increase cannot be predicted from in vitro data, caution is 
advised if arimoclomol is co-administered with medicinal products that are metabolised by 
CYP2D6. This may, for example, be relevant for Class I anti-arrhythmic, tricyclic 
antidepressants, betablockers, tramadol and selective serotonin reuptake inhibitors (SSRI’s) 
particularly if they are known to be sensitive and moderate sensitive CYP2D6 substrates 
and/or have a narrow therapeutic index.  
The product information for co-administered medicinal products should be consulted for 
guidance on concomitant treatment with a CYP2D6 inhibitor as dose adjustment of the 
CYP2D6 substrate may be appropriate. For compounds metabolised by CYP2D6 the dose 
may be reduced and for pro-drugs that are converted to the active compound by CYP2D6 the 
dose may be increased to ensure efficacy. 
 


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


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


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


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


 
 
 
 
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Training will be provided at face to face meetings and will also be available through the 
course of the trial as remediation including an on-line learning portal. 
Raters will be trained by completing the specific training courses for each scale. Certification 
will be issued as appropriate to each scale. 
7.1.4 
Subject Instruction 
7.1.4.1 
Investigational Medical Product 
IMP must be dispensed to subjects at the specified visits (see Table 1). IMP will be dispensed 
to the subject by the site, hospital pharmacy or equivalent. At the randomisation visit, the 
subjects will be instructed in the handling and administration of IMP (Section 6.2). 
7.1.4.2 
Subject Diary  
The subject must be provided with diaries to record IMP compliance, mode of administration, 
concomitant medication uses and use of non-invasive ventilation at the specified visits (see 
Table 1) the investigator or delegate should instruct the subjects on how to complete the diary 
at the Baseline visit and provide ongoing instruction as necessitated by data quality. The 
diaries dispensed to subjects should be collected at the specified visits (see Table 1) and data 
used to complete the eCRF. 
7.1.4.3 
Patient Reported Outcomes (PROs) 
Site staff who have undergone training will instruct subjects on the completion of 
questionnaires, measurements and assessments as described in Section 7.1.3. Education 
materials on minimising placebo response/ research alliance will be provided to all subjects 
and reviewed at the Screening visit. 
7.1.5 
Sequence of Assessments 
Assessments should be conducted in a sequence which allows for best clinical practice and 
patient experience while also ensuring protocol compliance. 
Patient and caregiver health-related quality of life (HRQoL) assessments should be completed 
prior to investigator efficacy assessments to minimise responder fatigue on most sensitive 
HRQoL scales and to limit investigator influence over patient and caregiver responses. 
Sequence of scale assessments; 
1. ALSFRS-R 
2. ECAS 
3. EuroQol Five-Dimensional, Five-Level Descriptive System (EQ-5D-5L) 
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5. Columbia Suicide Severity Rating Scale (C-SSRS) 
7.1.6 
Visit Scheduling 
All visits should be scheduled within the visit window (+/- 7 days) relative to the date of the 
Baseline visit. Every effort should be made to ensure that the in-person visits at Week 52 and 
Week 76 are arranged as close as possible to the scheduled time-point. 
7.1.7 
Subject Assessment when Unable to Travel to the Trial Site 
Following baseline, if a subject is still on IMP and is unable to attend the trial site for a 
scheduled in-person visit (e.g. due to ALS progression) or at Weeks 8, 16 and 24, a sub-set of 
clinical assessments as listed below in Table 6 will be conducted, in accordance with Table 1, 
Schedule of Trial Procedures. 
The visit will be conducted both in attendance at the subject’s home/residency and by 
telephone call. If the subject does not give consent for attendance to their home/residency, 
only the telephone call will be conducted and the appropriateness for the subject to continue 
trial participation will be assessed by the investigator, considering the ability to assess safety. 
Clinical assessment in the subject’s home/residency may be performed by site staff or 
contract nursing service, according to Table 1, Schedule of Trial Procedures. 
 




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


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


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


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


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


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


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


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


 
 
 
 
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Serious Adverse Event Definition 
An SAE is any AE that; 
• results in death. 
• is life-threatening. 
• requires inpatient hospitalisation or prolongation of existing hospitalisation. (Planned 
hospitalisation or planned prolonged hospitalisation do not fulfil the criteria for being 
an SAE but should be documented in the subject’s medical record). 
• results in persistent or significant disability/incapacity. 
• is a congenital anomaly/birth defect. 
or  
• is a medically important condition.  
 
A medically important condition is an event that may not be immediately life-threatening or 
result in death or hospitalisation but may jeopardise the subject or may require intervention to 
prevent one of the other outcomes listed in the definition above. Examples are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias and 
convulsions that do not result in hospitalisation, development of drug dependency or drug 
abuse. 
If there is any doubt as to whether an adverse event meets the definition of an SAE, a 
conservative viewpoint must be taken, and the adverse event must be reported as an SAE. 
7.5.7.2 Collection of adverse events 
Adverse Events should be obtained through observation of the patient, from any information 
volunteered by the patient and through asking non-leading questions such as “How have you 
been doing since your last visit?”  
 
Adverse events (including pre-treatment adverse events) must be recorded in the eCRF.  The 
investigator must provide information on the adverse event, preferably with a diagnosis, or at 
least with signs and symptoms; start and stop dates and start and stop time; severity; causal 
relationship to the IMP; action taken; and outcome.  If the adverse event is not related to the 
IMP, an alternative aetiology must be recorded, if available.   
 
If the adverse event is serious, this must be indicated on the Adverse Event Form.  
Furthermore, the investigator must fill out a Serious Adverse Event Form and report the SAE 
to the Safety vendor immediately (within 24 hours) after becoming aware of it (see section 
7.5.7.6.). If individual adverse events are later linked to a specific diagnosis, the diagnosis 
should be reported instead of the symptoms. 
 
 


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


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


 
 
 
 
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7.5.7.3 Disease Progression 
Disease progression can be considered as a worsening of a patient’s condition that is being 
studied. It may be reflected by an increase in the severity of the condition or an increase in the 
symptoms. Disease progression and any events that are unequivocally due to disease 
progression should not be reported as an AE or SAE.  
Any AE or SAE which is secondary to ALS must always be reported (e.g. secondary lung 
infection in respiratory compromised subjects). 
7.5.7.4 Death 
All deaths that occur during the AE reporting period must be reported as follows: 
• Death clearly due to disease progression should be documented in the eCRF but 
should not be reported as an SAE.  
• Death that is not clearly due to disease progression should be documented in the eCRF 
and the reason for death should be reported as an SAE within 24 hours. 
Refer to Appendix 10.2.6.3 for principles for data entry in the eCRF. 
7.5.7.5 Follow-Up for Final Outcome of Adverse Events 
The investigator should follow up for final outcome on all AEs until resolution or the Safety 
Follow Up visit whichever comes first. SAEs must be followed up until a final outcome has 
been established, i.e. the follow-up may continue beyond the end of the clinical trial. For 
SAEs which have stabilised and cannot be expected to recover during the trial, for example 
chronic illnesses, the final outcome should be considered ‘recovered with sequalae’ or ‘not 
recovered’ and a statement that the SAE has stabilised should be added to the narrative in the 
SAE form.   
7.5.7.6 Reporting of Serious Adverse Events 
Any SAE must be reported to the Safety vendor on the (paper) SAE Form immediately 
(within 24 hours) of first knowledge.  
This report should contain as much information as possible and include an assessment of 
available information on seriousness, severity, causal relationship to the IMP or trial 
procedure, the action taken, the outcome to date, and a narrative description of the course of 
the event. 
Photocopies of the subject’s medical records should not be sent in lieu of completion of the 
SAE Form. Medical records, laboratory reports etc. should only be sent to the Safety vendor 
upon request. Importantly, when subject records are shared outside the site, all subject 
identifiers, with the exception of the subject number, shall be redacted on the copies of the 
medical records before submission. 


 
 
 
 
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The completed SAE form must be faxed or scanned and e-mailed to the Safety vendor.  
Please refer to the SAE Reporting Contact Details document. 
Follow-up information received by the investigator concerning an SAE should be reported to 
the Safety vendor using the same time line (24 hours) as for the initial report. 
The Safety vendor may request further information in order to fully assess the SAE. The 
investigator must forward such information to the Safety vendor upon request by fax or e-mail 
(see contact details above). 
SAEs occurring after the completion of the clinical trial (i.e., after the Safety Follow Up visit) 
should not be routinely sought or collected. However, such events should be reported to the 
Safety vendor if the investigator becomes aware of them and considers them at least possibly 
related to IMP. 
Reporting to Competent Authorities and IRBs/IEC 
The investigator is responsible for reporting SAEs to the institutional review board(s) 
(IRB[s])/ independent ethics committee(s) (IEC[s]) as required by current applicable 
legislation for the concerned country.  
Orphazyme is responsible for assessing whether or not an SAE is expected. The reference 
safety information for this clinical trial is the current version of the Investigator’s Brochure. 
Oprhazyme is responsible for reporting all SAEs which are assessed as causally related to the 
IMP(s) by either the investigator or Orphazyme, and which are unexpected (suspected, 
unexpected serious adverse reactions [SUSARs]), in an expedited manner to regulatory 
authorities according to the current applicable legislation in the concerned countries. 
Investigators will be notified of such SUSARs and the evolving safety profile on an ongoing 
basis. 
Orphazyme is also responsible for reporting to the IRB(s)/IEC(s) that require unblinded 
reporting. 
7.5.7.7 Pregnancies 
Any pregnancy occurring during the clinical trial must be reported to the Safety vendor 
immediately (within 24 hours) of first knowledge using the (paper) Pregnancy Form. All 
pregnancies must be followed up until delivery or termination and final outcome must be 
reported on the (paper) Pregnancy Follow Up Form within 24 hours of first knowledge. 
The completed Pregnancy (Follow Up) Forms must be faxed or scanned and e-mailed to the 
Safety vendor. Please refer to the SAE Reporting Contact Details document. 


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


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




 
 
 
 
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7.5.9.2 Local Laboratory 
In addition to the above clinical safety laboratory parameters which are analysed and reported 
by a central laboratory, local laboratory services are required for the analysis and reporting of 
coagulation parameters and thrombocytes prior to performing lumbar puncture. Local safety 
laboratory assessments may also occur in case of close monitoring for increased 
transaminases (see Section 7.5.10.2).  
7.5.10 Follow-up for Specific Laboratory Abnormalities 
7.5.10.1 
Increased Serum Creatinine 
Serum creatinine values > 2-3-fold compared to the subject’s baseline value should be further 
investigated for signs of kidney injury. Estimation of the subject’s GFR based on BUN, 
creatinine, and cystatin C should be performed. Follow-up may include measurement of 
oliguria, urine analysis, glomerular filtration rate, vital signs, ultrasound of the kidney, blood 
sampling for parathyroid hormone, metabolic status, and investigation of other markers of 
kidney dysfunction and alternative causes of increased creatinine. 
 
In addition, follow-up should be done according to local hospital guideline (if applicable) or 
may include the consultation of a local nephrologist if required in the opinion of the 
investigator. 
 
7.5.10.2 
Increased Transaminases 
Transaminases (ASAT, ALAT) > 3 x ULN must be further investigated in line with the FDA 
Guidance on Drug-Induced Liver Injury (39). 
 
Upon first observation of transaminases (ASAT, ALAT) > 3 x ULN, a repeat test must be 
performed within 48-72 hours (ALAT, ASAT, ALP, bilirubin) and the subject should be 
enquired for presence of symptoms (fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, or rash). 
 
If the increase is confirmed, close observation must be performed: 
 
• Repeating of ALAT, ASAT, ALP, GGT, bilirubin, eosinophils (differential count) 2-3 
times weekly. Frequency of retesting may be decreased to once a week or less (after 
agreement with the medical monitor) if abnormalities stabilize or the trial drug has 
been discontinued and the subject is asymptomatic. 
• Obtaining/confirming detailed history of symptoms and prior or concurrent diseases. 
• Obtaining/confirming concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug use, 
and special diets. 
• Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic 
hepatitis; NASH; hypoxic/ischemic hepatopathy; and biliary tract disease (e.g. 


 
 
 
 
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performing an abdominal ultrasound or Magnetic resonance 
cholangiopancreatography (MRCP)). 
• Obtaining a history of exposure to environmental chemical agents. 
• Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct 
bilirubin). 
• 
Considering gastroenterology or hepatology consultations. 
 
If close observation is not possible, IMP must be interrupted or discontinued (see section 6.5  
Dose modification and IMP discontinuation). 
 
If the subject cannot attend the trial site for close monitoring, the analyses may be conducted 
at a local laboratory. 
At the earliest possible opportunity, a single serum sample should be taken for use in case 
further analyses to explore possible mechanisms behind the transaminase elevations are 
conducted.  
The sample may be processed and shipped under ambient or frozen conditions and will be 
stored frozen at the central laboratory. This sample will be discarded as soon as it is decided 
that such analyses are not warranted or after sample processing and analysis is completed 
which will be no longer than 2 years after the completion of the trial. 
All local laboratory assessments and other assessment performed in relation to increased 
transaminases must be recorded in the eCRF including the appropriate reference ranges. 
For scenarios where a permanent halt in the IMP is required, please see Section 6.5. 
 
 
7.6 
Biological Sample Assessments 
7.6.1 
Genomic Assessments 
At Screening, blood samples will be drawn to test for the presence of genetic mutations 
identified and described in subjects with ALS.  
The analysis of these samples will be reported in a specific genomic assessment report, 
separate to the clinical trial report.  
The subjects and/or caregivers will not be informed of the results of this genomic assessment 
unless mandated by local regulation or law. 
The genomic assessment will only be performed where all required permissions are granted 
and in accordance with local regulation or law. 


 
 
 
 
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7.6.2 Pharmacokinetics Assessments 
The plasma and CSF samples will be analysed for arimoclomol using a bioanalytical method 
validated in accordance with the US FDA Guidance for Industry (35) and EMA Guideline on 
bioanalytical method validation (36). If other ongoing research studies identify significant 
metabolites, these may be analysed in samples collected from this trial using a scientifically 
validated bioanalytical method or by a method validated in accordance with the US FDA 
Guidance for Industry (35). 
The bioanalysis will be performed by Covance (see Appendix 10.3.6.3) according to a 
protocol approved by Orphazyme before the samples are analysed. 
Selected plasma samples will be subject to incurred sample re-analysis (ISR) as part of the in-
study validation of the bioanalytical method.  
The plasma concentration values will be reported in the clinical trial report and the results will 
be used for population PK analyses. In addition to the population PK analysis an exposure 
response analysis, evaluating correlation between exposure of arimoclomol and e.g. change in 
biomarker levels, will be performed. A separate modelling analysis plan will be issued before 
DBL and results will be reported separately. 
If a subject is no longer able to travel to the site to attend the in-person visits, samples 
required for PK assessment will not be drawn in the subject’s home/residency. 
7.6.2.1 Blood Samples 
Blood samples will be taken for bioanalysis of concentrations of arimoclomol in plasma at 
Week 20 and Week 52 (see Table 1).  
At Week 20 a blood sample will be drawn pre-dose and at 0.5 hours post-dose. At Week 52 
blood samples will be drawn pre-dose and at 1.5 hours post-dose. 
The exact time for drawing the samples must be recorded in the eCRF.  
The first dose of IMP will be administered while at the site to allow for PK assessment on the 
day of the Week 20 and Week 52 site visit. 
The subject must not administer IMP within 8 hours of the site visit to allow for a trough PK 
sample to be taken. The time of the last dose administered prior to the visit should be recorded 
in the subject diary and transcribed to the eCRF. 
Blood sampling and handling procedures will be described in a separate laboratory manual. 
7.6.2.2 Cerebrospinal Fluid (CSF) Samples 
Lumbar puncture will be taken for bioanalysis of concentrations of arimoclomol in CSF 
according to the schedule of procedures in Table 1. Lumbar puncture will only be performed 
in subjects who are able to attend the trial site. 


 
 
 
 
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The CSF sample should be drawn at 3 hours post-dose at Week 20 and Week 52 (see 
Table 1).  
The exact time for drawing the samples must be recorded in the eCRF.  
CSF sampling and handling procedures are described in a separate laboratory manual. 
Lumbar puncture will be performed by the investigator (or delegate that is a physician by 
training) in accordance with local clinical practice including procedural guidelines and/or 
regulation. CSF sample handling procedures are described in a separate laboratory manual. 
Coagulation parameters and thrombocytes should be reviewed via local laboratory services 
prior to performing lumbar puncture. The results of the local analysis will not be recorded in 
the eCRF. Subjects should not undergo lumbar puncture if local laboratory results indicate an 
abnormality, the subject is receiving concomitant therapy with anti-coagulants or if in the 
opinion of the investigator the procedure is not appropriate (including for reasons related to 
ALS progression or practical reasons).  
Examinations will only be conducted in those subjects able to attend the trial site. If a lumbar 
puncture is missed it will not be considered a protocol deviation. 
7.6.3 Biomarker Assessments 
Blood samples, urinalysis and CSF samples will be taken for exploratory bioanalysis of 
biomarkers in blood, urine and CSF according to the schedule of procedures in Table 1.  
For details regarding lumbar puncture see Section 7.6.2.2. 
The biomarkers (see Table 8) will be analysed at the bioanalysis laboratory (see Appendix 
10.3.6.3) using a validated method.  
Guidance for biomarker sample handling are provided in the laboratory manual. 
If a subject is no longer able to travel to the site to attend the in-person visits, samples 
required for biomarker assessment will not be drawn in the subject’s home/residency. 




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


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




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


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


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


 
 
 
 
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9 
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22. Berry, James D., Robert Miller, Dan H. Moore, Merit E. Cudkowicz, Leonard H. Van 
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31. European Union. The rules governing medicinal products in the European Union, 
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Wanger, J,. 2005. Standardisation of spirometry. Series ‘‘ATS/ERS Task Force: 
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34. European Parliament and Council of The European Union. Directive 2001/20/EC of 4 
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Bioanalytical method validation. May 2001. 
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Use (CHMP). Guideline on bioanalytical method validation. 
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37. Stokes, Maura E., Davis, Charles S., Koch, Gary G.: Categorical Data Analysis Using 
SAS, Third Edition 2012. 
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39. FDA Guidance for Industry on Drug-Induced Liver Injury: Premarketing Clinical 
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Arimoclomol. Niemann-Pick disease type C, Gaucher’s disease, amyotrophic lateral 
sclerosis, sporadic inclusion body myositis. Release date 04-Jun-2020. 
 


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


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


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


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


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


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


 
 
 
 
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7. All sexually active female subjects of child-bearing 
potential (postmenarchal)* must agree not to intend to 
become pregnant and use a highly effective method of 
contraception** during the trial through 1 month after the 
last dose of trial medication. If the subject is a sexually 
active male with female partners of child-bearing potential 
(postmenarchal) he must use a condom with or without 
spermicide in addition to the birth control used by their 
partners during the trial until 3 months after the last dose 
of trial medication. 
8. Stable dose of riluzole (50 mg twice daily) for a minimum 
of 14 days prior to Day 1 (Baseline),or has not taken it for 
14 days prior to Day 1. 
 
Exclusion criteria 
1. Tracheostomy or use of non-invasive ventilation for more 
than 2 hours during waking hours at the time of 
Screening and Baseline visits. 
2. Pregnant or breast-feeding. 
3. Current or anticipated use of diaphragmatic pacing during 
the trial. 
4. Exposure to any investigational treatment within 4 weeks 
or <5 half-lives of the Screening visit, whichever is 
longest and/or advanced therapy medicinal product 
(ATMP), i.e. treatments based on genes, cells or tissues 
and/or participated in any prior ALS clinical trial 
receiving active drug treatment (with the exception 
described in exclusion criterion 5).  
5. Treatment with edaravone within 4 weeks of the Baseline 
visit. However, up to 18 subjects on stable (i.e. minimum 
6 months’) treatment with edaravone and who otherwise 
fulfil the eligibility criteria are planned for enrolment 
(limited to countries where edaravone has a marketing 
authorisation for treatment of ALS). 
6. Any of the following medically significant conditions: 
a. 
Neurological impairment/dysfunction or unstable 
psychiatric illness that in the investigator’s 
opinion is likely to interfere with assessment of 
ALS disease progression. 
b. 
Clinically significant unstable medical condition 
other than ALS, which would present a risk to a 
subject to participate in the trial 
c. 
Presence of dementia that impairs the ability of 
the subject to provide informed consent, 
according to the PI decision. 


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


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


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


 
 
 
 
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GCP (4.8) and all applicable laws and regulations. The authorised person obtaining the 
informed consent must also sign the ICF. 
Subjects unable to provide informed consent prior to the commencement of the screening and 
baseline visits cannot participate in the trial. 
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the trial.  
A copy of the ICF(s) must be provided to the subject or the subject’s legally authorised 
representative.  
Since ALS is a rapidly progressing neurological condition, the ability of a trial subject to 
confirm ongoing / provide new consent may be diminished (i.e. the trial subject may decline 
to a legal status of an incapacitated adult). Since there is the possibility of needing to 
reconsent subjects in the clinical trial due to unforeseen circumstances, a primary caregiver 
will be nominated as a legal representative prior to commencement of the trial will be 
nominated by the time of the Baseline visit to ensure that this occurs while the subject is 
competent. In this circumstance (and in accordance with local legislation or guidelines) a 
legal representative will ensure the subject’s best interests and legal rights are protected 
throughout the trial should the subject become incompetent. Legal representation certificate 
must be obtained as per applicable country legal requirements and procedures. While the 
subject is competent, informed consent for any research procedure or intervention is sought 
from the subject only. The subject may freely decline consent and the legal representative will 
not be consulted. Based on the selection criteria, this trial will not prompt legislation 
regarding enrolment of incapacitated adults into clinical trials in emergency situations.  
Additionally, this individual will give consent to be contacted during the conduct of the trial 
should contact with the subject become challenged. 
For competent trial subjects who have lost dexterity in the hands and cannot personally sign 
and date the informed consent form, an impartial witness signature may be used to document 
that the participant understands the study, the consent process, and has consented to continue 
to participate in the trial (if permitted by local regulations). 
10.2.3 Subject card 
At Screening, subjects will be provided with a card stating that they are participating in a 
clinical trial and which contains contact address(es) and telephone number(s) of relevant trial 
site staff. The subject will use this card to notify non-investigator physicians of their trial 
participation. The contact details of the appointed medical monitor will be included on the 
card should medical information be required by the non-investigator physician. These contact 
details are not provided for use by the subject. 


 
 
 
 
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10.2.4 Subject and data confidentiality 
This clinical trial protocol as well as all other information, data and results relating to this 
clinical trial and/or to the IMP is confidential information of Orphazyme and shall not be used 
by the investigator for purposes other than this clinical trial. 
The investigator agrees that Orphazyme may use any and all information, data and results 
from this clinical trial in connection with the development of the IMPs and, therefore, may 
disclose and/or transfer information, data and/or results to other investigators, regulatory 
authorities and/or commercial partners. 
Subjects will be assigned a unique identifier (subject ID) by Orphazyme. Any subject’s 
records or datasets that are transferred to Orphazyme will contain the identifier only; subject 
names or any information which would make the subject identifiable will not be transferred.  
Subjects must be informed that their personal trial-related data will be used by Orphazyme in 
accordance with local data protection law.   
The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by Orphazyme, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.2.5 Processing of personal data 
This protocol specifies the personal data on trial subjects (for example age, gender, health 
condition, height, medical history, test results, etc.) which shall be collected as part of the 
clinical trial and processed during and after trial completion. 
Personal data collected as part of the clinical trial will be transferred to/from the 
institution/investigator, Orphazyme and third parties acting on behalf of Orphazyme. 
Processing of personal data on behalf of Orphazyme requires a written agreement between 
Orphazyme and the relevant party which covers collection, processing and transfer of 
personal data in the clinical trial. In certain cases an agreement on transfer of personal data 
may also be required. 
Investigators and Orphazyme must ensure that collection, processing and transfer of personal 
data are in compliance with applicable legislation on data protection and privacy. 
Subjects (or their legally acceptable representative) must be asked to consent to the collection, 
processing and transfer of their personal data to EU and non-EU countries for the purpose of 
conducting the clinical trial, research and development of new or existing products/services, 
improving existing products/services, applying for marketing authorisations for 
products/services, marketing of products/services and other related activities. 
Orphazyme has obtained the necessary authorisations for the processing of personal data 
collected in the trial. 


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


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


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




 
 
 
 
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10.2.6.9 
Archiving of trial documentation 
The investigator at each trial site must make arrangements to store the essential trial 
documents including the Investigator Trial File (ICH E6, Guideline for Good Clinical 
Practice) for a retention period of approximately 15 years or in accordance to national/local 
standards as stated in the clinical trial agreement or until Orphazyme informs the investigator 
that the documents are no longer to be retained or longer if required by local regulations. 
In addition, the investigator is responsible for the archiving of all relevant source documents 
so that the trial data can be compared against source data after the completion of the trial (for 
example in case of an inspection from regulatory authorities). 
The investigator is required to ensure the continued storage of the documents even if the 
investigator leaves the trial site or retires before the end of the required storage period. 
No records may be destroyed during the retention period without the written approval of 
Orphazyme. No records may be transferred to another location or party without written 
acceptance from Orphazyme. 
The destruction process must ensure confidentiality of data and must be done in accordance 
with local regulatory requirements. 
For archiving purposes, each investigator will be supplied with a copy of the eCRFs 
(including audit trail, closed queries and metadata), centralised spirometry and laboratory data 
for all subjects enrolled at the trial site. This is done after completion of the trial and before 
access to the eCRF is revoked. Audit trail information will be included. eCRFs and 
centralised spirometry and laboratory data must be available for inspection by authorised 
representatives from Orphazyme, from regulatory authorities and/or IEC/IRBs. 
10.2.7 Registration, reporting and publication policy 
Basic information of this clinical trial will be registered in the global data registry, 
www.clinicaltrials.gov before the first subject enters into the trial. The trial may also become 
registered in other online data registries, according to applicable law and regulations. 
Orphazyme will report the results of this trial on www.ClinicalTrials.gov, 
www.clinicaltrialsregister.eu and national data registries in accordance with applicable law 
and regulations after clinical trial completion or premature termination. Results may also be 
posted on the corporate website of Orphazyme or be otherwise communicated as deemed 
appropriate by the Orphazyme Management Team.  
The first publication will be a joint multi-centre publication. Multi-centre publications will be 
prepared in collaboration between Orphazyme and the members of a writing group, which 
shall be appointed by Orphazyme. The Chair of the Arimoclomol in ALS Advisory 
Committee will lead the writing group. 
Publication by an investigator of his/her trial results shall not be made public before the first 
multi-centre publication. 


 
 
 
 
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If no multi-centre publication has been submitted for publication within 18 months (or in 
accordance with national/local standards) after the clinical trial has been completed or 
terminated at all trial sites and all data have been received, defined as database lock of the 
clinical trial, the investigator shall have the right to publish the results from the clinical trial 
generated by the investigator, subject to the following notice requirements: 
At least 60 days prior to submitting or presenting a manuscript relating to the clinical trial to a 
publisher, reviewer or other outside person, or in accordance with national/local standards as 
agreed in the Clinical Trial Agreement, the investigator shall provide to Orphazyme a copy of 
all such manuscripts, and Orphazyme shall have rights to review and comment. Upon the 
request of Orphazyme, the investigator shall remove any confidential information (other than 
results generated by the investigator) prior to submitting or presenting the manuscripts.  
The investigator shall, upon the request of Orphazyme, delay the publication or presentation 
for up to 90 days (or in accordance with national/local standards, as agreed in the Clinical 
Trial Agreement) to allow Orphazyme to protect its inventions and other intellectual property 
rights described in any such manuscripts. In case the first multi-centre publication is still 
ongoing and has not been made public at the time of notification, Orphazyme and the writing 
group may also delay the publication or presentation if the manuscript is deemed to harm the 
ongoing multi-centre publication. 
In case of publications made by the investigator after the first multi-centre publication has 
been published, the above-mentioned requirements must still be followed. 
10.2.8 Insurance 
Orphazyme has taken out relevant insurances covering the subjects in the present clinical trial 
in accordance with applicable laws and regulations. 
10.2.9 Financial disclosure 
Investigators will provide Orphazyme with sufficient, accurate financial information as 
requested to allow Orphazyme to submit complete and accurate financial certification or 
disclosure statements to the appropriate regulatory authorities as required by local legislation. 
Investigators are also responsible for providing information on financial interests during the 
course of the clinical trial and for 1 year after completion of the clinical trial, or for a longer 
period of time if required by local legislation. 
10.2.10 Data Monitoring Committee 
Subject safety will be carefully assessed by an independent DMC. All members will be 
independent of the trial (i.e. they will not be participating investigators or employees at 
participating sites) and of Orphazyme (i.e. they will not be Orphazyme employees). The DMC 
members are experienced with clinical trials and will be responsible for assessing the safety of 
the subjects through assessment of the safety of the treatment regimen during the trial and 


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


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


 
 
 
 
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Table 10 
Parameters for neurological examination 
 
General 
Level of Consciousness 
Level of Appearance/ Facial/Motor Expression 
Mental Status 
Language 
Cranial Nerves 
Vision (II) 
Eye Movements (III, IV, VI) 
Jaw movement and facial sensation (V) 
Facial motion (VII) 
Hearing (VIII) 
Swallowing, pharynx, larynx (IX, X) 
SCM, trapezious (XI) 
Tongue (XII) 
Reflexes 
Biceps 
Brachioradialis 
Triceps 
Knee Jerk 
Achilles tendon 
Motor System 
General Movement 
Muscle Bulk/ Mass 
Muscle Strength: 
Trunk 
Upper Extremities 
Lower Extremities 
Muscle Tone: 
Upper Extremities 
Lower Extremities 
Coordination / Cerebellar 
Function 
Gait 
Romberg 
Nystagmus 
Tremor 
Finger-Nose 
Heel-shin 
Rapid Rhythmic Movement 
Sensation: 
Upper Extremities 
Pain/ Temperature 
Light Touch 
Position 
Vibration 
Lower Extremities 
Pain/ Temperature 
Light Touch 
Position 
Vibration 






 
 
 
 
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Returns depot and destruction, North America; 
Catalent CTS (Kansas City), LLC, Attn: Returned Goods Dock 10, 10245 Hickman Mills 
Drive, Kansas City, Missouri 64137-9724 
World Courier 
Responsible for ‘direct to patient’ (DtP) distribution and logistics as agreed in a contract. 
World Courier Denmark A/S, Avedøreholmen 96-98, Hvidovre, DK-2650, Denmark 
10.3.6.3 
Contract Laboratory Services 
Covance Laboratories 
Responsible for centralised bioanalysis of safety laboratory parameters (biochemistry, 
haematology and urinalysis), PK and biomarkers and biorepository management as agreed in 
a contract. 
Pharmacokinetic analysis; 
Covance Laboratories Ltd., Otley Road, Harrogate, North Yorkshire, HG3 1PY England 
Biomarker analysis; 
Covance Laboratories Inc., Translational Biomarker Solutions, 220 Building/Dock 229, 671 
South Meridian Road, Greenfield IN 46140  
Covance Laboratories Inc., 3635 Concorde Parkway, Suite 100, Chantilly, VA 20151 
Biorepository; 
Covance Laboratories Inc., Covance Biorepository, Building 210, 671 South Meridian Road, 
Greenfield IN 46140  
Clinical Safety Laboratory, North America; 
Covance Inc., 8211 SciCor Drive, Indianapolis, IN 46214 USA 
Clinical Safety Laboratory, EU; 
Covance Central Laboratory Sàrl, 7 rue Marcinhes, 1217 Geneva, Meyrin Switzerland 


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


 
 
 
 
Protocol number: ORARIALS-01 
Date: 08-Jun-2020 
Version: Final 7.0 
 
Orphazyme A/S - Strictly Confidential 
Clinical Trial Protocol 
Page 112 of 112  
 
If a subject discontinues treatment and does not meet any of the survival endpoint definitions 
the subject should be invited to attend the remaining trial visits as per the schedule of 
procedures. Additionally, an in-person follow-up visit should be scheduled for 2 weeks after 
the last treatment. 
ECG Assessments 
For subjects in France, the ECG examinations should be conducted in all subjects for visits at 
week 20, 52 and 76 regardless of whether the visit is at the trial site or a home visit. Hence 
footnote k is not applicable. 
 
Adverse Events 
For subjects in France, the wording below on AE collection is added to the protocol. The 
wording was removed in error as the actual data collection is performed as requested in the 
sentence.   
AEs must be collected from the time that the subject has signed the informed consent. 
10.5 
Coronavirus (COVID) operational changes 
The document ORARIALS-01 (COVID-19) Addendum 1.0 dated 24-Mar-2020 shall remain in 
effect with this Clinical Trial Protocol. The Addendum to the Clinical Trial Protocol is 
designed to mitigate the operational impact resulting from COVID-19, and shall only be 
applied as an interim solution during the period that normal Clinical Trial Protocol logistics 
cannot be adhered to. Once containment measures have ceased and operations return to 
normal on both a site and subject level, procedures will resume as per the site’s currently 
approved Clinical Trial Protocol. 
 


Protocol number: ORARIALS-01 
Date: 16-Sep-2020 
Version: Final 1.0 
(CYP2D6 DDI) Addendum 1.0 to 
Clinical Trial Protocol v7.0 dated 08-Jun-2020 
A Phase 3, Randomised, Placebo-Controlled Trial of 
Arimoclomol in Amyotrophic Lateral Sclerosis
Sponsor: Orphazyme A/S, Ole Maaløes Vej 3, DK-2200 Copenhagen N, Denmark 
Coordinating investigator: 
, MD PhD 
Protocol number: ORARIALS-01 
EudraCT No.: 2018-000137-13 
ClinicalTrials.gov Identifier: NCT03491462
Trial product name: Arimoclomol Capsules 
Date of Addendum: 16-Sep-2020 
The trial will be conducted according to the protocol and in compliance with Good Clinical Practice (GCP), with 
the Declaration of Helsinki and with other applicable regulatory requirements 
Orphazyme A/S - Strictly Confidential 
(IB, CYP2D6 DDI) Addendum 1.0 to CTPv7.0, dated 16-Sep-2020 
Page 1 of 9 
This document contains information which is the property of Zevra Denmark 
A/S and is provided here as part of the results registration on 
clinicaltrials.gov. It is understood that this information cannot and will not be 
disclosed to others without written approval from Zevra Denmark A/S.




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


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











SAP_001.pdf: 
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Statistical Analysis Plan 
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Statistical Analysis Plan 
Title: A Phase 3, Randomised, Placebo-Controlled Trial of Arimoclomol in 
Amyotrophic Lateral Sclerosis 
Protocol Number: ORARIALS-01 
ClinicalTrials.gov Identifier: NCT03491462
Version 2.0 
Issue Date: 19-APR-2021 
Author: 
, Ph.D, 
, MS 
Previous Versions 
Version 1.0, Issue Date 23-FEB-2021 
Clinicaltrials.gov ID: NCT03491462
This document contains information which is the property of Zevra Denmark A/S 
and is provided here as part of the results registration on clinicaltrials.gov. It is 
understood that this information cannot and will not be disclosed to others without 
written approval from Zevra Denmark A/S.


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SAP Amendments before database lock 
Version Issue Date 
Section 
Revision/Addition 
Rationale 
1.0 
19-APR-2021
8.4 
& 
8.5.2 
Added additional 
sensitivity analysis to 
CAFs and ALSFRS-R 
During the review of 
blinded data of ALSFRS-R 
prior to unblinding, it was 
discovered that quite a few 
patients had assessments of 
ALSFRS-R at Visit 22 
(safety follow-up) after 
having had a scheduled 
Visit 21 (Landmark at 
week 76) with an 
assessment of the 
ALSFRS-R. According to 
protocol (version 7, 08-
Jun-2020) ALSFRS-R 
should not be assessed at 
the safety follow- up and 
the SAP’s definition of the 
end-of the in-trial period, 
for reasons discussed in 
detail herein, ends at the 
Landmark Visit 21. 
To assess the impact of 
including Visit 22 
ALSFRS-R assessments 
that were excluded from 
primary analyses due to in-
trial period definition. 
Therefore, two additional 
post hoc sensitivity 
analyses are specified – 
one for ALSFRS-R per se 
and one for CAFS. 
1.0 
6.2 
Include details for 
windowing weight 
assessments and 
clarify windowing for 
Week 76. 
Current windowing does 
not provide details for 
windowing of weight 
assessments and details for 
Week 76 windowing may 
be confusing. 


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1.0 
8.12.3 
Corrected the PCS 
High the vital sign 
parameters PCS table 
(Pulse, DBP, SBP) 
and removed 
Temperature. 
SAP 1.0 incorrectly 
displays “< X” value when 
should display “>X” for 
Pulse, DBP, SBP and 
temperature should have 
been removed prior 
signing version 1. 
1.0 
Appendix 
13 
Update TOC 
Additions/corrections were 
made.  


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Table of Contents 
1 
INTRODUCTION .......................................................................................... 7
2 
STUDY OBJECTIVES .................................................................................. 7
2.1 
Primary objective ....................................................................................................... 7 
2.2 
Secondary objectives ................................................................................................. 7 
2.3 
Exploratory Objectives .............................................................................................. 7 
2.4 
Safety Objective ......................................................................................................... 7 
3 
ENDPOINTS .................................................................................................. 8
3.1 
Primary Endpoint ....................................................................................................... 8 
3.2 
Secondary Endpoints ................................................................................................. 8 
3.3 
Exploratory Endpoints ............................................................................................... 8 
3.4 
Safety Endpoints ........................................................................................................ 8 
4 
ANALYSIS POPULATIONS, OBSERVATION PERIODS AND 
CENSORING ........................................................................................................ 9
4.1 
Analysis populations .................................................................................................. 9 
4.2 
Observation Periods ................................................................................................... 9 
4.2.1 
In-Trial ............................................................................................................... 10 
4.2.2 
On-Treatment ..................................................................................................... 12 
Safety ........................................................................................................... 12 
Efficacy ........................................................................................................ 12 
4.3 
Observation periods and population sets ................................................................. 13 
5 
ESTIMANDS ............................................................................................... 13
5.1 
Primary Estimand..................................................................................................... 13 
5.2 
Secondary Estimand................................................................................................. 14 
5.3 
While on treatment/alive estimands ......................................................................... 14 
6 
VISIT WINDOWING AND BASELINE .................................................... 16
6.1 
Baseline .................................................................................................................... 16 
6.2 
Windowing ............................................................................................................... 16 
7 
SAMPLE SIZE ............................................................................................. 18
8 
STATISTICAL ANALYSIS AND REPORTING ....................................... 19
8.1 
Introduction .............................................................................................................. 19 
8.1.1 
Decimal Places ................................................................................................... 20 
8.2 
Statistical models ..................................................................................................... 20 
8.3 
Primary endpoint and analyses ................................................................................ 21 


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8.3.1 
ALS Functioning Rating Scale – Revised (ALSFRS-R) ................................... 21 
8.3.2 
Time to PAV/Tracheostomy/Death ................................................................... 22 
8.3.3 
CAFS: Combined Assessment of Function and Survival .................................. 22 
Generic scoring algorithm............................................................................ 22 
Primary endpoint .......................................................................................... 23 
Analysis........................................................................................................ 23 
8.4 
Sensitivity analyses of the primary endpoint ........................................................... 23 
8.4.1 
Subgroup analyses ............................................................................................. 26 
8.5 
Secondary endpoints and analyses ........................................................................... 26 
8.5.1 
Time to event ..................................................................................................... 26 
8.5.2 
ALSFRS-R ......................................................................................................... 27 
8.5.3 
% predicted SVC................................................................................................ 27 
8.5.4 
Subgroup analyses ............................................................................................. 29 
8.6 
Other efficacy endpoints .......................................................................................... 29 
Edinburgh Cognitive and Behavioral ALS Screen (ECAS) ........................ 29 
Schedule for the Evaluation of Individual Quality of Life-Direct Weighting 
(SEIQoL-DW).............................................................................................................. 30 
EQ-5D-5L .................................................................................................... 30 
8.7 
Multiplicity .............................................................................................................. 31 
8.8 
Columbia-Suicide Severity Rating Scale ................................................................. 31 
8.9 
Other reporting issues .............................................................................................. 32 
8.9.1 
Derived Data ...................................................................................................... 32 
8.9.2 
Patient Disposition ............................................................................................. 36 
8.9.3 
Protocol Deviations ............................................................................................ 36 
8.9.4 
Baseline Comparability ...................................................................................... 37 
8.9.5 
Medical History ................................................................................................. 37 
8.9.6 
Prior and Concomitant Medications .................................................................. 37 
8.9.7 
Exposure to Study Drug ..................................................................................... 37 
8.9.8 
Treatment Compliance ....................................................................................... 38 
8.10 
Pharmacokinetic Analyses ....................................................................................... 38 
8.11 
Biomarker Analyses ................................................................................................. 38 
8.12 
Safety Analyses ........................................................................................................ 38 
8.12.1 
Adverse Events .................................................................................................. 38 
8.12.2 
Laboratory Data ................................................................................................. 40 
8.12.3 
Vital Signs .......................................................................................................... 42 


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8.12.4 
Electrocardiogram Data ..................................................................................... 43 
8.12.5 
Neurological Examination ................................................................................. 43 
8.12.6 
Physical Examination......................................................................................... 43 
9 
SARS-COV-2 IMPACT ............................................................................... 43
10 DATA MONITORING COMMITTEE ANALYSIS .................................. 44
11 CHANGES TO PLANNED PROTOCOL ANALYSIS .............................. 44
11.1 
Base Strengths (doses) of arimoclomol ................................................................... 44 
11.2 
Populations ............................................................................................................... 44 
11.3 
Analyses ................................................................................................................... 45 
11.4 
Data Collection ........................................................................................................ 45 
12 REFERENCES ............................................................................................. 45
13 LIST OF TABLES, FIGURES AND LISTINGS ........................................ 46
14 APPENDICES .............................................................................................. 61
14.1 
Appendix 1 ............................................................................................................... 61 
14.2 
Appendix 2 ............................................................................................................... 62 
14.3 
Appendix 3 ............................................................................................................... 69 
14.4 
Appendix 4 ............................................................................................................... 69 
14.5 
Appendix 5 ............................................................................................................... 70 
14.6 
Appendix 6 ............................................................................................................... 71 


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1 INTRODUCTION 
This document details the planned statistical analyses of protocol “ORARIALS-01” study titled 
“A Phase 3, Randomised, Placebo-Controlled Trial of Arimoclomol in Amyotrophic Lateral 
Sclerosis”.  The proposed analyses are based on the contents of the amended protocol, version 
7.0 (dated 08-Jun-2020). 
This is a multicenter, randomized, double-blind, placebo-controlled, parallel group trial to 
evaluate the efficacy and safety of 744 mg arimoclomol (248 mg TID) over a 76 weeks’ 
treatment period consisting of a combination of in-person visits and remote visits (telephone 
calls). An independent DMC has been established to monitor the benefit: risk.  
The current protocol 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).  
For details regarding change from protocol please see Section 11. 
2 STUDY OBJECTIVES 
2.1 Primary objective  
To determine the efficacy of chronic treatment with 744 mg/day arimoclomol (248 mg t.i.d.) 
compared to placebo over 76 weeks in patients with ALS as assessed with CAFS  
2.2 Secondary objectives 
To evaluate the impact of 744 mg/day arimoclomol (248 mg t.i.d.) compared to placebo on: 
•
Disease progression as measured by change from baseline of the ALSFRS-R
•
Time to PAV/tracheostomy free (PAV)/tracheostomy free survival
•
Progression of respiratory dysfunction as measured by change from baseline in SVC
2.3 Exploratory Objectives 
•
To explore the potential effect of 744 mg/day arimoclomol (248 mg t.i.d.) compared to
placebo on cognitive and behavioral changes.
•
To evaluate the effect of 744 mg/day arimoclomol (248 mg t.i.d.) compared to placebo
on health-related quality of life
2.4 Safety Objective 


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To assess the safety and tolerability of 744 mg/day arimoclomol (248 mg t.i.d) compared to 
placebo. 
3 ENDPOINTS 
The endpoints listed herein are further detailed in Section 8. 
3.1 Primary Endpoint 
CAFS over a treatment period of 76 weeks (or end-of trial) 
3.2 Secondary Endpoints 
•
Change from Baseline during 76 weeks in ALSFRS-R[*]
•
Time to PAV/tracheostomy/death from Baseline as assessed by
o
hazard ratio
o
median event-free survival time
•
Change from Baseline during 76 weeks in percent (%) predicted SVC (PPSVC) [*]
[*]: The ALSFRS-R and the % predicted SVC will in fact be analyzed on the absolute scale (the actually observed
values) but reported as both as such and as a change from baseline. 
3.3 Exploratory Endpoints 
•
Change from baseline during 76 weeks in cognitive and behavioural changes as
evaluated by ECAS[*]
•
Change from baseline in SEIQoL-DW index for the patient[*] over a treatment period
of 64 weeks
•
Change from baseline in SEIQoL-DW index for the caregiver[*] over a treatment period
of 64 weeks
•
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
•
Change from Baseline to Week 76 in ALSFRS-R domains[*]
[*]: Will in fact be analyzed on the absolute scale (the actually observed values) but reported as both as such and
as a change from baseline. 
3.4 Safety Endpoints 
•
Incidence and severity of TEAEs over a treatment period of 76 weeks


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•
Mean and change from Baseline over a treatment period of 76 weeks 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
4 ANALYSIS POPULATIONS, OBSERVATION PERIODS AND 
CENSORING 
4.1 Analysis populations 
The following analysis populations are planned for this trial: 
•
Enrolled Population: The Enrolled Population includes all patients who gave informed
consent and were allocated a patient number. This population will be used for the
summary of patient disposition only.
•
Intent-To-Treat Population (ITT): The ITT population includes all randomized patients
except for screen failure patients who were randomized in error and did not receive any
investigational medicinal product (IMP). Patients in the ITT population will contribute
to the evaluation ‘as randomized’.
•
Modified ITT (mITT): The mITT population includes patients in the ITT Population
who are not on edaravone at baseline. The mITT population will be the primary
population for all efficacy analyses. Patients in the mITT population will contribute to
the evaluation ‘as randomized’.
•
Safety Population: The safety population includes all patients who receive any amount
of IMP but excludes patients on edaravone at baseline. Patients in the Safety population
will be analyzed according to treatment actually received for safety analyses. This will
be the population used for all safety analyses unless otherwise specified.
•
Edaravone Population: Patients in ITT who were on stable treatment (i.e. minimum of
6 months) with edaravone and receive at least one dose of IMP. Subset of displays will
be repeated for this population no formal analyses, however, will be conducted.
The “actual treatment” will be based on a simple count of capsules administered from either 
one of the two trial treatments (e.g., treatment with largest number of capsules will be 
considered the actual treatment). 
4.2 Observation Periods 
Patients and the data to be used in an analysis will be selected in a two-step manner. 


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Firstly, patients will be selected based on the specified analysis set. 
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 treated as missing 
and therefore excluded from the corresponding analysis. 
Two observation periods are defined 
4.2.1 
In-Trial 
This observation period represents the time period where patients are considered to be 
randomized, enrolled in the trial and as such under systematic follow-up. While the in-trial 
period unambiguously starts at randomization the end of the in-trial period is more involved: 
some patients die before the landmark visit and some withdraw informed consent (IC) prior to 
the landmark visit – some of which allow follow-up on the survival endpoint at the planned 
landmark visit and other don’t allow this. Moreover, some patients completing the landmark 
visit “roll-over” to the open label extension trial with the week-76 visit being the baseline in 
the OL extension while other patients complete the current trial with or without a safety follow-
up visit scheduled some 4 weeks after the landmark. Lastly, patients experiencing one of the 
three events comprising the composite survival endpoint are per protocol to be considered as 
completers and should per protocol be removed from follow-up. While certainly death and 
most cases of tracheostomies have indeed been treated as stipulated in the protocol, some cases 
of PAV have been reported with some time lag and, consequently, have not been treated as 
“completers” at the reported time of event. 
Briefly, the in-trial period will be defined to end no later than at the week 76 visit irrespective 
of observations post that visit. The reason for censoring the in-trial at the week 76 visit is that 
follow-up post this time may be quite biased due to the selection taking place into the open 
label extension trial. 
Due to the SARS-CoV-2 pandemic in 2020 and 2021 some study procedures have been 
difficult to implement as thoroughly as one might otherwise have implemented in different 
circumstances. Consequently, the database prior to lock and unblinding may seem ambiguous 
on the data points used to define the end of the below mentioned in-trial period. Prior to lock, 
a meeting will be held where the recorded data for all ITT patients (including site comments 
and note to file information) will be reviewed and a patient-by-patient end-date of the in-trial 
period set (based on the rules detailed below). The minutes of this meeting will be signed, 
locked and be part of the TMF. For further details see section 9. 


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Consequently, we define the in-trial period to start at randomization and to end at the date of 
below: 
1. Patients recorded dead:
1.1. Patients with withdrawal date: end date is the maximum of withdrawal date and all
visit dates where assessments took place[1,§] 
1.2. Patients with completion date: end date is the minimum date of date of death, date of  
completion and maximum date of all visit dates where assessments took place 
2. Patients withdrawing without being registered as dead or with non-lethal event: end date is
the maximum of withdrawal date and all visit dates where assessments took place[1,2,§]
3. Patients completing without being registered as dead or with non-lethal event: end date is
date of visit 21
4. Patients completing without being registered as dead but with non-lethal event:
4.1. for patients with scheduled visits 21:
4.1.1. if the last scheduled visit (either 21 or 22) is less than 76 weeks after 
randomization, the end date is the  date of the last scheduled visit 
4.1.2. if the last scheduled visit (either 21 or 22) is more than 76 weeks after 
randomization, the end date is the date of visit 21 
4.2. for patients without scheduled visits 21: end date if the date completion 
5. If end-of-study date is still missing after the above algorithm, the end-of-study date will be
set to the date of the last recorded visit
[1]: for patients allowing follow-up of survival endpoint after withdrawal[§], if a recorded death (or non-lethal 
event) lies before the 76 weeks mark, the end-date is set to this recorded date-of-death (or non-lethal event). If a 
death lies after the 76 weeks mark, the end-date is set to the date of post-withdrawal contact. 
[2]: for patients allowing follow-up of survival endpoint after withdrawal without being recorded as dead or with 
a non-lethal event, the end-date is set to the date of post-withdrawal contact. 
[§]: The protocol stipulates that for withdrawn patients, if allowed by patients or caregiver, follow-up regarding
PAV/tracheostomy/death is allowed. With regard for 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. Rather, this time period is only relevant for
PAV/tracheostomy/death – these events are the only ones the patients are at risk for while being observed.
Consequently, for the patients allowing “post withdrawal follow-up PAV/tracheostomy/-death” (the End-of-trial 
eCRF page has a “For subjects that withdrew without meeting survival endpoint, did subject and/or caregiver 
consent to be followed up regarding survival endpoints (PAV/tracheostomy/death) at the scheduled week 76?” 
field), the in-trial period pertaining to PAV/tracheostomy/death, and for these endpoints only, ends at the time of 
what would have been the patients’ scheduled Week 76 or time of PAV/tracheostomy/death whichever came first. 
It means that for the analysis of CAFS and for these survival endpoints the in-trial period may be “extended”. 
Specifically, the end-date of the in-trial period is defined as date of contact if the patient didn’t have an event or 
onset date of event if the patient had an event. 


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It is important to stress that this “exception” only has to do with the aforementioned endpoints and the detailed 
patients 
The above prioritized numbered list of checks to find the end of the in-trial period implies that 
once a date “up” in the hierarchy is identified dates “further down” in the hierarchy are ignored. 
It also means that deaths and SAEs, say, between landmark and the safety follow-up visit will 
be considered as “post-trial” and only reported in lists. 
Data assessed at the randomization visit (no 2) or screening data considered as baseline belongs 
to the in-trial period. 
4.2.2 
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. 
Because the on-treatment period serves two different purposes: as a vehicle for safety reporting 
and as sensitivity analysis for efficacy, end of the on-treatment period will be defined slightly 
different for the purpose of the safety and efficacy presentations: 
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. 
Efficacy 
The on-treatment for the evaluation of efficacy endpoints is intended to reflect an effect that 
can be attributed as close as possible to a continuous treatment regimen (i.e. without 
interruptions that potentially can weaken the effect following an interruption).  
For that reason, the on-treatment period used for efficacy evaluation ends at the first time point 
where a patient has not administered IMP for consecutive 15 days or more, or at or the end-
date for the in-trial period, whichever comes first. 


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4.3 Observation periods and population sets 
Unless otherwise specified, the primary estimand (Section 5) is associated with analyses on the 
mITT population and in-trial period while the secondary estimand is associated with analyses 
on the Safety populations and the on-treatment period. 
However, for efficacy analyses planned/randomized treatments will be used whereas for safety 
analyses actual treatments will be used. 
5 ESTIMANDS 
In the following, estimands for the primary and secondary objectives are specified. These 
specifications include high-level considerations regarding either de facto missing data or data 
treated as missing for a specific analysis.  
Two estimands are defined for the primary composite endpoint, the CAFS. An attractive feature 
of the CAFS is that it is meaningfully defined also for patients who die during the course of the 
trial. The same feature is present for the 3-composite survival endpoint. 
The same feature is, however, not present for any of the other endpoints: for example, it is 
nonsensical to consider the ALSFRS-R score for a dead person and, likewise, a dead person 
has no heart rate. Because it is expected that a substantial number of the randomized patients 
will die during the course of the trial, the interpretation of, say, a mean change from baseline 
in a safety lab parameter, either becomes meaningless for the dead patients, or, rather, 
conditional on patients being alive at planned follow-up at 76 weeks after baseline. Therefore, 
two parallel “while on treatment/alive”-estimands will be defined mirroring the estimands 
pertaining to the primary endpoint and the survival endpoints. Further discussion below. 
5.1 Primary Estimand 
The primary estimand – “Treatment policy” is defined as follows: 
•
Rank difference in the CAFS instrument between arimoclomol and control at 76 weeks
for all randomized patients regardless of exposure, adherence to randomized treatment
and changes in standard of care.
The treatment policy estimand assesses the expected (rank) benefit on the CAFS instrument in 
a future population that results from patients being offered treatment with arimoclomol as add-
on to standard-of-care as compared to standard-of-care alone. 
Generalization of this estimand depends among other things on the extent to which the 
standard-of-care provided in this trial reflects clinical practice and whether the adherence to 


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trial product administration in this trial reflects the behavior of the target population. 
Accordingly, data collected regardless of discontinuation of trial product or background 
therapy will be used to draw inference. 
The analysis of the primary estimand will be based on the mITT and the in-trial observation 
period (see caveats regarding “in-trial” definition for the CAFS Section 4.2.1). 
5.2 Secondary Estimand 
The secondary and supportive estimand – “Hypothetical” estimand, is defined as follows: 
•
Rank difference of the CAFS instrument between arimoclomol and control at 76 weeks
for all randomized and exposed patients if all patients adhered to treatment up until
experiencing the PAV/Tracheostomy/Death endpoint or the week-76 visit.
The hypothetical estimand assesses the rank benefit on the CAFS instrument that a future 
population would be expected to experience if the patients did not discontinue arimoclomol 
when compared to standard-of-care. It is considered a clinically relevant estimand as it provides 
information to treating clinicians about the expected efficacy of arimoclomol compared to 
standard-of-care for purposes of treating individual patients. Generalization of this estimand 
depends among other things on the extent to which the adherence to trial product administration 
in this trial could reflect the behavior of the target population. Accordingly, only data collected 
while patients were exposed to trial IMP will be used to draw inference. 
The analysis of the primary estimand will be based on the Safety and the on-treatment 
observation period. 
5.3 While on treatment/alive estimands 
The two estimands defined above could in principle easily be converted to cover, say ALSFRS-
R or PPSVC by replacing the CAFS with, say; PPSVC. The problem with this approach is that 
death is an integral part of the disease progression in ALS and as such it may be nonsensical to 
address a change to week 76 as many patients will not survive for that long. Rather, to 
accommodate this feature of the disease “while on treatment/alive”-estimands are detailed in 
the ICH E9 guideline on estimands. One crucial feature of this types of estimands is that the 
interpretation of a treatment effect is not linked to any particular time (like for example week 
76). 
We will define the estimands generically to apply to all the relevant efficacy parameters 
detailed herein. The estimands do, therefore, not address any particular endpoint like PPSVC 
nor specify the “unit” of the treatment comparison. The two main features of each of the 
estimands below are 1) the treatment contrast/comparison is not linked to any particular time 


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point and 2) the specifically mentioned intercurrent events used for (de)selecting data used in 
a particular analysis. 
“De facto and while alive[x]”-estimand is defined as follows: 
•
Treatment contrast in a particular parameter[*] between arimoclomol and control
during 76 weeks for all randomized patients regardless of exposure, adherence to
randomized treatment and changes in standard of care.
o
All data for all randomized patients obtained before onset of 3-composite event,
loss of follow-up (withdrawal) or before the Landmark week 76 visit will be
applicable for this estimand. In other words, the first occurrence of any of these
intercurrent events will terminate the follow-up on a patient for this estimand:
PAV/tracheostomy/death/withdrawal/loss of follow-up/Week 76 visit
“De jure and while alive[x] and on treatment”-estimand 
•
Treatment contrast in a particular parameter[*] between arimoclomol and control
during 76 weeks for all randomized and exposed patients as long as the patients
remained exposed to treatment.
o
All data for all randomized and treated patients obtained before onset of 3-
composite event, loss of follow-up (withdrawal), date of last dose plus 14 days
or before the Landmark week 76 visit will be applicable for this estimand. In
other words, the first occurrence of any of these intercurrent events will
terminate 
the 
follow-up 
on 
a 
patient 
for 
this 
estimand:
PAV/tracheostomy/death/withdrawal/loss of follow-up/Week 76 visit/Date of
last dose plus 14 days.
[*]: the term “particular parameter” is used to imply that a feature of the statistical model used to analyze the 
endpoints and the estimands is an estimate of a treatment effect. This treatment effect, can be a difference/ratio 
in means, a difference/ratio between regression coefficients etc. 
[x]: Any event of the 3-composite survival endpoint used for the primary analysis of the CAFS 
(PAV/tracheostomy/death) will serve as intercurrent event. 
The “while on . . “-estimands will be analyzed using random slope- and intercepts models (see 
details in Section 8.2) using the entire sequence of observations pertaining to any observation 
period regardless of obtained as scheduled or unscheduled visits. 
The analysis of the de facto and while alive estimand will be based on the mITT and the in-
trial observation period using randomized treatment. 
The analysis of the de jure and while alive and on treatment estimand will be based on the 
Safety and the on-treatment observation period using randomized treatment. 


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6 VISIT WINDOWING AND BASELINE 
6.1 Baseline 
Baseline is defined as the last non-missing value (either scheduled, unscheduled or repeat) 
before the patient receives the first dose of study drug (IMP).  
6.2 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 are included in the process whereas for on-treatment windowing only visits at or 
before date of last dose+14 are included (for the latter identify the assessments that meet these 
criteria before windowing).  It should be noted that the last 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 sign, Clinical safety 
laboratory test, ECG, SEIQol-DW (patient; caregiver), 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). 
The analysis of all visits (including unscheduled visits) may be performed as sensitivity 
analyses.  For efficacy endpoints, both in-trial and on-treatment 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 falls into a window with another assessment and based on rules 


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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* 
Screening 
-28 
Assigned as collected (if applicable) 
Assigned as collected (if applicable) 
2* 
Baseline 
1 
3* 
Week 4 
28 
2 
56 
2  
42 
2  
42 
4r,*v5 
Week 8 
56 
43 
70 
43 
70 
5* 
Week 12 
84 
57 
112 
71 
98 
71 
98 
6r,*v5 
Week 16 
112 
99 
126 
99 
126 
7* 
Week 20 
140 
113 
168 
2 
252 
127 
154 
127 
154 
8r,*v5 
Week 24 
168 
155 
182 
155 
182 
9* 
Week 28 
196 
169 
224 
183 
210 
183 
224 
10r 
Week 32 
224 
211 
238 
11* 
Week 36 
252 
225 
280 
239 
266 
225 
280 
12r 
Week 40 
280 
267 
294 
13* 
Week 44 
308 
281 
336 
295 
322 
281 
336 
14r 
Week 48 
336 
323 
350 
15* 
Week 52 
364 
337 
406 
253 
448 
351 
378 
337 
406 
2 
448 
16r 
Week 56 
392 
379 
406 
17r 
Week 60 
420 
407 
434 
18* 
Week 64 
448 
407 
490 
435 
462 
407 
490 
19r 
Week 68 
476 
463 
490 
20r 
Week 72 
504 
491 
518 
21* 
Week 76 
532 
491 
EOPa 
449 
EOPa 
519 
EOPa 
491 
EOPa 
449 
EOPa 
* 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.  
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v5In-person visits per protocol amendment v5 
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). 
7 SAMPLE SIZE 
Two hundred and thirty-one (231) patients are planned for randomization. This number 
includes 213 patients according to the main trial eligibility criteria and up to an additional 18 
patients on stable (i.e. minimum 6 months’) treatment with edaravone and who otherwise fulfil 
the eligibility criteria. The sample size calculation has been made for the 213 patients in the 
main trial population (not including the additional patients in the edaravone sub-population). 
The primary endpoint is the CAFS over a 76 weeks’ treatment period comparing 744 mg/day 
arimoclomol (248 mg t.i.d) vs. placebo. The trial will be powered for the primary endpoint.   
In the Phase 2 trial in ALS patients with pathogenic SOD1 mutation associated with rapid 
progression, the effect size in CAFS between arimoclomol and placebo ranged between 
0.41 (entire patient population) to 0.5 (patients with baseline ALSFRS-R ≥35). 
Further, an examination of the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) 
Database reveals that the effect of active drugs versus placebo increases from 12 to 18 months 
on both survival and change in ALSFRS-R. 
While the precise magnitude of the increase in the comparative efficacy from 12 to 18 months 
is difficult to assess, the rate of increase appears to be greater than a linear increase. 
Applying this observation to the effect of arimoclomol compared to placebo, it is expected that 
the effect size (which is estimated to be at least 0.41 at 12 months) will be no less than 0.48 
assuming a minor increase from 12 to 18 months, and as high as 0.61 with a linear increase 
from 12 to 18 months. Assuming an effect size of 0.48, 213 patients randomized 2:1 to 
arimoclomol and placebo will provide 90% power to detect a statistically significant difference 
between arimoclomol and placebo, at a two-sided type-1 error of 0.05. 
The following table provides scenarios for power and sample sizes: 
Effect size at 76 weeks 
Power at final analysis 
0.44 
85% 
        Assumed 
0.48 
90% 


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0.54 
95% 
0.61 
98% 
The assumed effect size of 0.48 will provide 90% power with a final analysis done with a two-
sided type-1 error of 0.05. 
8 STATISTICAL ANALYSIS AND REPORTING 
8.1 Introduction 
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations, except for PK parameter estimation, will be performed primarily 
using SAS (release 9.4 or higher). If the use of other software is warranted, the final statistical 
methodology report will detail what software was used for what purposes. 
Continuous (quantitative) variable summaries will include the number of patients (n) with non-
missing values, mean, standard deviation (SD), median, minimum, maximum, quartile 1 and 
quartile 3.  
Categorical (qualitative) variable summaries will include the number of patients (n) with non-
missing values, frequency and percentage of patients who are in the particular category or each 
possible value. In general, the denominator for the percentage calculation will be based upon 
the total number of patients in the 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 6.2 describes rules for deciding which visits/assessments are eligible for (which) 
analysis. Please note that all data will appear in lists and for analysis non-eligible datapoints 
will be highlighted in the lists. 
Treatment group labels will be displayed as follows: »Arimoclomol 744 mg « and »Placebo«. 
The above apply to all efficacy (including single items and sub-scales) and safety endpoints of 
vital signs, laboratory assessments and biochemistry. 
Furthermore, all summary tables of efficacy endpoints will include / be repeated for both 
observation periods and for absolute and change from baseline values, respectively. 


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Furthermore, all summary tables of safety endpoints will be performed for the on-treatment 
observation period and for absolute and change from baseline values, respectively. 
8.1.1 
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.
8.2 Statistical models 
Unless otherwise indicated, all statistical tests will be conducted at the 0.05 significance level 
using 2-tailed tests, and P values will be reported. Corresponding 95% confidence intervals 
(CIs) will be presented for statistical tests. 
Unless otherwise indicated the following model-specifications will apply to the random 
intercept and slope: this is a regression model of the absolute value of (assumed) continuous 
endpoints: 
𝑦𝑖(𝑗),𝑗,𝑡= (μ + 𝑏𝑖(𝑗),𝑗)
⏟      
𝑖𝑛𝑡𝑒𝑟𝑐𝑒𝑝𝑡
+ (α𝑗+ 𝑎𝑖(𝑗),𝑗) ⋅𝑡
⏟          
𝑠𝑙𝑜𝑝𝑒
+ C𝑖(𝑗),𝑗+ ϵ𝑖(𝑗),𝑗,𝑡
where the two random terms (b and a) vary according to a 2-dimensional normal distribution 
with zero-mean and unstructured covariance matrix. The model includes all baseline and post 
baseline absolute assessments of the endpoint as dependent variables. The fixed slopes vary 
with treatment and the residual terms are assumed independently normally distributed with 
zero mean. The term C is also an intercept-term which may be added to the model controlling 


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for baseline effects (including treatment). In the model time (t) is (actual) time in years since 
baseline. To ease interpretation the scale (unit) of the time covariate will be years. 
The different between regression coefficients of the two treatments will be output as well as 
estimates of absolute and change from baseline values after 52 (t = 1 in the model above) and 
76 weeks (t = 1½ in the model above), respectively. 
To assess the adequacy of the linear model a quadratic (fixed) term will be added (γ + γ𝑗) ⋅𝑡2
where γ represents an overall effect of squared time and the γ𝑗 represents treatment specific 
effects of squared time. If either of these effects are significant at a 10% significance level, 
outputting the difference between linear slopes provides little information pertaining to 
treatment effects. Instead, the estimated difference between active and placebo will be 
outputted for time 52 weeks and 76 weeks, respectively. 
8.3 Primary endpoint and analyses 
The Combined Assessment of Function and Survival (CAFS) is the primary endpoint. It is a 
composite endpoint based on change from baseline in ALSFRS-R and survival endpoint (PAV, 
tracheostomy or death). A patient’s CAFS score represents a patient’s rank in the study based 
on comparing said patient’s outcome to all other patients in the study in a pairwise fashion. 
The following description is detailed. First, we detail the composite parts (the ALSFRS-R and 
the survival endpoints), then we outline how to “score” or “rank” the CAFS.  
In Appendix 2 we provide a further discussion on details on the implementation and analyses 
of the CAFS. 
8.3.1 
ALS Functioning Rating Scale – Revised (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. Additionally, the 
items can be grouped into 4 functional domains consisting of 3 questions each (domain score 
ranges 0-12) as follows: 
Domain 
ALSFRS-R item number 
Bulbar 
Items: 1,2,3 
Fine Motor 
Items: 4, 5a or 5b, 6 


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Gross Motor 
Items: 7, 8, 9 
Respiratory 
Items: 10, 11, 12 
8.3.2 
Time to PAV/Tracheostomy/Death 
For patients who experience an event, their time-to-event will be determined from date of 
randomization to the date of the event (date of event-randomization date +1). Type of event 
met, and date of the event is captured on the end of trial CRF page. This also includes patients 
who withdrew prematurely from the study without having an event and consented to be 
contacted at what would have been their scheduled week 76 visit to find out if they had an 
event since withdraw. If multiple events occur (e.g., tracheostomy then death), time to first 
event will be used (e.g., tracheostomy). Date of PAV event is the first day of 7 consecutive 
days on which PAV was used for > 22 hours/day.     
Patients who do not experience an event will be censored. Their censoring time will be the 
end of the observation period being used for analysis: for patients not allowing post-
withdrawal follow-up this time date of withdrawal while for patients consenting to follow-up 
the time of contact. Patients who are censored will have a censoring variable, CENSORED 
set to 1 whereas patients who had an event will have CENSORED=0.  
8.3.3 
CAFS: Combined Assessment of Function and Survival 
All analyzed patients contribute with their time of event (if relevant) and sequence of observed 
(observation period specific) change from baseline in ALSFRS-R. The coding/calculation of 
CAFS depends on the pair-wise comparison of all patients using the following algorithm: 
 Generic scoring algorithm 
Below we use the term “at risk” to imply that patients are “at risk and under observation” for 
the first of any of the event-types comprising the 3-composite survival endpoint. 
•
Patient S is compared to patient _S. In each patient-to-patient comparison only the
index patient “S” gets scored – the comparator patient “_S” gets scored when she (later)
is becomes the index patient of the algorithm
o
if S has an event at time tS and _S is at risk at time tS, S get a score of –1
o
if S has is at risk at time t_S and _S has an event at time t_S, S get a score of +1
o
if S and _S experience events at the same time, comparison will follow the
methods when comparing patients without events, noting that ALSFRS-R after
event date(s) are (treated as) missing regardless of event-type
o
if none of S or _S have events, or they have coinciding events:


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▪
find the minimum/first time/visit number of S’s and _S’s maximal/last
value of change from baseline in ALSFRS-R[1]
▪
compare the thus identified “last common” change from baseline in
ALSFRS-R (CfB)[2]:
▪
if S’s CfB is smaller than _S’s CfB then S get a score of –1
▪
if S’s CfB is larger than _S’s CfB then S get a score of +1
▪
if S’s CfB is equal to that of _S’s CfB then S get a score of 0
•
Once all pairwise comparisons are made, sum the scores within each patient and denote
the sum scores 𝒮𝒾.
•
The 𝒮𝒾-scores are ranked from the lowest values (negative) to the highest (positive) of
𝒮𝒾
•
The ranks are then analyzed using non-parametric methods suited for such ranks.
[1]: min(max(tS1, tS2, tS3, ..) , max(t_S1, t_S2, t_S3, ..)) where tix is the time (months) of i’s visit x. 
If the two compared patients have coinciding events ALSFRS-R observations after the event(s) 
will be treated as missing. 
[2]: For the calculation of CAFS based on “actual time” (see Appendix 2) there is no problem 
with intermittent missing data but there may indeed be problems with “how” to perform the 
matching of ALSFRS-R values from the two compared patients. On the other hand, when 
performing the matching based on “visits” the matching is trivial but here we may run into 
problems with intermittent missing data. Appendix 2 details different ways of handling these 
issues and thus some of the different sensitivity analyses planned. 
Primary endpoint 
The primary derived CAFS will use the scoring algorithm above based on all in-trial data 
regardless of whether obtained from scheduled or unscheduled visits and using the actual time 
of the assessment as “time”. The included assessments are based on in-trial data (no censoring 
at time of last dose) and using (linear) interpolation to get matching ALSFRS-R pairs. 
 Analysis  
The rank scores will be analyzed using Gehan’s extended Wilcoxon’s test (Gehan 1965). The 
test is implemented in SAS’s lifetest procedure. 
8.4 Sensitivity analyses of the primary endpoint 
To investigate the sensitivity of the primary analysis results, complementary and separate 
analyses will be performed for the primary and secondary estimand. In line with European 
Medicines Agency (4) recommendations and with a report from the US National Research 


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Council (5), these analyses will primarily evaluate the sensitivity of the results due to the 
impact of missing data. 
Moreover, 
 it was recommended not to impute survival 
endpoints/time for withdrawn patients not allowing follow-up on the survival endpoints after 
planned 76 weeks. 
 expressed some concerns regarding the CAFS as 
detailed above, essentially due to the (simple) censoring of patients at time of withdrawal, 
 
 
Lastly, as discussed in Appendix 2 there are a number of rather arbitrary choices to be made 
when implementing the patient-to-patient CAFS scoring. These will have to be addressed as 
part of the sensitivity analyses also, although not particularly associated with “missing data”. 
List of in-trial sensitivity analyses: 
A) Visit windows: CAFS "as is" based on in-trial data using the in-windowed assessments
of ALSFRS-R and with linear interpolation to account for intermittent missing data.
B) Closest match: CAFS "as is" based on in-trial data using the assessments' actual time
and using closest-match to get matching ALSFRS-R pairs.
C) Largest lower: CAFS "as is" based on in-trial data using the assessments' actual time
and using the use largest/latest assessment with actual time ≤ the patient with the
shortest follow-up's last assessment to get matching ALSFRS-R pairs.
D) Copy2Reference (C2R): for patients with follow-up on survival endpoint after
withdrawal, simulation of ALSFRS-R from withdrawal to min(76𝑤, 𝑡𝑑) at scheduled
time-points beginning with/at the first planned visit after withdrawal.
Withdrawn patients without follow-up / lost to follow-up will be censored at the time
of last ALSFRS-R assessment.
E) C2R worst case: as detailed above (D) but where the withdrawn patients without follow-
up on the survival endpoints will be treated as if they experienced an event at the time
of withdrawal (last observed ALSFRS-R assessment)
F) C2R best case: as detailed above (D) but where the withdrawn patients without follow-
up on the survival endpoints will be treated as if they did never experience an event
during the course of the trial and consequently will have their ALSFRS-R imputed as
any other withdrawals up until min(76𝑤, 𝑡𝑑) .
G) On the primary derived CAFS scores apply a semi-parametric rank analysis of
covariance, adjusting for baseline ALSFRS-R and PPSVC. This is a three-step
procedure akin to that outlined in Stokes et al (1) section 7.6. See Appendix 3 for
details.
Details on the above analyses are described in Appendix 2. 


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For clarity, in the above analyses, patients withdrawing from the trial because of meeting non-
lethal components the three-composite survival endpoints are (obviously) treated as indeed 
meeting the survival endpoint. 
One on-treatment analysis will be performed: 
H) As the primary analysis but where
a.
use only ALSFRS-R data obtained while on-treatment
b. censor withdrawn patient at end-of on-treatment or withdrawal date whichever
comes first (i.e. only survival-events no later than 14 days after date of last dose
to be included)
Analysis where ALSFRS-R assessments not bounded by in-trial period will be performed: 
During the review of blinded data of ALSFRS-R prior to unblinding, it was discovered that 
quite a few patients had assessments of ALSFRS-R at Visit 22 (safety follow-up) after having 
had a scheduled Visit 21 (Landmark at week 76) with an assessment of the ALSFRS-R. 
According to protocol (version 7, 08-Jun-2020) ALSFRS-R should not be assessed at the 
safety follow- up and the SAP’s definition of the end-of the in-trial period, for reasons 
discussed in detail, in general ends at the Landmark Visit 21. Potentially, for some of the 
affected cases, a patient may have their end-of-in- trial period end on/after V22 date, 
consequently, have their V22 ALSFRS-R assessments included in the in-trial period.     
Although the values of the ALSFRS-R are quite consistent between the two visits and that the 
periods between visits are in general small, one has to assess the impact of leaving out the 
Visit 22 assessments for some patients. One caveat will be that for patients that entered into 
the open-label extension of this study. For these patients, Visit 21 (Week 76) is considered 
baseline and hence any 01 assessments collected after this date will not be included in the 
analysis.   
Thus, the selection of the patients’ ALSFRS-R trajectories used  for the CAFS will be augmented by 
the possibly censored ALSFRS-R obtained after the end-date of the in-trial period. 
The analysis will thus use exactly the same methodology as the primary analysis of CAFS but with 
”adding a few more observations on the ALSFRS-R” – potentially one for each of the subjects in the 
table above. 
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It is not obvious how one should be graphically present CAFS, but for the primary analysis two 
plots will be output: The first is a simple CDF-plot of the ranks (scaled to lie between 0-1) 
where the CDFs are estimated within each treatment. Secondly, a histogram of the ranks where 
each treatment’s rank scores (scaled to lie between 0-1) get grouped into deciles. 
Effect size 
The 
CAFS 
analyses 
will 
be 
supplemented 
by 
calculating 
Cliff’s 
δ-statistic 
#(𝑆𝑖,𝐴>𝑆𝑗,𝐵)−#(𝑆𝑖,𝐴<𝑆𝑗,𝐵)
𝑛𝐴𝑛𝐶
 for all patients i in Arimoclomol and all patients j in placebo and where 
𝑆𝑥,𝑦 is the CAFS score of patient x in treatment y. 
8.4.1 
Subgroup analyses 
The primary analysis of CAFS will additionally be analyzed in subgroups (separately) based 
on onset of ALS »Bulbar« vs »Limb«. Patients with ALS onset in both bulbar and limb will be 
grouped into the »Bulbar« group. 
8.5 Secondary endpoints and analyses 
8.5.1 
Time to event 
Time to PAV/tracheostomy/death will be analyzed with a Cox proportional hazards model 
controlling for randomized treatment and (centered) baseline ALSFRS-R and PPSVC scores, 
respectively. Hazard ratio and 95% CI will be presented along with p-value.  
Analyses will use data from both the in-trial and on-treatment observation periods, 
respectively, and the in-trial analyses will be carried out both including and excluding any post-
withdrawal event information.  
The primary analysis of interest though is the in-trial analysis including post-withdrawal event 
information.  
In addition to the semi-parametric analyses above, the in-trial analysis including post-
withdrawal event information, will be repeated using a parametric survival model assuming 
Weibull distributed event-times similarly controlling for randomized treatment and (centered) 
baseline ALSFRS-R and PPSVC scores. In this Weibull analysis, the test performed will be 
the estimated median event-free survival in the Arimoclomol group compared to the estimated 
median event-free survival in the Placebo group. 
Figures 
The in-trial time to first event based on all recorded events will be presented graphically using 
Kaplan-Meier estimates. 


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Two figures will be output for the Weibull analysis: 1) the integrated hazard for each treatment 
from the Cox-analysis and the integrated hazard for each treatment Weibull analysis are to be 
plotted against time since randomization. And 2) the log integrated hazard for each treatment 
from the Cox-analysis and the log integrated hazard for each treatment Weibull analysis are to 
be plotted against log time since randomization. 
SAS detailed in Appendix 3. 
8.5.2 
ALSFRS-R 
For this endpoint, one analysis for each of the “while on . .” estimands is performed: 
•
Absolute ALSFRS-R will be analyzed to estimate rate of change using the random
intercept and slope model previously specified. In addition to the previous
specification, the regression model will include treatment as a factor and baseline
centered[§]  PPSVC as a covariate. The data included in the analysis include all observed
observation period specific data regardless of windowing and whether the data originate
from scheduled or unscheduled visits.
[§]: individual baseline values subtracted the overall population mean at baseline.
Figures 
Three figures of ALSFRS-R will be presented: 
•
A simple (in-trial) mean-plot (±SD) by treatment and visit corresponding to the simple
summary table. Sample size per treatment and visit to be displayed.
•
A (panel) plot of all individual (in-trial) trajectories using all recorded values
(regardless of being in-windowed) grouped by time of last ALSFRS-R assessment. x-
axis to be actual time in weeks. Use either nine or six panels and color code each
treatment.
•
A (panel) by-treatment plot with each subject’s estimated “regression line” is plotted
overlaid the treatment (specific) regression.
Sensitivity Analysis 
Consistent with section 8.4, a sensitivity analysis using the same model as for the primary 
analysis of ALSFRS-R will be performed where in general all records of ALSFRS-R (from 
baseline and onwards) will be included irrespective of the end-date of the in-trial period.   
8.5.3 
% 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 


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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: 
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)).   For PPSVC, as for 
ALSFRS-R, one analysis for each of the two “while on... ” estimands is performed: 
•
Absolute PPSVC will be analyzed to estimate rate of change using the random intercept
and slope model previously specified. In addition to the previous specification the
regression model will include treatment as a factor and baseline centered ALSFRS-R
as a covariate. The data included in the analysis include all observed observation period
specific data regardless of windowing and whether the data originate from scheduled
or unscheduled visits and regardless of whether obtained in-clinic or home-based.
Observed values and (change from baseline values) of PPSVC will only be analyzed 
descriptively. 
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Three figures akin to the ones detailed for ALSFRS-R will be presented. 
8.5.4 
Subgroup analyses 
The in-trial analysis of ALSFRS-R and PPSVC will additionally be analyzed in subgroups 
(separately) based on onset of ALS »Bulbar« vs »Limb«. Patients with ALS onset in both 
bulbar and limb will be grouped into the »Bulbar« group. 
8.6 Other efficacy endpoints 
The three groups of endpoints detailed in this section will be summarized descriptively as 
detailed previously. Only the ECAS will be subjected to formal analysis and this just for the 
in-trial observation period. This analysis will be carried out using a by-visit ANCOVA which 
include baseline ECAS, region [pooled countries] and treatment as main effects. The least 
square mean estimates of change from baseline and least square mean estimates of absolute 
values will be reported adjusted according to observed baseline distribution. As ANCOVAs 
are adjusted for baseline and region, this adjustment means that estimates of change from 
baseline and absolute values represent predictions of a patient with baseline corresponding to 
the overall value of the baseline parameter and who is from an “average” region. 
 Edinburgh Cognitive and Behavioral ALS Screen (ECAS)  
ECAS determines cognitive and behavioral changes of patients suffering from ALS. It is a 
global measure for the evaluation of cognitive impairments in ALS patients. 
ECAS consists of 15 individual tasks, which rely on standard procedures and tests used in neuropsychology. 
These 15 individual tasks correlate with certain cognitive functions which are split up into 5 different 
subdomains of which; 3 are ALS-specific (‘language’, ‘verbal fluency’ and ‘further executive functions’) and 
2 are non-specific functions (‘memory’ and ‘visuospatial’). The ECAS total score of 136 points is the sum of 
scores of all 15 individual tasks. The lower the score the more cognitive impairment. 
ECAS total Score: 
ALS-Specific 
ALS non-specific 
Language 
Naming 
Comprehension 
Spelling 
Memory 
Immediate Recall 
Delayed retention  
Delayed recognition 
Verbal 
Fluency 
Fluency – letter S 
Fluency – letter T 
Visu
ospa
tial 
Dot Counting 


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Executive 
functions 
Reverse Digit Span 
Alternation 
Sentence Completion 
Social Cognition 
Cube Counting 
Number location 
The primary caregiver will complete the behavior screen (score 0-10) and the psychosis screen 
(0-3). 
Schedule for the Evaluation of Individual Quality of Life-Direct Weighting 
(SEIQoL-DW) 
The SEIQoL-DW is a semi-structured interview for assessment of quality of life (QoL) of the 
individual. The interviewer first elicits the 5 areas of life (cue) considered most important by 
the individual in determining his/her QoL. The level of satisfaction/functioning in each area 
for the moment is captured by the interviewer by asking the patient to mark a bar on a scale 
that measures from 0 (worst possible) to 100 mm (best possible). The interviewer measures the 
vertical height of each bar (mm) [ each measurement is known as a cue level (mm)]. Then the 
interviewer asks the patient to rate how important each of the 5 areas are relative to each other 
in his/her life at the present [each measurement is known as a weight]. This is based on a 0 to 
100 scale (%). Once this is done the weight for each cue is divided by 100 so that the final cue 
weights range from 0-1 (known as cue weight). An overall index called the SEIQOL-DW index 
(score range 0-100) is calculated as the sum of (cue leveli × cue weighti) where i represents the 
5 cues (important areas of life).  
This HRQoL interview will be administered to both the patient and their primary caregiver. 
Separate SEIQoL-DW Index will be calculated. If the caregiver changes in course of the study, 
this assessment will not be administered to the new caregiver.  
EQ-5D-5L 
The EQ-5D-5L assesses a patient’s health-related quality of life. The EQ-5D-5L consists of 2 
components: the EQ-5D descriptive system and the health EQ visual analogue scale (EQ-
VAS). The version adapted for interview over the telephone will be used in this study. 
The EQ-VAS records a patient’s self-rated health as a score of 0 (worst health you can imagine) 
to 100 (best health you can imagine). 
The EQ-5D comprises the following five dimensions: 
•
mobility
•
self-care


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•
usual activities
•
pain/discomfort
•
anxiety/depression.
Each dimension has 5 response levels ranging from no problem to extreme problem. 
8.7 Multiplicity 
To prevent type-1 error inflation, the secondary endpoints will be tested sequentially in the 
following order: 
•
ALSFRS-R: the in-trial analysis of ALSFRS-R using the random intercept and slope
model
•
Time to PAV/tracheostomy/death: The Cox-model applied to the in-trial observation
period data including post-withdrawal information.
•
Time to PAV/tracheostomy/death: The Weibull-model’s estimated difference in
median event-free survival applied to the in-trial observation period data including post-
withdrawal information.
•
PPSVC: the in-trial analysis of PPSVC using the random intercept and slope model
using all data regardless of obtained in-clinic or at-home
This will be done at the final analysis (following statistical significance of the primary 
endpoint) at a two-sided 0.05 level of significance. These confirmatory tests will be based on 
the estimands specified in Section 5 with associated analyses in Section 8. 
8.8  Columbia-Suicide Severity Rating Scale 
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 
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Category 9 
Actual Attempt (non-fatal) 
Category 10 
Completed Suicide 
In this study, two versions of the C-SSRS is used at Screening (Baseline): lifetime assessment 
and recent (past 18 months). For post-baseline assessments, “Since Last Visit” version is used. 
Suicidal Ideation since baseline – A “yes” answer at any time during double blind treatment to 
any one of the 5 suicidal ideation questions (categories 1-5) on the C-SSRS. 
Suicidal Behavior since baseline – A “yes” answer at any time during double blind 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 double-blind 
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. 
Number (percent) of patients with Suicidal Ideation, Suicidal Behavior, and Self-Injurious 
Behavior without Suicidal Intent Based on the C-SSRS will be summarized by treatment group 
and overall at any Time Post-baseline and separately for Lifetime and 18 months (baseline). 
8.9 Other reporting issues 
8.9.1 
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. 
Country 
For the purpose of statistical analyses, “country” will in some cases be taking into account as 
a covariate. Due to, however, small sample sizes, some countries will be “merged” into 
“regions”. Thus, Germany, Sweden, Italy, France, Poland, and Spain are reported “as is” and 
the Netherlands, Belgium and Great Britain and Switzerland get merge into “Benelux, CHE 
and GBR” and, lastly, Canada and the United States of America get merge into “North 
America”. 
Age 
Age at time of informed consent will be used to represent age of patient in the study. 
Race 


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Where more than one race category has been selected for a patient, these race categories will 
be combined into a single category labelled “Multiple Race” in the summary tables. The listings 
will reflect the original selected categories.  
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.
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). 
Missing/Partial Start/Stop Date of death, tracheostomy and PAV 
No event date of any of the three events of interest are observed to less precision than “months”: 
If the year and month matches the end of study date and if the end of study day is less than the 
15th of the month then the event date is set to end of study date, otherwise the event dates are 
imputed to the 15th of each month. 
Missing/Partial Start/Stop Date of Adverse Events 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 study drug or the event/concomitant
medication is ongoing, the start date will be imputed as the date of the first dose of
study drug.


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•
If the stop date occurs before the start of study drug, 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 study drug 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 study drug
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 study drug, 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 study drug 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 study drug in
which case the date of first dose of study drug will be used.
•
If the stop date occurs before the start of study drug, 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 study drug. The time 
will be imputed as the time as the first dose of study drug+ 1 min. In all other cases the time 
will not be imputed. 
Missing Last Date 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.  


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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.  
Study Completer 
Per protocol, a patient is followed for 76 Weeks or until they meet the survival endpoint of 
PAV/Tracheostomy/Death whereby once they meet survival endpoint, the patient is withdrawn 
from the study.  Hence, a patient that completes Visit 21 (Week 76) visit or meets the survival 
endpoint during the study is for reporting purposes considered a completer.  
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. 
Patient-years of exposure will be calculated as the sum of the above treatment durations by 
treatment group for safety patients divided by 365.25. 
Dose De-escalation 
Per protocol, at any time during the trial, the IMP may be temporarily halted (e.g., interrupted) 
for up to 4 weeks for an intolerable AE. Following re-challenge at the intended dose of 744 
mg/day, de-escalation from 744 mg/day (248 mg t.i.d.) to 372 mg/day (124 mg t.i.d.) may be 
considered. The patient will remain on this decreased dose for the remainder of the trial. A flag 
will be created to identify these patients.  
Sites record start and stop dates of an interruption, then the sites record if dosing was re-
initiated after the temporary interruption and at what dose (744 mg/day or 372 mg/day). The 
site also is asked if there was a de-escalation to 372 mg/day.  If yes, then the site records the 
stop date of the 744 mg/day dose and the start date of the 372 mg/day dose.   
In addition to calculating overall exposure (see above), for patients that do de-escalate, number 
of days exposed to 744 mg/day will be calculated as follows stop date of the 744 mg/day dose 
minus the first day of dosing +1. In addition, number of days exposed to 372 mg/day will be 
calculated as last date of 372 mg/day dose minus start date of the 372 mg/day dose + 1.  
Compliance 
Overall treatment compliance will be determined as follows 
Compliance = 100 x (capsules taken/capsules expected to be taken) 
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capsules taken = number of capsules expected to be taken – number of missed capsules 
(regardless of reason including investigator instituted temporary halt). 
In this study, patients can have their dose reduced hence number of capsules expected to be 
taken should take into account prescribed dose. 
Protocol deviation Categories 
Worldwide PD Categories will be mapped to Sponsor defined categories for presentation 
purposes (see Appendix 4).  
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. 
8.9.2 
Patient Disposition 
Patient disposition will be summarized as follows: 
•
The number of patients in each analysis population (enrolled, ITT, mITT, Safety,
Edaravone) will be tabulated by treatment group and overall
•
Reasons for screen failure will be tabulated
•
Number (percent) of ITT patients within country and site will be tabulated by treatment
group and overall.
•
The number of mITT patients that completed (on or off treatment, met survival
endpoint), withdrew early  along with reasons for withdrawal, 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 and overall.
•
The number of mITT patients that discontinued IMP prematurely and primary reason
for withdrawal will be tabulated by treatment group and overall.
8.9.3 
Protocol Deviations 
Number (percent) of patients with Major Deviations will be presented by treatment group and 
Overall.   Important Deviations are defined as deviations classified as critical or major.   
A listing of protocol deviations will be provided within Appendix 16.2. 


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8.9.4 
Baseline Comparability 
The comparability of treatment groups with respect to patient demographics and baseline 
characteristics will be assessed in a descriptive manner, and no formal statistical testing will be 
performed for the mITT population. 
Standard continuous or categorical variable summaries will be presented by randomized 
treatment group for the following variables  
•
Demographics
•
General medical history
•
ALS characterization/History
•
El Escorial
•
Body Height
•
Tobacco History
8.9.5 
Medical History 
Separate tabulations of previous and ongoing conditions at screening will be presented by 
randomized treatment group and overall for mITT population. Conditions will be presented by 
Medical Dictionary of Regulated Activities (MedDRA) primary system organ class and 
preferred term.  
8.9.6 
Prior and Concomitant Medications 
Separate tabulations will be produced for prior and concomitant medications presented by 
randomized treatment group and overall for the mITT population. 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. Concomitant medications 
will be summarized using ATC Level 2. 
8.9.7 
Exposure to Study Drug 
Extent of exposure (number of days of exposure to IMP and patient-years of exposure) and 
mode of administration will be presented by treatment group and overall for the Safety 
population.  
The number (percent) of patients that fall into the following “number of interruptions” 
categories (0, 1, 2, >3 interruptions). Duration of longest interruption of IMP and last dose 
received will be summarized by treatment group and overall for the Safety population.   


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8.9.8 
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%).
8.10 Pharmacokinetic Analyses 
A PK analysis plan will be defined, and data reported separately. 
8.11 Biomarker Analyses 
A Biomarker analysis plan will be created, and data reported separately. 
8.12 Safety Analyses 
Unless otherwise stated, Safety summaries are based on the on-treatment period, however, all 
data will be listed in the appropriate listings.  
8.12.1 
Adverse Events 
A »pre-treatment AE« is defined as any AE that has an onset prior to the first dose of IMP. 
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 (Section 4.2.2.1) TEAE is defined as  
•
Any TEAE that has an onset in the on-treatment period as defined for safety (see section
4.2.2.1).
An in-trial period TEAE is defined as 
•
Any TEAE that has an onset during the in-trial period (see Section 4.2.1)
Maximum severity will be assumed for an AE with missing severity. 
The following tables will be presented for AEs: 


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•
Overall incidence and the number of Pre-treatment AEs, 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, on-treatment period TEAEs
leading to IMP interruption, on-treatment TEAEs leading to dose reduction.
•
TEAE by system organ class and preferred term, incidence and number of events
•
TEAE by preferred term in decreasing incidence
•
TEAEs > 10% in any treatment group by preferred term in decreasing incidence
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
•
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
•
TEAEs leading to Dose Reduction by system organ class and preferred term, incidence
and number of events
Additionally, two (TEAE) displays will be produced based the following standardized 
MedDRA Queries (SMQs)  
•
Liver-Related Investigations, Signs and Symptoms (SMQ)
•
Drug Related Hepatic Disorders, Severe Events only (SMQ)
Incidence, number of events and number of events per 100 patient-years will be summarized. 
•
In-trial period
o
TEAE by system organ class and preferred term, incidence and number of
events


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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).  
8.12.2 
Laboratory Data 
Individual lab parameters will be summarized descriptively by treatment and visit. Descriptive 
statistics will be presented for each hematology, urinalysis 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(𝜎2) −1 
where 𝜎2 is the variance of the log transformed parameter of interest.
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, two “specific” lists will be presented: 
•
a list of all (in-trial) AEs in patients with ALAT or ASAT ≥ 3 × ULN (in-trial).
•
a list of all (in-trial) AEs in patients fulfilling criteria {ALAT ≥ 3 × ULN and
eosinophilia[*] > 5%} or {ASAT ≥ 3 × ULN and eosinophilia > 5%} (in-trial).
[*]: SDTM.LB$LBTEST=”Eosinophils/Leukocytes” 
In addition, a summary of creatinine over time (continuous) will be presented according to 
concomitant use of MATE/OCT-02 medications at any time (see Appendix  for list of 
concomitant medications). 
Further, number (%) of patients that have potentially clinically significant (PCS) laboratory 
values overall and by visit will be presented as specified below.   


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The following categorical lab parameters of interest with defined PCS values (Appendix 6) will 
be summarized descriptively by visit and overall, respectively.  
Liver function 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
•
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)


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•
(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. 
Figures 
eDISH plot: a scatter plot based on all (both in-windowed and not in-windowed) “on-
treatment” pair (identified as from the same sampling date) of bilirubin (y-axis) vs ALAT (x-
axis) where each parameters has been scaled (divided) by its respective ULN-value(s). The x-
axis (ALAT) will have a vertical line placed at “x = 3” (corresponding to “3 × ULN”) and the 
y-axis (bilirubin) a vertical line located at “y = 2”) (corresponding to “2 × ULN”). Both axes
to be displayed as log10.
Spaghetti plots: For all patients with ALAT or ASAT >= 3 × ULN, plots of all individual 
ALAT and ASAT on-treatment trajectories, respectively. Overlaid should be included the 
geometric mean corresponding to the data presented in tabular summaries with a band 
indicating the SD calculated using the delta-method approximation: Geometric mean × SD of 
the log-transformed values. 
8.12.3 
Vital Signs 
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)


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•
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% 
8.12.4 
Electrocardiogram Data 
Summary tables in relation to the overall interpretation (Normal, Abnormal NCS, and 
Abnormal CS) by visit will be presented. 
8.12.5 
Neurological Examination 
All data will be listed only. 
8.12.6 
Physical Examination 
All data will be listed only. 
9 SARS-COV-2 IMPACT 
The SARS-CoV-2 pandemic of 2020 and 2021 affected trial conduct in several ways. The most 
obvious are “conversions” of planned in-clinic visits to “phone-visits”. For invasive procedures 
like lab sampling the impact is missing data while the assessment of ALSFRS-R would be 
conducted via phone. The scale is, however, validated for remote assessments and the impact 
of the pandemic therefore is or should be small. For SVC, things are a bit different as the 
apparatus used at sites differ from the apparatus used for home spirometry. While all the 
apparatus used have been calibrated and are assumed to measure the different lung function 
parameters adequately, the home spirometers do not estimate predicted values and, 
consequently, not percent-predicted values of SVC. The in-clinic apparatus does this. For the 
home-based assessments of SVC, therefore, the (percent-)predicted values are calculated using 
standard equations based on sex and age. 


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Another impact of the pandemic worth noting in this SAP are some ambiguities in the 
information collected typically on the end-of-trial form. The end-of-trial form has several 
different date-fields like “date of last contact”; “date of completion”; “date of death” etc. 
Together with the dates recorded for the held (both scheduled and unscheduled) visits these 
dates constitutes “milestones” by which one can determine the fate and in-trial eligibility of 
each patient. Due to stress under which the trial’s last year was conducted, a few patients’ 
“milestones dates” appear somewhat inconsistent. A few examples are appropriate (with the 
caveat that the below examples are based on data pre-lock possibly with some outstanding 
queries):  
•
Patient 25002 has recorded last contact on 06/07/2020. There’s no completion date; no
withdrawal date; no 3-compoite survival event date and the last visit took place at
05/05/2020. This visit is recorded on the V21 eCRF page (which indicate that the
patient withdrew IC as site used the V21 eCRF page at withdrawal visits).
•
Patient 24015 has completion date on the 09/07/2020 but with a last contact some three
months prior to this on the 08/04/2020. Patient’s last visit is recorded at the 08/04/2020
(= last contact) which is V22 without a preceding V21. The patient has a recorded PAV
at the 15/04/2020 and later a death at the 03/09/2020. While, for the statistical analysis
the April PAV is the index event, based alone on the dates it is not clear how to interpret
the sequence of trial milestones.
Because of such data discrepancies prior to DBL and unblinding, a meeting will be held where 
the end-date of each patients’ in-trial period will be decided upon. The algorithm detailed in 
section 4.2 will be applied.  
10 DATA MONITORING COMMITTEE ANALYSIS 
Data monitoring committee (DMC) analyses are described in DMC statistical analysis plan.  
11 CHANGES TO PLANNED PROTOCOL ANALYSIS 
11.1 Base Strengths (doses) of arimoclomol  
SAP presents arimoclomol base strengths instead of arimoclomol citrate strengths per Protocol. 
Based on sponsor provided information, 124 mg arimoclomol is equivalent to 200 mg 
arimoclomol citrate. Hence, the following equivalents were determined: 
•
1200 mg arimoclomol citrate (400 mg TID) = 744 mg arimoclomol (248 mg TID)
•
600 mg arimoclomol citrate (200 mg TID) = 372 mg arimoclomol (124 mg TID)
11.2 Populations 


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ITT population definition was changed from “including all randomized patients, excluding 
patients on edaravone, who received at least one dose of IMP” to including all randomized 
patients.   
A modified ITT population was defined as all patients in the ITT Population who are not on 
edaravone. The mITT population will be the primary population for all efficacy analyses 
instead of the ITT population.  
Safety population was defined as all randomized patients who have had at least one dose of 
IMP. For safety analyses, patients will be analyzed based on treatment received instead of 
assigned. The protocol specifies ITT as the primary population for safety.  
PP population and supportive analyses based on this population have been dropped.  Other 
supportive analyses will be done with respect to the primary and secondary endpoints.  
11.3 Analyses 
Randomization was stratified by riluzole use (yes or no). Majority of analyses included riluzole 
use as a factor in the model. However, randomization has been completed and it has been 
determined that majority of randomized patients (>90%) are on riluzole hence due to small 
number of patients not taking riluzole, riluzole use has been dropped as a factor from analysis 
models. 
The primary analysis of CAFs was changed from using a nonparametric rank analysis of 
covariance to Gehan’s extended Wilcoxon test (see section 8.3.3.3).  The nonparametric rank 
of analysis will be conducted as a sensitivity analysis.   
Clarified that the secondary endpoint, SVC, in the protocol was % predicted SVC (PPSVC). 
The primary analyses for ALSFRS-R and % predicted SVC is a random intercept- and slope- 
analysis rather than the protocol specified analysis of covariance (ANCOVA) or  . 
11.4 Data Collection 
Per protocol, SEIQ-DW (subject and caregiver) questionnaire was scheduled to be 
administered at all in-clinic visits including end of trial (Visit 21 [Week 76/ET]), however, 
the schedule of trail procedures table (table 1) in the protocol did not clearly show this.  Thus, 
unfortunately,  the questionnaire was not collected at Visit 21.    
12 REFERENCES 
SAS Institute Inc., Cary, NC, 27513, USA 


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Stokes, ME., Davis, DS. and Koch, GG. Categorical Data Analysis Using SAS, Third Edition. 
SAS Institute Inc., Cary, North Carolina, USA. 2012. 
Little RJA, Rubin DB. Statistical analysis with missing data: New York: John Wiley & Sons. 
1987. 
O'Kelly, K and Ratitch, B. Clinical Trials with Missing Data: A Guide for Practitioners. Wiley. 
2014. 
Committee for Medicinal Products for Human Use (CHMP). Guideline on Missing Data in 
Confirmatory Clinical Trials. EMA/CPMP/EWP/1776/99 Rev. 1. 2 Jul 2010. 
National Academy of Sciences (NAS). The Prevention and Treatment of Missing Data in 
Clinical Trials. Washington D.C.: The National Academies Press. 2010. 
Gehan, E. (1965) A Generalized Wilcoxon Test for Comparing Arbitrarily Singly-Censored 
Samples. Biometrika, 52, 203-223. 
Quanjer Ph.H, Tammeling G.J, Cotes J.E., Perdersen O.F., Peslin R. & Yernault J-C. (1993), 
Lung Volumes and Forced Ventilatory Flows. European Respiratory Journal, 6 (suppl 16),  5-
40. 
13 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 


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Table Number 
Table Title 
Validation 
Method 
Shell Number (if 
repeat) 
14.1.1.1 
Patient Disposition, Analysis Populations-Enrolled 
Population-In-trial period 
IP 
14.1.1.2 
Patient Disposition, Screen Failures-Enrolled 
Population-In-trial period 
IP 
14.1.1.3 
Patient Disposition, Early Withdrawals-mITT 
Population-In-trial Period 
IP 
14.1.1.3.1 
Patient Disposition, Early Withdrawals-Edaravone 
Population-In-trial Period 
IP 
14.1.1.3 
14.1.1.4 
Patient Disposition, Premature Discontinuation of IMP-
mITT Population-In-trial Period 
IP 
14.1.1.4.1 
Patient Disposition, Premature Discontinuation of IMP-
Edaravone Population-In-trial Period 
IP 
14.1.1.4 
14.1.1.5 
Patient Disposition, ITT population by Country and site-
ITT Population-In-trial Period 
IP 
14.1.1.6 
Patient Disposition, mITT population by Country and 
site-mITT Population-In-trial Period 
IP 
14.1.1.7 
Patient Disposition, Safety population by Country and 
site-Safety Population-In-trial Period 
IP 
14.1.1.6 
14.1.1.8 
Patient Disposition, Major Protocol Deviations-mITT 
Population-In-trial Period 
IP 
14.1.1.9 
In Clinic Post-baseline Visits Switched to remote or 
home visit or not done due to COVID-19 Pandemic-
mITT Population-In-trial Period 
IP 
14.1.2 
Demographics 
IP 
14.1.2 
Demographics-mITT Population-In-trial Period 
IP 
14.1.2.1 
Demographics-Edaravone Population-In-trial Period 
IP 
14.1.2 
14.1.3 
Baseline Characteristics 
IP 
14.1.3.1 
Prior Medical History-mITT Population-In-trial Period 
IP 
14.1.3.2 
On-Going Medical History-mITT Population-In-trial 
Period 
IP 
14.1.3.1 
14.1.3.3 
ALS Characterization-mITT Population-In-trial Period 
IP 


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Table Number 
Table Title 
Validation 
Method 
Shell Number (if 
repeat) 
14.1.3.3.1 
ALS Characterization-Edaravone Population-In-trial 
Period 
IP 
14.1.3.3 
14.1.3.4 
Tobacco History-mITT Population-In-trial Period 
IP 
14.2 
Efficacy Data 
14.2.1 
Primary Efficacy Endpoint 
14.2.1.1 
CAFs (Rank Score)-Primary Analysis-mITT 
Population-In-trial Period 
STAT IP 
14.2.1.2 
CAFs (Rank Score)- Visit Window Sensitivity 
Analysis-mITT Population-In-trial Period 
STAT IP 
14.2.1.1 
14.2.1.3 
CAFs (Rank Score)- Closest Match Sensitivity 
Analysis-mITT Population-In-trial Period 
STAT IP 
14.2.1.1 
14.2.1.4 
CAFs (Rank Score)- Largest lower Sensitivity Analysis-
mITT Population-In-trial Period 
STAT IP 
14.2.1.1 
14.2.1.5 
CAFs (Rank Score)- C2R Sensitivity Analysis-mITT 
Population-In-trial Period 
STAT IP 
14.2.1.6 
CAFs (Rank Score)- C2R Worst Case Sensitivity 
Analysis-mITT Population-In-trial Period 
STAT IP 
14.2.1.5 
14.2.1.7 
CAFs (Rank Score)- C2R Best Case Sensitivity 
Analysis-mITT Population-In-trial Period 
STAT IP 
14.2.1.5 
14.2.1.8 
CAFs (Rank Score)- nonparametric rank analysis of 
covariance  Sensitivity Analysis-mITT Population-In-
trial Period 
STAT IP 
14.2.1.9 
CAFs (Rank Score)- on-treatment Period Sensitivity 
Analysis-Safety Population-On-treatment Period 
STAT IP 
14.2.1.1 
14.2.1.10 
CAFs (Rank Score)- Limb-onset ALS-mITT Population 
with limb-onset ALS-In-trial Period 
STAT IP 
14.2.1.1 
14.2.1.11 
CAFs (Rank Score)-Bulbar-onset ALS-mITT 
Population with Bulbar-onset ALS-In-trial Period 
STAT IP 
14.2.1.1 
14.2.1.12 
CAFs (Rank Score) – ALSFRS-R Sensitivity 
STAT IP 
14.2.1.1 
14.2.2 
Secondary Efficacy Endpoints 
STAT IP 
14.2.2.1 
Time to PAV/Tracheostomy/Death - Primary analysis 
(In-trial Period including post-withdrawal events)-mITT 
Population-In-trial Period 
STAT IP 


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Table Number 
Table Title 
Validation 
Method 
Shell Number (if 
repeat) 
14.2.2.2 
Time to PAV/Tracheostomy/Death - Sensitivity analysis 
(In-trial Period excluding post-withdrawal events)-mITT 
Population-In-trial Period 
STAT IP 
14.2.2.1 
14.2.2.3 
Time to PAV/Tracheostomy/Death - Sensitivity analysis 
(On-treatment Period)-Safety Population-On-treatment 
Period 
STAT IP 
14.2.2.1 
14.2.2.4 
Time to PAV/Tracheostomy/Death - Weibull Analysis 
(In-trial Period including post-withdrawal events)-mITT 
Population-In-trial Period 
STAT IP 
14.2.2.5 
Slope analysis of ALSFRS-R Score-De Facto and while 
alive-mITT Population-In-trial Period 
STAT IP 
14.2.2.6 
Slope analysis of ALSFRS-R Score- De jure and while 
alive and on-treatment-Safety Population-On-treatment 
Period 
STAT IP 
14.2.2.5 
14.2.2.7 
ALSFRS-R, Descriptive Summary by Visit (De facto and 
while alive)-mITT Population-In-trial Period 
IP 
14.2.2.8 
Slope analysis of % Predicted SVC- De facto and while 
alive-mITT Population-In-trial period 
STAT IP 
14.2.2.5 
14.2.2.9 
Slope analysis of % Predicted SVC- De jure and while 
alive and on treatment-Safety Population-On-treatment 
period 
STAT IP 
14.2.2.5 
14.2.2.10 
% Predicted SVC, Descriptive Summary by Visit (De 
facto and while alive)-mITT Population-In-trial Period 
IP 
14.2.2.7 
14.2.2.11 
Slope analysis of ALSFRS-R Score-De Facto and while 
alive- Limb onset ALS-mITT Population with limb onset 
ALS-In-trial Period 
STAT IP 
14.2.2.5 
14.2.2.12 
Slope analysis of ALSFRS-R Score-De Facto and while 
alive- Bulbar onset ALS-mITT Population with Bulbar 
onset ALS-In-trial Period 
STAT IP 
14.2.2.5 
14.2.2.13 
Slope analysis of % Predicted SVC-De Facto and while 
alive- Limb onset ALS-mITT Population with limb onset 
ALS-In-trial Period 
STAT IP 
14.2.2.5 
14.2.2.14 
Slope analysis of % Predicted SVC-De Facto and while 
alive- Bulbar onset ALS-mITT Population with Bulbar 
onset ALS-In-trial Period 
STAT IP 
14.2.2.5 
14.2.2.15 
Slope Analysis of ALSFRS-R Score-Sensitivity 
STAT IP 
14.2.2.5 
14.2.3 
Exploratory Endpoints 


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Table Number 
Table Title 
Validation 
Method 
Shell Number (if 
repeat) 
14.2.3.1 
ECAS, Descriptive Summary by Visit-mITT Population-
In-trial Period 
14.2.2.7/14.3.4.1 
14.2.3.2 
ECAS-Caregiver Screens, Descriptive Summary by 
Visit-mITT Population-In-trial Period 
14.2.2.7/14.3.4.1 
14.2.3.3 
Change from baseline to Week 76/ET in ECAS Total 
Score- De facto and while alive-mITT Population-In-trial 
Period 
STAT IP 
14.2.2.4 
14.2.3.4 
SEIQoL-DW (Subject), Descriptive Summary by Visit-
mITT Population-In-trial Period 
14.2.2.7 
14.2.3.5 
SEIQoL-DW (Caregiver), Descriptive Summary by 
Visit-mITT Population-In-trial Period 
14.2.2.7 
14.2.3.6 
EQ-5D-5L, Categorical Summary of Dimensions by 
Visit-mITT Population-In-trial Period 
14.2.3.7 
EQ-5D-5L, Descriptive Summary of VAS Score by 
Visit-mITT Population-In-trial Period 
14.2.2.7 
14.2.3.8 
ALSFRS-R, Categorical Summary of Item Responses by 
Visit-mITT Population-In-trial Period 
14.2.3.6 
14.2.3.9 
Slope analysis of ALSFRS-R Bulbar Domain- De facto 
and while alive-mITT Population-In-trial period 
STAT IP 
14.2.2.5 
14.2.3.10 
Slope analysis of ALSFRS-R Fine Motor Domain- De 
facto and while alive-mITT Population-In-trial period 
STAT IP 
14.2.2.5 
14.2.3.11 
Slope analysis of ALSFRS-R Gross Motor Domain- De 
facto and while alive-mITT Population-In-trial period 
STAT IP 
14.2.2.5 
14.2.3.12 
Slope analysis of ALSFRS-R Respiratory Domain- De 
facto and while alive-mITT Population-In-trial period 
STAT IP 
14.2.2.5 
14.2.3.13 
ALSFRS-R Domains, Descriptive Summary by Visit (De 
facto and while alive)-mITT Population-In-trial period 
IP 
14.2.2.7/14.3.4.1 
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 
14.3.1.1.1 
Adverse Events, Overall Summary of Adverse Events-
Edaravone Population 
IP 
14.3.1.1 


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Table Number 
Table Title 
Validation 
Method 
Shell Number (if 
repeat) 
14.3.1.1.2 
Adverse Events, Overall Summary of Adverse Events-
Safety Population + Edaravone Population-In-trial Period 
14.3.1.2 
Adverse Events, Pre-treatment by Primary System Organ 
Class and Preferred Term-Safety Population-In-trial 
Period 
IP 
14.3.1.2.1 
Adverse Events,  Pre-treatment by Primary System 
Organ Class and Preferred Term-Edaravone Population-
In-trial Period 
14.3.1.3 
Adverse Events, TEAEs by Primary System Organ Class 
and Preferred Term-Safety Population-On-treatment 
Period 
IP 
14.3.1.2 
14.3.1.3.1 
Adverse Events, TEAEs by Primary System Organ Class 
and Preferred Term-Edaravone Population-On-treatment 
Period 
IP 
14.3.1.2 
14.3.1.4 
Adverse Events, TEAEs by Preferred Term in decreasing 
frequency-Safety Population-On-treatment Period 
IP 
14.3.1.4.1 
Adverse Events, TEAEs >10% in any treatment group-
Safety Population-On-treatment Period 
14.3.1.5 
Adverse Events, Treatment Related TEAEs by Primary 
System Organ Class and Preferred Term-Safety 
Population-On-treatment Period 
IP 
14.3.1.2 
14.3.1.6 
Adverse Events, Serious TEAEs by Primary System 
Organ Class and Preferred Term-Safety Population-On-
treatment Period 
IP 
14.3.1.2 
14.3.1.6.1 
Adverse Events, Serious TEAEs by Primary System 
Organ Class and Preferred Term-Edaravone Population-
On-treatment Period 
IP 
14.3.1.2 
14.3.1.7 
Adverse Events, Treatment Related Serious TEAEs by 
Primary System Organ Class and Preferred Term-Safety 
Population-On-treatment Period 
IP 
14.3.1.2 
14.3.1.8 
Adverse Events, TEAEs Leading to IMP Withdrawal by 
Primary System Organ Class and Preferred Term-Safety 
Population-On-treatment Period 
IP 
14.3.1.2 
14.3.1.9 
Adverse Events, TEAEs Leading to IMP Interruption by 
Primary System Organ Class and Preferred Term-Safety 
Population-On-treatment Period 
IP 
14.3.1.2 


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Table Number 
Table Title 
Validation 
Method 
Shell Number (if 
repeat) 
14.3.1.10 
Adverse Events, TEAEs Leading to Dose Reduction by 
Primary System Organ Class and Preferred Term-Safety 
Population-On-treatment Period 
IP 
14.3.1.2 
14.3.1.11 
Adverse Events, TEAEs by Primary System Organ Class, 
Preferred 
Term 
and 
Maximum 
Severity-Safety 
Population-On-treatment Period 
IP 
14.3.1.12 
Adverse Events, TEAEs by Primary System Organ Class, 
Preferred Term and Relationship-Safety Population-On-
treatment Period 
IP 
14.3.1.13 
Adverse Events,  TEAEs by Primary System Organ Class 
and Preferred Term-Safety Population-In-trial Period 
IP 
14.3.1.2 
14.3.1.13.1 
Adverse Events, TEAEs by Primary System Organ Class 
and 
Preferred 
Term-Edaravone 
Population-In-trial 
Period 
IP 
14.3.1.2 
14.3.1.14 
Adverse Events, Serious TEAEs by Primary System 
Organ Class and Preferred Term-Safety Population-In-
trial Period 
IP 
14.3.1.2 
14.3.1.14.1 
Adverse Events, Serious TEAEs by Primary System 
Organ Class and Preferred Term-Edaravone Population-
In-trial Period 
IP 
14.3.1.2 
14.3.1.15 
Adverse Events, TEAEs - Liver-Related Investigations, 
Signs and Symptoms  (SMQ)-Safety Population-On-
treatment Period 
IP 
14.3.1.16 
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-Enrolled Population-In-trial Period 
IP 
14.3.2.2 
SAE, Listing-Enrolled Population-In-trial Period 
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 


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Table Number 
Table Title 
Validation 
Method 
Shell Number (if 
repeat) 
14.3.4.1.1 
Hematology, Descriptive Summary of Parameters by 
Visit-Edaravone Population-On-treatment Period 
IP 
14.3.4.1 
14.3.4.2 
Hematology, Categorical Summary of Potentially 
Clinically Significant Values at Any Time, Post-
Baseline-Safety Population-On-treatment Period 
IP 
14.3.4.2.1 
Hematology, Categorical Summary of Potentially 
Clinically Significant Values at Any Time,Post-Baseline- 
Edaravone Population -On-treatment Period 
IP 
14.3.4.2 
14.3.4.3 
Hematology, Categorical Summary of Potentially 
Clinically Significant Values at by Visit-Safety 
Population-On-treatment Period 
IP 
14.3.4.3.1 
Hematology, Categorical Summary of Potentially 
Clinically Significant Values at by Visit- Edaravone 
Population-On-treatment Period 
IP 
14.3.4.3 
14.3.4.4 
Hematology, Categorical Summary of In/Out of Normal 
Range Values at by Visit-Safety Population-On-
treatment Period 
IP 
14.3.4.4.1 
Hematology, Categorical Summary of In/Out of Normal 
Range Values at by Visit-Edaravone Population-On-
treatment Period 
IP 
14.3.4.4 
14.3.4.5 
Chemistry, Descriptive Summary of Parameters by Visit-
Safety Population-On-treatment Period 
IP 
14.3.4.1 
14.3.4.5.1 
Chemistry, Descriptive Summary of Parameters by Visit 
(on-treatment 
Period)-Edaravone 
Population-On-
treatment Period 
IP 
14.3.4.1 
14.3.4.6 
Chemistry, 
Categorical 
Summary 
of 
Potentially 
Clinically Significant Values at Any Time, Post-
Baseline-Safety Population-On-treatment Period 
IP 
14.3.4.2 
14.3.4.6.1 
Chemistry, 
Categorical 
Summary 
of 
Potentially 
Clinically Significant Values at Any Time, Post-
Baseline-Edaravone Population-On-treatment Period 
IP 
14.3.4.2 
14.3.4.7 
Chemistry, 
Categorical 
Summary 
of 
Potentially 
Clinically Significant Values at by Visit-Safety 
Population-On-treatment Period 
IP 
14.3.4.3 


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Table Number 
Table Title 
Validation 
Method 
Shell Number (if 
repeat) 
14.3.4.7.1 
Chemistry, 
Categorical 
Summary 
of 
Potentially 
Clinically Significant Values at by Visit-Edaravone 
Population-On-treatment Period 
IP 
14.3.4.3 
14.3.4.8 
Chemistry, Categorical Summary of In/Out of Normal 
Range Values at by Visit-Safety Population-On-
treatment Period 
IP 
14.3.4.4 
14.3.4.8.1 
Chemistry, Categorical Summary of In/Out of Normal 
Range Values at by Visit-Edaravone Population-On-
treatment Period 
IP 
14.3.4.4 
14.3.4.9 
Creatinine, Descriptive Summary by Visit-Safety 
Population-Patients who have used a MATE/OTC-02 
medication during the treatment period-On-treatment 
Period 
IP 
14.3.4.1 
14.3.4.10 
Creatinine, Descriptive Summary by Visit-Safety 
Population-Patients who did not use a MATE/OTC-02 
medication during the treatment period-On-treatment 
Period 
IP 
14.3.4.1 
14.3.4.11 
Lab Parameters, Categorical Summary of Potentially 
Clinically Significant Categories by Post-Baseline Visit-
Safety Population-On-treatment Period 
IP 
14.3.4.11.1 
Lab Parameters, Categorical Summary of Potentially 
Clinically Significant Categories by at Any Time, Post-
Baseline-Safety Population-On-treatment Period 
14.3.4.11.2 
Adverse Events in patients with ALAT or ASAT 
≥3x ULN, Listing-Safety Population-In-trial Period 
14.3.4.11.3 
Adverse Events in patients with ALAT or ASAT≥3x 
ULN in combination with esinophils > 5%, Listing-
Safety Population-In-trial Period 
14.3.4.11.4 
Lab parameters,  listing of patients with ALAT or ASAT 
≥ 3x ULN in combination with esinophils > 5%, Listing-
Safety Population-In-trial Period 
14.3.4.12 
Hematology Lab Parameter Results where at least one 
value is Abnormal Clinically Significant, Listing-Safety 
Population-In-trial Period 
IP 
14.3.4.13 
Chemistry Lab Parameter Results where at least one 
value is Abnormal Clinically Significant, Listing-Safety 
Population-In-trial Period 
IP 
14.3.4.13 


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Table Number 
Table Title 
Validation 
Method 
Shell Number (if 
repeat) 
14.3.4.14 
Hematology Lab Parameter Results where at least one 
value is Potentially Clinically Significant, Listing-Safety 
Population-In-trial Period 
IP 
14.3.4.12 
14.3.4.15 
Chemistry Lab Parameter Results where at least one 
value is Potentially Clinically Significant, Listing-Safety 
Population-In-trial Period 
IP 
14.3.4.12 
14.3.5 
Extent Of Exposure, Dosage Information, And 
Compliance 
14.3.5.1 
Extent of Exposure and mode of Dose administration-
Safety Population-In-trial Period 
IP 
14.3.5.2 
Investigational Medicinal Product Interruptions-Safety 
Population 
IP 
14.3.5.3 
Investigational Medicinal Product Interruptions-Safety 
Population-In-trial Period 
IP 
14.3.6 
Vital Signs and Physical Examination 
14.3.6.1 
Vital Signs, Descriptive Summary of Parameters by 
Visit-Safety Population-On-treatment Period 
IP 
14.3.4.1 
14.3.6.1.1 
Vital Signs, Descriptive Summary of Parameters by 
Visit-Edaravone Population-On-treatment Period 
IP 
14.3.4.1 
14.3.6.2 
Vital Signs, 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 
14.3.7.1.1 
ECG, Categorical Summary of Overall Interpretation of 
findings by Visit-Safety Population-On-treatment Period 
IP 
14.3.7.1 
14.3.7.2 
C-SSRS, Number and Percentage of Patients with a
Response of Yes to any of the Suicidal Ideation Items-
(timeframe assessed: lifetime and 18 months prior to
Screening)-Safety Population-In-trial Period
IP 
14.3.7.3 
C-SSRS, Number and Percentage of patients with a
Response of Yes to Any Suicidal Behavior and Non-
suicidal self-injurious behavior Items (timeframe
IP 


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Table Number 
Table Title 
Validation 
Method 
Shell Number (if 
repeat) 
assessed: lifetime and 18 months prior to Screening)-
Safety Population-In-trial Period 
14.3.7.4 
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 
Prior Medications – Safety Population 
IP 
14.3.8.1.1 
Prior Medications – Edaravone Population 
IP 
14.3.8.1 
14.3.8.2 
Concomitant Medications – Safety Population-In-trial 
Period 
IP 
14.3.8.1 
14.3.8.2.1 
Concomitant Medications – Edaravone Population-in-
trial Period 
IP 
14.3.8.1 


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Figure 
Number 
Figure Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
14.2.1.1 
CAFs, CDF plot-mITT Population-In-trial Period 
14.2.1.2 
CAFs, Grouped Histogram-mITT Population-In-trial Period 
14.2.1.3 
CAFs, Scatter plot-mITT Population-In-trial Period 
14.2.2.1 
Time 
to 
PAV/Tracheostomy/Death 
(includingpost-withdraw 
events). Kaplan-Meier-mITT Population-In-trial Period 
14.2.2.4.1 
Weibull, Time to PAV/Tracheostomy/Death, Integrated hazard 
plotted against time-mITT Population-In-trial Period 
14.2.2.4.2 
Weibull, Time to PAV/Tracheostomy/Death,log Integrated hazard 
plotted against time-mITT Population-In-trial Period 
14.2.2.5.1 
ALSFRS-R Total Score by Visit (De facto and while alive)-mITT 
Population-In-trial Period 
14.2.2.5.2 
Spaghetti plot of ALSFRS-R Total Scores by timing of last 
assessment (monthly interval)-mITT Population-In-trial Period 
14.2.2.5.3 
Spaghetti plot of patient's estimated regression line for ALSFRS-R 
total Score by treatment group-mITT Population-In-trial Period 
14.2.2.8.1 
% Predicted SVC by Visit (De facto and while alive)-mITT 
Population-In-trial Period 
14.2.2.8.2 
Spaghetti plot of % Predicted SVC by timing of last assessment 
(monthly interval)-mITT Population-In-trial Period 
14.2.2.8.3 
Spaghetti plot of patient's estimated regression line for % Predicted 
SVC by treatment group-mITT Population-In-trial Period 
14.2.2.9 
Scatter plot of baseline ALSFRS-R and % predicted SVC-mITT 
population 
14.3.1.1 
Hematology, Mean by Visit – mITT population 
14.3.1.2 
Chemistry, Mean by Visit – mITT population 
14.3.1.1 
14.3.1.3.1 
EDISH-Safety population 
14.3.1.3.2 
Spaghetti plot of ALAT and ASAT values for patients with ALAT 
or ASAT ≥ 3xULN-Safety Population-On-treatment Period 
14.3.1.4 
Creatinine by Visit -ITT Patients who have used a MATE/OCT-02 
medication during the Treatment Period-Safety population 
14.3.1.5 
Creatinine by Visit – ITT Patients who did not use a MATE/OCT-
02 medication during the treatment period-Safety population  
14.3.1.6 
Scatterplot of Change from baseline in Creatinine levels vs Number 
days since last dose of MATE/OTC-02 medication by treatment 
Safety subjects who have used a MATE/OCT-02 medication during 
the Treatment Period 


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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-ITT Population-In-trial Period 
IP 
16.2.1.2 
Early Discontinuation From Study Drug-ITT Population-
In-trial Period 
IP 
16.2.1.3 
Screen Failures-Enrolled Population-In-trial Period 
IP 
16.2.1.4 
Inclusion/Exclusion-Enrolled Population-Screen Failures-
In-trial Period 
IP 
16.2.1.5 
Analysis Population-ITT Population-In-trial Period 
IP 
16.2.1.6 
Randomization Scheme-ITT Population-In-trial Period 
IP 
16.2.2 
Protocol Deviations 
16.2.2.1 
Protocol Deviations-ITT Population-In-trial Period 
IP 
16.2.2.1.1 
Site-Level Subject Related Protocol Deviations-ITT 
Population-In-trial Period 
IP 
16.2.4 
Demographic Data 
16.2.4.1 
Demographic Data-ITT Population-In-trial Period 
IP 
16.2.4.2 
Medical History-ITT Population-In-trial Period 
IP 
16.2.4.3 
ALS Characterization-ITT Population-In-trial Period 
IP 
16.2.4.4 
Tobacco History-ITT 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: Changes 
in Mode of IMP adminstration-ITT Population 
IP 
16.1.5.4 
Investigation Medicinal Product Administration: Overall 
Compliance and Extent of exposure-ITT Population 
IP 
16.2.6 
Individual Efficacy Response Data 


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Listing 
Number 
Listing Title 
Validation 
Method 
Shell Number 
(if repeat) 
16.2.6.1 
 CAFs-(Primary Analysis)-mITT Population-In-trial Period 
IP 
16.2.6.1.1 
CAFs (Sensitivity Analyses without multiple imputation)-
mITT Population-In-trial Period 
IP 
16.2.6.1.2 
CAFs (Sensitivity Analyses -C2R)-mITT Population-In-
trial Period 
IP 
16.2.6.1.3 
CAFs (Sensitivity Analyses -C2R Best)-mITT Population-
In-trial Period 
IP 
16.2.6.1.4 
CAFs 
(Sensitivity 
Analyses 
-C2R
Worst)-mITT 
Population-In-trial Period 
IP 
16.2.6.2 
ALSFRS-R total Score and Functional Domains-mITT 
Population-In-trial Period 
IP 
16.2.6.3 
ALSFRS-R individual Items-mITT Population-In-trial 
Period 
IP 
16.2.6.4 
Time to PAV/Tracheostomy/Death-mITT Population-In-
trial Period 
IP 
16.2.6.5 
SVC-mITT population-In-trial Period 
IP 
16.2.6.6 
ECAS total Score and Subdomains-mITT Population-In-
trial Period 
IP 
16.2.6.7 
ECAS individual Items-mITT Population-In-trial Period 
IP 
16.2.6.8 
SEIQol-DW Index Score (Subject and Caregiver)-mITT 
Population-In-trial Period 
IP 
16.2.6.9 
SEIQol-DW - Subject individual Items-mITT Population-
In-trial Period 
IP 
16.2.6.10 
SEIQol-DW 
- 
Caregiver
individual 
Items-mITT 
Population-In-trial Period 
IP 
16.2.6.11 
EQ-5D-5L-mITT Population-In-trial Period 
IP 
16.2.7 
Adverse Event Listings 
16.2.7.1 
Adverse Events-ITT population-in-trial Period 
IP 
16.2.8 
Individual Laboratory Measurements and Other Safety 
16.2.8.1 
Hematology -ITT population-in-trial Period 
IP 
16.2.8.2 
Chemistry-ITT population-in-trial Period 
IP 
16.2.8.3 
Vital Signs-ITT population-in-trial Period 
IP 
16.2.8.4 
ECG Findings-ITT population-in-trial Period 
IP 


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Listing 
Number 
Listing Title 
Validation 
Method 
Shell Number 
(if repeat) 
16.2.8.5 
Neurological 
Exam 
Findings-ITT 
population-in-trial 
Period 
IP 
16.2.8.6 
Physical Exam Findings-ITT population-in-trial Period 
IP 
16.2.8.7 
C-SSRS-ITT population-in-trial Period
IP 


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14 APPENDICES 
14.1 Appendix 1 
-9 point change ALSFRS-R
at end of study 
(completed  study)
- 7 point change ALSFRS-R 
at 2 months
Tracheostomy 1 month
Died 10 months; -6 point 
change ALSFRS-R  at month 2 
-5 point change ALSFRS-R 
(withdrew early at 2 months)
Subject 1
Score 
(subject 1)
-1
+1
+1
-10 point change ALSFRS-R
(completed study)
-10 point change ALSFRS-R at 2 months
+1
Total score: +2
Rank subjects (CAFS) based on the total score:
Subject 2  
   Total score: +4; Rank: 5 
Subject 1  
   Total score: +2; Rank: 4
Subject 5  
   Total score: 0;   Rank: 3
Subject 3   
   Total score: -2;  Rank: 2
Subject 4  
   Total score: -4;  Rank: 1
2
3
4
5
1
Total score (based on pairwise comparison)
Subject 1:  +2
Subject 2:  +4
Subject 3:   -2
Subject 4:  -4
Subject 5:   0


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14.2 Appendix 2 
Introduction 
The Combined Assessment of Function and Survival (CAFS) was introduced by Berry et al 
(2013) is the primary endpoint. It is a composite endpoint based on change from baseline in 
ALSFRS-R and survival endpoint (PAV, tracheostomy or death). 
The CAFS scoring algorithm is described in Berry et al as If both participants die, the one 
surviving longer fared better; if only one survives then that participant fared better; and if both 
participants  survive, the one with the smaller decline in ALSFRS-R from baseline fared better. 
If a participant discontinues early, comparison to each other participant uses time to death if 
the comparator died before the patient’s discontinuation time; otherwise, the comparison is 
based on the last ALSFRS-R time-point available for both participants. (The implementation 
in this trial is to treat the composite survival endpoint as "death" implying, among other things, 
that there's no follow-up relevant to the CAFS after event.) 
The immediate problem is that the above algorithm is ambiguous and could be implemented 
in different ways based on the same data source. Moreover, the choices to be made seem 
arbitrary and cannot be said to have little or no impact on the result of the analysis (significance 
testing). 
Data collected 
In the current trial, patients withdrawing from trial are asked whether they would allow follow-
up at the time of the planned landmark visit regarding the composite survival endpoint.  
For patients accepting this, the observed "history" collected is then a series of ALSFRS-R 
assessments ending at some intermediate visit followed by the period without observed 
ALSFRS-R ending with a yes/no on the question on "did patient experience event" (and if "yes" 
the associated time of event). 
 
At the time writing this, the enquiring whether withdrawals would allow follow-up on the 
survival endpoint has been implemented haphazardly across trial sites with a presently 
unknown result. 
The scoring algorithm 
In an e-mail correspondence with James Berry, he stressed that the individual subject-to-subject 
comparisons were to be considered as a prospective comparison. That is, he stressed that if one 
was to compare, say, a subject with an event at day 200 to a subject lost to follow-up at day 
100, and let the subject with an event “loose” the comparison, one would risk introducing a 


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bias as one couldn’t know the destiny of the subject lost to follow-up after day 100. Instead 
Berry stressed that the comparison was to be performed around the day-100 assessment. 
This is important to realize as it then does not allow for comparisons where one would score 
the trial patients at the landmark visit retrospectively as might otherwise be concluded from 
Berry et al (2013). 
As stated above, when implementing the scoring algorithm, a number of arbitrary choices 
on “data handling” have to be made. For clarity and to enable thorough evaluation of how to 
construct the primary analysis and sensitivity analyses, the following outlines these choices. 
Prospective interpretation and withdrawals 
The prospective interpretation of the subject-to-subject comparisons implies that when we 
compare two subjects, X and Y, the one with the shortest follow-up in essence determines not 
only the timing but also the "premises" for the subject-to-subject comparison. To see this, 
consider the following scenarios. 
1. Assume that X has observed ALSFRS-R from 𝑡= 0, . . , 𝑡𝑋≤𝑡𝑋
𝑑 where 𝑡𝑋
𝑑 is X's event time.
Subject Y has observed ALSFRS-R from 𝑡= 0, . . , 𝑡𝑌< 𝑡𝑋. Leaving aside any difficulty in
finding matching assessments of the ALSFRS-R assessments, the X vs. Y comparison will be
based on ALSFRS-R at some time-point 𝑡= 0, . . , 𝑡𝑌 -- preferably at time 𝑡𝑌.
The next scenarios are slightly different: 
2A.    Assume, as above, that X has observed ALSFRS-R from 𝑡= 0, . . , 𝑡𝑋≤𝑡𝑋
𝑑 where 𝑡𝑋
𝑑 is
X's event time. Subject Y has observed ALSFRS-R from 𝑡= 0, . . , 𝑡𝑌< 𝑡𝑋 but at her 
withdrawal visit allows the site to follow-up on vital-status. Assume that this follow-up shows 
that she had an event at 𝑡𝑌
𝑑, in which case the comparison will be based on 𝑡𝑋
𝑑 vs. 𝑡𝑌
𝑑.
2B.    As 2A but now we imagine that the follow-up showed that she didn't have an event but 
was indeed alive at the time of the planned landmark visit. This would imply that 𝑡𝑋
𝑑 is smaller
than the unobserved 𝑡𝑌
𝑑 and consequently X would "loose" the comparison.
3.
Assume that X has observed ALSFRS-R from 𝑡= 0, . . , 𝑡𝑋 and subject Y has observed
ALSFRS-R from 𝑡= 0, . . , 𝑡𝑌< 𝑡𝑋. In this case, both subjects allowed post-dropout follow-up
on vital status which, as it happened, in both cases showed that both were event-free at the time
of the planned landmark visit. One therefore has to decide on at which time-point to perform
the comparison between ALSFRS-R scores: basically -- do we impute ALSFRS-R scores out
to landmark visit?
4.
Assume that X has observed ALSFRS-R from 𝑡= 0, . . , 𝑡𝑋 and subject Y has observed
ALSFRS-R from 𝑡= 0, . . , 𝑡𝑌< 𝑡𝑋. In this case, only Y allowed post-dropout follow-up on vital


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status which showed that she was event-free at the time of the planned landmark visit. One 
therefore has to decide on at which time-point to perform the comparison between ALSFRS-R 
scores: basically -- do we impute ALSFRS-R scores for Y up until 𝑡𝑋 (or further)? 
----------------- 
 
  
    
 
 
 
 
 
Because vital status (knowledge of the 3-composite survival endpoint) is an integrated part 
of the endpoint, ascertaining information on this becomes important. But the fact of the matter 
is that this information will not be obtained for all subjects (far from it). 
Logically it makes little sense to impute ALSFRS-R from the time of withdrawal to 
min(76𝑤, 𝑡𝑑) for withdrawals allowing follow-up while at the same time not imputing
survival times and ALSFRS-R for withdrawals not allowing follow-up. However, Orphazyme 
has 
 been advised 
 not to impute survival-times (for the 
primary analysis). 
 one could impute ALSFRS-R for subjects where vital status would be 
unknown(able), but this would essentially imply a mixed estimand where these subjects were 
conditioned on being alive after withdrawal. 
Perspectives on "time" 
In Berry et al (2013) there is no explicit discussion on "what" constitutes "time": Time is used 
for two types of subject-subject comparisons. Firstly, when comparing subjects with event(s) 
the one with the first event "loses" the subject-subject comparison; comparing a subject with 
an event with onset while the comparator is at risk and under observation time per se is used 
for the comparison. Secondly, when doing a subject-subject comparison where e.g. none of the 
subjects are observed with events, "time" is used to find matching-in-time assessments of the 
ALSFRS-R. 
As the survival events occur continuously in time and not in connection with visits, 
obviously event-times are on an actual time scale like event date minus randomization date +1. 


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On the other hand, ALSFRS-R is assessed at visits occurring at discrete/planned time points, 
say every month, but in reality, may happen haphazardly during the course of the trial. In 
particular, unscheduled visits occur at time points more or less randomly distributed throughout 
the trial. 
The reason why "unit" of time is relevant is that, when doing subject-subject comparison 
where none of the subjects are observed with events, finding the assessments to use for the 
comparison becomes a focus point. When using the actual time of the visits, the likelihood of 
an exact match to-the-date is small, so some kind of method, with which to find the matching 
pair, would indeed be warranted. Yet, when using (planned) visits as the unit, where the 
matching is trivial, other problems have to be dealt with:  
1.
How to assign assessments to planned visit "slots" including handling of unscheduled visits
and dealing with the assessments being "windowed in" to the same visit "slot".
2.
How to handle intermittent missing data.
A somewhat distinctive feature of using actual time is that the distinction between
withdrawals and those that do not withdraw (actively) from the trial is erased. If one uses actual 
time, whether the subject's latest ALSFRS-R assessment has anything to do with withdrawing 
is irrelevant -- all that matters is that observation on the subject ceases at this last assessment. 
Another technical issue with using actual time rather than planned visits is that is becomes 
less obvious how one should impute missing ALSFRS-R data from planned visit after 
withdrawal conditional on the sequence of (scheduled and unscheduled) visits and their actual 
timings.  
Analyses 
 
 
 
 
 
In list below included in the analyses are all in-trial observed (first) events of the 3-
composite survival endpoint along with the specified ALSFRS-R (change from baseline) 
assessments. The following analyses are therefore planned: 
•
Primary Analysis: CAFS "as is" based on in-trial data (no censoring at time of last dose)
using the assessments' actual time and doing (linear) interpolation to get matching
ALSFRS-R pairs.


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•
Visit windows: CAFS "as is" based on in-trial data (no censoring at time of last dose)
using the in-windowed assessments of ALSFRS-R.
•
Closest match: CAFS "as is" based on in-trial data (no censoring at time of last dose)
using the assessments' actual time and using closest-match to get matching ALSFRS-R
pairs.
•
Largest lower: CAFS "as is" based on in-trial data (no censoring at time of last dose)
using the assessments' actual time and using the use largest/latest assessment with
actual time ≤ the subject with the shortest follow-up's last assessment to get matching
ALSFRS-R pairs.
Linear interpolation: Assume that subject X has observed ALSFRS-R from 𝑡= 0, . . , 𝑡𝑋 and 
subject Y has observed ALSFRS-R from 𝑡= 0, . . , 𝑡𝑌< 𝑡𝑋. Assume further that  𝑡𝑌 is not part 
of subject X’s sequence of sample time points. Rather, we have that 𝑋: 0 < 𝑡1 < 𝑡2 < ⋯<
𝑡𝑌−< 𝑡𝑌< 𝑡𝑌+ < ⋯< 𝑡𝑋 and corresponding assessments of ALSFRS-R (𝑦𝑡ℎ for ℎ =  1, ..).
The linear interpolation of X’s ALSFRS-R data at time 𝑡𝑌 will then be 
ytY
̂ = ytY−+
𝑦𝑡𝑌+−𝑦𝑡𝑌−
𝑡𝑌+−𝑡𝑌−⋅(𝑡𝑌−𝑡𝑌−).
Visit windows: Here the input for the CAFS is the subset of (only) in-windowed ALSFRS-R 
assessments together with the in-trial observed events of the 3-composite survival endpoint. 
Matching of ALSFRS-R will be based on visit number/label. Patients with intermittent missing 
data will have the intermittent missing data imputed by linear interpolation between adjacent 
observed ALSFRS-R values based on the planned time in months of the visits as “weights”. 
For a particular patient with intermittent missing data, let the points (ti, yi)  for i =
0,1,2, . . , L with “L” for landmark represent the observation schedule (planned time) and 
associated assessment of the endpoint. The linear interpolation will only use the adjacent 
observed values for the interpolation: 
𝑡0 
𝑡1 
𝑡2 
𝑡3 
𝑡4 
𝑡5 .. 𝑡𝐿 
𝑦0 
𝑦1 
𝑦2  𝑦3
̂ = 𝑦2 +
𝑦5−𝑦2
𝑡5−𝑡2 × (𝑡3 −𝑡2)
𝑦4̂ = 𝑦2 +
𝑦5−𝑦2
𝑡5−𝑡2 × (𝑡4 −𝑡2)
𝑦5 .. 𝑦𝐿 
Closest match: Assume that subject X has observed ALSFRS-R from 𝑡= 0, . . , 𝑡𝑋 and subject 
Y has observed ALSFRS-R from 𝑡= 0, . . , 𝑡𝑌< 𝑡𝑋. Assume further that  𝑡𝑌 is not part of 
subject X’s sequence of sample time points. Rather, we have that 𝑋: 0 < 𝑡1 < 𝑡2 < ⋯< 𝑡𝑌−<
𝑡𝑌< 𝑡𝑌+ < ⋯< 𝑡𝑋 and corresponding assessments of ALSFRS-R (𝑦𝑡ℎ for ℎ =  1, ..). The


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“closest match” identifies the match to (𝑦𝑡𝑌, 𝑡𝑌) as min(|𝑡1 −𝑡𝑌|, |𝑡2 −𝑡𝑌|, . . , |𝑡𝑋−𝑡𝑌|) and
selects the first of X’s assessments in case of a tie. 
Largest lower: Assume that subject X has observed ALSFRS-R from 𝑡= 0, . . , 𝑡𝑋 and subject 
Y has observed ALSFRS-R from 𝑡= 0, . . , 𝑡𝑌< 𝑡𝑋. Assume further that  𝑡𝑌 is not part of 
subject X’s sequence of sample time points. Rather, we have that 𝑋: 0 < 𝑡1 < 𝑡2 < ⋯< 𝑡𝑌−<
𝑡𝑌< 𝑡𝑌+ < ⋯< 𝑡𝑋 and corresponding assessments of ALSFRS-R (𝑦𝑡ℎ for ℎ =  1, ..). The
“largest lower” uses X’s assessment at time 𝑡𝑌−. 
----------------- 
 
 
 
 
•
Copy2Reference (C2R): for subjects with follow-up on survival endpoint after
withdrawal, simulation of ALSFRS-R from withdrawal to min(76𝑤, 𝑡𝑑) at scheduled
time-points beginning with/at the first planned visit after withdrawal. Withdrawn
subjects without follow-up / lost to follow-up will be censored at the time of last
ALSFRS-R assessment.
While the imputations (see below) per se will be based on the in-windowed subset of
ALSFRS-R data used for the “Visit Window CAFS” analysis, the C2R-analysis per se
will include all observed ALSFRS-R data augmented with the imputed values using the
primary (linear interpolation) CAFS calculation.
The imputations will be based on observed in-windowed ALSFRS-R assessments (data used 
for the “Visit Window CAFS” analysis) and baseline SVC. The imputations will be based on 
observed placebo subjects (see below). 
Two other C2R imputations and associated analyses of CAFS are planned, treating the 
withdrawn subjects without follow-up on the survival endpoints in two different (extreme) 
ways 
•
C2R worst case: as detailed above but where the withdrawn subjects without follow-up
on the survival endpoints will be treated as if they experienced an event at the time of
withdrawal implemented as the time of the last observed ALSFRS-R assessment
•
C2R best case: as detailed above but where the withdrawn subjects without follow-up
on the survival endpoints will be treated as if they did never experience an event during
the course of the trial and consequently will have their ALSFRS-R imputed as any other
withdrawals up until min(76𝑤, 𝑡𝑑) .


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Details on the Copy2Reference (C2R) imputation 
The imputation approach is based on a pattern mixture modelling (PMM) approach assuming 
the missing data mechanism is missing at random (MAR) conditional under the observed data 
under the data selection scheme under the studied estimand. 
Under this assumption, the statistical behavior of the missing data can be described by the 
observed data included in the model, thus, observed values of the endpoint responses at all 
visits and the observed effects adjusted for in the model. 
Consequently, MAR will reflect randomization and allowing follow-up after randomization. 
Thus, no conditioning of adherence to protocol (except coming in for visits) is implied. Of note, 
an analysis based on MAR may attribute benefits to patients who withdraw from trial altogether 
regardless of the reason for discontinuation. The imputation of the monotone missing data will 
accordingly be performed separately within each of the two randomized treatment. 
By performing the imputations in separate groups, the model effectively allows parameters to 
vary freely amongst the two groups. Moreover, the imputation model will include baseline 
SVC and previous endpoint values as predictors. 
More specifically, let (𝑦𝑖(𝑘),𝑡
𝑠
) and (𝑦𝑖(𝑘),𝑡
𝑢
) for 𝑖(𝑘) = 1,2, . . , 𝑁(𝑘) and 𝑡= 0,1, … represent 
the observed scheduled (and in-windowed) assessments of the ALSFRS-R for subject i from 
the k'th treatment at time t. The imputations will sequentially loop over each post baseline visit 
(with missing data) using a monotone regression model as predictor equations: 
𝐸𝑦𝑖(𝑘),𝑡+1
𝑠
= μ + βSVCi(k),0 + γ0𝑦𝑖(𝑘),0
𝑠
+ ∑γ𝑔𝑦𝑖(𝑘),𝑔
𝑠
,
𝑡
𝑔=𝑡−2
 
where the sum includes maximally the two previous visits prior to the t’th visit (the one being 
imputed) and (always) baseline. Here the subjects to have 𝑦𝑖(𝑘),𝑡+1
𝑠
 imputed are included
regardless of treatment and adherence whereas the subjects with observed 𝑆𝑉𝐶𝑖(𝑘),0  and 
𝐴𝐿𝑆𝐹𝑅𝑆−𝑅𝑖(𝑘),𝑔, for 𝑔= 0, . . , 𝑡 (i.e. the subjects used to "inform" the imputations) include 
only subjects randomised to placebo. SAS code for doing this imputation is in Appendix 3. 
Details on the MAR-based imputation 
We may perform imputation using the exact same imputation model but within the treatment 
arms separately. This may be used for analyses under the secondary estimand. (With reference 
to  Appendix 3 the MAR based imputations can be achieved by running almost the same SAS 
code but for each treatment separately and making sure that the argument ControlGrp gets 
updated in each run accordingly.). 


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14.4 Appendix 4 
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 
14.3 Appendix 3 
Appendix 3 contains SAS code and is not included.


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If  a worldwide category is not listed in the above table, the worldwide category by default 
will be assigned to Orphazyme category of Other. 
14.5 Appendix 5 
MATE/OCT-02 medications (inhibitors and substrates) 
AMANTADINE 
AMILORIDE 
CIMETIDINE 
DOPAMINE 
FAMOTIDINE 
MEMANTINE 
METFORMIN 
PINDOLOL 
PROCAINAMIDE 
RANITIDINE 
VARENICLINE 
OXALIPLATIN 
DOFETELIDE 
TRIMETROPRIM 
VERAPAMIL 
LEVOFLOXACIN 
CIPROFLOXACIN 
MOXIFLOXACIN 
PYRIMETHAMINE 
ONDANSETRON 
QUINIDINE 


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14.6 Appendix 6 
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 
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 


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Laboratory Test 
CDISC 
Unit 
PCS LOW 
PCS HIGH 
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 
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 


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Laboratory Test 
CDISC 
Unit 
PCS LOW 
PCS HIGH 
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 
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