Conditions: Amyotrophic Lateral Sclerosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 313
Healthy volunteers: no

Brief summary:
Multicenter, multinational, double-blind, randomized (2:1), placebo-controlled Phase III study to investigate the efficacy and safety of 100 mg FAB122 once daily as oral formulation in ALS patients.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: FAB122 intervention 2: Placebo
Intervention descriptions: intervention 1: Daily dose 100 mg intervention 2: Daily dose

Protocol document:
Prot_000.pdf: 
Ferrer Internacional, S.A. 
 
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Confidential  
CLINICAL STUDY PROTOCOL 
 
 
Title 
 
A multicenter, randomized, double-blind, placebo-controlled study to 
investigate the efficacy and safety of FAB122 in patients with Amyotrophic 
Lateral Sclerosis 
 
ADORE (ALS Daily ORal Edaravone) study 
 
 
THE SPONSOR STUDY CODE: FAB 122-CT-2001 
EudraCT NUMBER:  2020-003376-40 
 
 
 
Sponsor: 
Ferrer Internacional, S.A. 
 
Barcelona, Spain 
 
 
 
 
Study Drug Name:  
FAB122 
Development Phase: 
PHASE III  
Date of Protocol: 
24/05/2023 
 
 
 
 
 
 
CONFIDENTIAL 
This document is the property of Ferrer Internacional S.A. and must be kept in a 
confidential manner.  It must be returned to Ferrer Internacional S.A. upon request.  
No part of this document may be reproduced, transmitted, disclosed or used in any 
form without written permission from Ferrer Internacional S.A. 
 


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Confidential  
DOCUMENT VERSION HISTORY 
 
Date 
Version 
Reason for Revision 
 12/05/2021 
1.0 
Initial 
18/10/2021 
2.0 
Correction of typos and inconsistencies. 
Inclusion of requirements received from RAs 
and ECs and incorporated in country specific 
versions: 1.1 BEL, 1.1 FRA, 1.2 FRA, 1.1 
GBR, 1.1 IRL 
30/08/2022 
3.0 
Update of study endpoints and statistical 
analysis section.  
Administrative updates. 
24/05/2023 
4.0 
Non-Substantial Amendment 
Sub group analysis wording in statistical 
section (no change in primary or secondary 
endpoints), clarification if patients can not 
attend study visits or key safety 
assessments, clarification on IMP delivery. 
Minor administrative updates 
 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL APPROVAL SIGNATURES
Sponsor Signatures
Declaration of Sponsor 
Study title: A multicenter, randomized, double-blind, placebo-controlled study to 
investigate the efficacy and safety of FAB122 in patients with Amyotrophic Lateral 
Sclerosis
Version number: 4.0 
Date:
This study 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, the guidelines on Good Clinical Practice (GCP) and
other local and national laws and regulations, as well as any applicable guidelines. 
Clinical Project Lead
Name: Nuria Albareda
Ferrer Internacional, S.A.
Signature
Clinical Development
Diagonal 549
Date
08029 Barcelona
Spain
Medical Monitor
Name: Lubia Álvarez
Ferrer Internacional, S.A.
Signature
Clinical Development
Diagonal 549
Date
08029 Barcelona
Spain
Project Lead
Name: Cristina Tarragó
Ferrer Internacional, S.A.
Signature
Portfolio Management
Diagonal 549
Date
08029 Barcelona
Spain
Nuria Albareda
Lubia Álvarez
Cristina Tarragó


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Clinical Development Director
Name: Tània Nadal
Ferrer Internacional, S.A.
Signature
Clinical Development
Diagonal 549
Date
08029 Barcelona
Spain
Lead Investigator 
Name: Leonard H van den Berg, MD, PhD
Professor of Neurology
UMC Utrecht Brain Center
Director Netherlands ALS Centre
University Medical Center Utrecht
Signature
The Netherlands  
Date
Tània Nadal
Leonard H van den Berg, MD, PhD


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Investigator Signature Page 
 
Declaration of Investigator 
Study title: A multicenter, randomized, double-blind, placebo-controlled study to 
investigate the efficacy and safety of FAB122 in patients with Amyotrophic Lateral 
Sclerosis 
Version number: 4.0  
Date: 
  
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidentiality. This documentation includes this study 
protocol, Investigator's Brochure, Case Report Forms (CRFs), and other scientific data. 
The study will not be commenced without the prior written approval of a properly 
constituted Institutional Review Board (IRB) or Independent Ethics Committee (IEC) and 
the corresponding Competent Authority. No changes will be made to the study protocol 
without the prior written approval of the Sponsor and the IRB or IEC, except where 
necessary to eliminate an immediate hazard to the patients. 
I have read and understood and agree to abide by all the conditions and instructions 
contained in this protocol. 
 
 
Principal investigator name: 
Institution: 
 
 
 
 
 
 
Signature 
 
 
 
 
 
 
 
Date 
 
 
 


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STUDY CONTACTS
SPONSOR 
Clinical Project Lead 
Name: Nuria Albareda
Address: 
Ferrer Internacional, S.A.
Diagonal 549
08029 Barcelona
Spain
Mob.:
E-mail:
+34 649 442 389
nalbareda@ferrer.com
Project Lead 
Name: Cristina Tarragó
Address: 
Ferrer Internacional, S.A.
Diagonal 549
08029 Barcelona
Spain
Mob.
+34 620 295 263
E-mail:
ctarrago@ferrer.com
Medical Monitor
Name: Katarzyna Holub / 
Lubia Álvarez
Address:
Ferrer Internacional, S.A.
Diagonal 549
08029 Barcelona
Spain
Mob.
+34696426090
E-mail:
kholub@ferrer.com / lalvarez@ferrer.com
Nuria Albareda
Cristina Tarragó
Katarzyna Holub / 
Lubia Álvarez


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CRO   
Name: Julius Clinical  
Address: Broederplein 41-43 
               3703CD Zeist 
               The Netherlands 
 
Telephone No.: +31 30 656 9900 
Fax No.:             +31 30 656 9990 
 
PHARMACOVIGILANCE 
 
Name: Pharmalex 
Address: Calle del Coso, 103,  
50001 Zaragoza 
Spain 
 
Telephone No.: +34 976 20 44 00 
 
CENTRAL LABORATORY 
 
Name: Cerba Research 
Address: Industriepark Zwijnaarde 3 
39052 Ghent 
Belgium 
 
Telephone No: +32 9 240 94 21 
 
 
 


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TABLE OF CONTENTS 
 
PROTOCOL APPROVAL SIGNATURES .......................................................................... 3 
Sponsor Signatures .................................................................................................... 3 
Investigator Signature Page ........................................................................................ 5 
STUDY CONTACTS .......................................................................................................... 6 
TABLE OF CONTENTS .................................................................................................... 8 
LIST OF TABLES .............................................................................................................11 
LIST OF FIGURES ...........................................................................................................11 
ABBREVIATIONS ............................................................................................................12 
1. 
SYNOPSIS ..............................................................................................................15 
2. 
INTRODUCTION .....................................................................................................22 
2.1. Background and rationale ..................................................................................22 
2.2. Risk-Benefit Assessment ...................................................................................32 
3. 
OBJECTIVES AND OUTCOMES MEASURES .......................................................34 
3.1. Objectives .........................................................................................................34 
3.1.1. Primary Objective ..................................................................................34 
3.1.2. Secondary Objectives ............................................................................34 
3.1.3. Exploratory Objectives ...........................................................................34 
3.2. Endpoints ..........................................................................................................34 
3.2.1. Primary Endpoint ...................................................................................34 
3.2.2. Secondary Endpoints ............................................................................34 
3.2.3. Safety Endpoints ...................................................................................36 
3.2.4. Exploratory Endpoints ...........................................................................36 
4. 
STUDY DESIGN ......................................................................................................37 
5. 
STUDY POPULATION ............................................................................................39 
5.1. Study Participants .............................................................................................39 
5.2. Inclusion Criteria................................................................................................39 
5.3. Exclusion Criteria ..............................................................................................40 
6. 
STUDY PROCEDURES ..........................................................................................42 
6.1. Screening and Eligibility Assessment ................................................................46 
6.2. Baseline Assessments ......................................................................................47 
6.3. Subsequent Visits ..............................................................................................49 
6.4. Telephonic visits ................................................................................................57 
6.5. Early Discontinuation/Withdrawal of Participants ...............................................57 
6.6. Sample Handling ...............................................................................................59 
6.7. PK Samples ......................................................................................................59 
7. 
STUDY INTERVENTIONS .......................................................................................62 


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7.1. Investigational Medicinal Product(s) (IMP) Description ......................................62 
7.1.1. Packaging and Labelling ........................................................................64 
7.1.2. Blinding of IMP ......................................................................................64 
7.1.3. Compliance with Trial Treatment ...........................................................64 
7.1.4. Accountability of the Trial Treatment......................................................64 
7.1.5. Concomitant Medication ........................................................................65 
7.1.6. Post-trial Treatment ...............................................................................65 
7.2. Other Treatments (non-IMPS) ...........................................................................65 
8. 
PARAMETERS AND METHODS OF ASSESSMENT .............................................66 
8.1. Parameters ........................................................................................................66 
8.1.1. ALSFRS-R .............................................................................................66 
8.1.2. Survival Time .........................................................................................66 
8.1.3. Lung Function ........................................................................................66 
8.1.4. Staging of Disease Progression .............................................................66 
8.1.5. Strength Test .........................................................................................66 
8.1.6. Health Status .........................................................................................67 
8.1.7. Cognition ...............................................................................................67 
8.2. Safety Parameters .............................................................................................67 
8.2.1. Physical and neurological examination ..................................................68 
8.2.2. Laboratory Parameters ..........................................................................68 
8.2.3. ECG ......................................................................................................69 
8.2.4. Vital Signs .............................................................................................69 
8.2.5. Nerve Conduction Study ........................................................................69 
8.3. Pharmacokinetic Assessments ..........................................................................70 
8.3.1. Population and profiling PK Analysis .....................................................71 
8.3.2. Concentration-Response Relationship Analysis ....................................72 
9. 
SAFETY REPORTING ............................................................................................73 
9.1. Definitions .........................................................................................................73 
9.1.1. Adverse Event .......................................................................................73 
9.1.2. Adverse Reaction ..................................................................................74 
9.1.3. Unexpected Adverse Reaction ..............................................................74 
9.1.4. Adverse Event of Special Interest ..........................................................74 
9.2. Severity Assessment .........................................................................................74 
9.3. Serious Adverse Event ......................................................................................75 
9.4. Assessment of Causality ...................................................................................75 
9.5. Reporting Adverse Events .................................................................................76 
9.6. Reporting Serious Adverse Events ....................................................................77 
9.6.1. Adverse Event Follow-up .......................................................................77 
9.7. Expedited Reporting ..........................................................................................78 
9.8. Unblinding .........................................................................................................78 


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9.9. Pregnancy .........................................................................................................79 
10. 
HEALTH ECONOMICS ...........................................................................................80 
11. 
STATISTICS ............................................................................................................82 
11.1. Statistical Analysis Plan (SAP) ..........................................................................82 
11.2. Sample Size Determination ...............................................................................82 
11.3. Description of Statistical Methods ......................................................................82 
11.3.1. Analysis Populations .............................................................................82 
11.3.2. Demographics, baseline characteristics .................................................83 
11.3.3. Subject Disposition ................................................................................83 
11.3.4. Efficacy Analysis....................................................................................84 
11.3.5. PK Analysis ...........................................................................................87 
11.3.6. Safety Analysis ......................................................................................87 
11.4. Study Estimand and Handling of Missing Data ..................................................88 
11.5. Health Economics Analysis ...............................................................................90 
12. 
DATA MANAGEMENT ............................................................................................91 
12.1. Case Report Form .............................................................................................91 
12.2. Source Data ......................................................................................................91 
12.2.1. Remote Source Data Verification ...........................................................92 
12.3. Data Processing ................................................................................................94 
12.4. Central Data Monitoring .....................................................................................94 
13. 
QUALITY ASSURANCE PROCEDURES ................................................................95 
13.1. Monitoring .........................................................................................................95 
13.2. Study committees ..............................................................................................96 
13.2.1. Data Safety Monitoring Committee ........................................................96 
14. 
ETHICS AND REGULATORY CONSIDERATIONS ................................................97 
14.1. Approvals ..........................................................................................................97 
14.2. Ethical Conduct of the Study .............................................................................97 
14.3. Participant Information and Confidentiality.........................................................97 
15. 
FUNDING AND INSURANCE..................................................................................98 
16. 
PUBLICATION POLICY ..........................................................................................99 
17. 
ARCHIVING .......................................................................................................... 100 
18. 
REFERENCES ...................................................................................................... 101 
19. 
Annexes ............................................................................................................... 109 
Annex 1, El Escorial Criteria..................................................................................... 109 
Annex 2, ALS Functional Rating Scale  revised (ALSFRS-R) ................................. 111 
Annex 3, Treatment options for ALS ........................................................................ 112 
Annex 4, COVID-19 impact mitigation Plan .............................................................. 113 
Annex 5: Cost Questionnaire ................................................................................... 115 


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LIST OF TABLES  
Table 1: Study Scheduled Visits ............................................................................ 42 
Table 2: Overview of laboratory assessments ....................................................... 56 
Table 3: Overview of PK sampling ........................................................................ 61 
Table 4: The theoretical quantitative composition of FAB122 granules for oral 
solution in sachet ................................................................................................... 63 
Table 5: Pharmacokinetic parameters of FAB122 and riluzole .............................. 71 
 
 
LIST OF FIGURES 
 
Figure 1: Posible mechanism of action of edaravone ............................................ 27 
Figure 2: Study flowchart ....................................................................................... 38 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ABBREVIATIONS 
 
3-NT 
3-Nitrotyrosine 
4HNE   
4-hydroxy-2-nonenal 
8-OHdG  
 8-hydroxyguanosine 
ADR  
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest  
AIS 
Acute Ischaemic Stroke 
ALS   
Amyotrophic Lateral Sclerosis 
ALSFRS-R   
ALS Functional Rating Score  revised 
ALSAQ-40 
ALS Assessment questionnaire 40 
ALT 
Alanine transaminase 
aPTT 
Activated partial thromboplastin time  
AST 
Aspartate transaminase 
AUC 
Area Under the Curve 
BID 
Twice Daily 
BUN 
Blood urea nitrogen  
CAFS 
Combined Assessment of Function and Survival 
CAS 
Chemical Abstracts Service 
CHMP 
Committee for Human Medicinal Products 
CI 
Confidence Interval 
CK 
Creatinine kinase 
Cmax 
Maximum concentration 
CNS 
Central Nervous System 
CSF 
Cerebrospinal Fluid  
CYP 
Cytochrome P450  
CV 
Coefficient of Variation 
DSMB 
Data Safety Monitoring Board  
EC 
European Committee 
ECAS 
Edinburgh Cognitive and behavioural ALS Screen 
eGFR 
Estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EMG 
Electromyography 
fALS 
familial Amyotrophic Lateral Sclerosis 
FDA 
Food and Drug Administration 
FTD 
Frontotemporal dementia 
FVC 
Forced Vital Capacity 
G93A 
G93A-human Cu/Zn superoxide dismutase 


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GGT 
Gamma-glutamyl transpeptidase 
GI 
Gastrointestinal 
hct 
Haematocrit 
HEK 
Human Embryonic Kidney 
hERG 
human Ether-a-go-go-Related Gene 
hgb 
Haemoglobin 
hOAT 
Human Organic Anion Transporter 
HSP 
Hereditary Spastic Paraparesis 
IC50 
Half Maximal Inhibitory Concentration 
IDMC 
Independent Data Monitoring Committee 
IE 
Intercurrent Event 
INN 
International Non-proprietary Name 
iNOS 
Inducible Nitric Oxide Synthase  
IV 
Intravenous 
IUPAC 
International Union of Pure and Applied Chemistry 
Km 
Michaelis constant 
LD50 
Median Lethal Dose 
LDH 
Lactate dehydrogenase 
LMN 
Lower Motor Neurons 
MMRM 
Mixed Model for Repeat Measures 
MND 
Motor Neuron Disease 
MoA 
Mechanism of Action  
MOS 
Margin of Safety 
mSOD1 
Mutated Superoxide Dismutase 1 
MVV 
Maximum Voluntary Ventilation 
NAA 
N-Acetyl Aspartate 
NCS 
Nerve Conduction Study 
NF 
National Formula 
NFL 
Neurofilament Light 
NIPPV 
Non-invasive Positive Pressure Ventilation 
NMR 
Nuclear Magnetic Resonance spectroscopy 
NOAEL 
No Observed Adverse Effect Level 
Nrf2 
Nuclear erythroid 2-related factor 2 
OAT 
Organic Anion Transporter 
OD 
Once Daily 
P75ECD 
Extracellular domain of neurotrophin receptor p75 
PAP 
Pharmacokinetics Analysis Plan 
PEG 
Percutaneous Endoscopic Gastrostomy 
PEG 400 
Polyethylene glycol 400  
PK 
Pharmacokinetic(s) 
PLP 
Pyridoxal Phosphate 
PLS 
Primary Lateral Sclerosis  


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PMM 
Pattern Mixture Modeling 
PNS 
Peripheral Nerve System 
POC 
Proof of concept 
PTT 
Prothrombin Time  
Q1, Q3 
First quarter, third quarter 
QoL 
Quality of Life  
RBC 
Red blood cell 
RDW 
Red cell distribution width 
RNA 
Ribonucleic acid 
ROS 
Reactive Oxygen Species 
SAE 
Serious Adverse Event 
sALS 
Sporadic Amyotrophic Lateral Sclerosis  
SAH 
Subarachnoid Haemorrhage 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SLS 
Sodium Laurilsulfate 
SOC 
Standard of Care 
SOD1 
Superoxidase Dismutase 1 
SULT 
SulfoTransferase 
SVC 
Slow Vital Capacity 
t½ 
Half-life 
TDP-43 
Transactive response DNA/RNA Binding Protein 43 
TEAE 
Treatment Emergent Adverse Event 
TID 
Three Times Daily 
tmax 
Time to peak concentration 
TW 
Treeway 
UGT 
UDP-glucuronosyltransferases 
UMN 
Upper Motor Neurons 
US 
United States of America 
WBC 
White blood cell  
WFN 
World Federation of Neurology 
WHO 
World Health Organisation 
 


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1. 
SYNOPSIS 
TITLE: 
A multicenter, randomized, double-blind, placebo-controlled study to 
investigate the efficacy and safety of FAB122 in patients with Amyotrophic 
Lateral Sclerosis 
 
THE SPONSOR STUDY
CODE: 
FAB122-CT-2001 
EudraCT NUMBER: 
2020-003376-40 
SPONSOR: 
Ferrer Internacional, S.A. 
Barcelona, Spain 
 
STUDY PHASE: 
PHASE III  
STUDY DESIGN: 
Multicenter, multinational, double-blind, randomized (2:1), placebo-controlled 
Phase III study to investigate the efficacy and safety of 100 mg FAB122
(former TW001) once daily as oral formulation in ALS patients. 
 
Subjects will be screened to assess whether they comply with all enrolment 
criteria.  Approximately 300 patients will be randomized to 100 mg FAB122 or 
matched placebo in a 2:1 ratio.  Patients will be stratified by;    
 
1)their ALS progression rate at the start of the study (the slope ALSFRS-R 
score from time of first symptoms till Screening <1.0 
1.0), 
2)additional co-medication for ALS (a. riluzole, b. no riluzole). 
 
Riluzole (100 mg/day or less) may be used as background (add-on) therapy.
Patients on riluzole should be on stable doses at the start of the trial and for 
at least 30 days before the initiation of the study drug. It will not be allowed to 
initiate riluzole therapy during the trial. Additional supportive Standard Of
Care (SOC) treatments will be allowed in all patients and will be standardized 
as much as possible. 
 
Subjects will receive double-blind treatment up to a maximum of 72 weeks.  
The study is planned to continue until the last randomized subject has 
reached 48 weeks of follow-up (or has reached an intercurrent event) AND 
the first one third of the subjects randomized (100) have reached 72 weeks of
follow up (or has reached an intercurrent event). Subjects who discontinue 
treatment before week 72 will be followed as much as possible according to 
the planned visit schedule.  
 
Subjects will visit the clinic at Screening, Baseline, Week 4, Week 12, and
every 12 weeks thereafter. Monthly telephone visits are performed in
between the visits to the clinic until Week 48.   
 
Blood sampling for FAB122 plasma concentrations will be done in ~90
subjects treated with the study drug.  
 
After a subject completed the study (max at 72 weeks), he/she will be offered 


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the possibility to roll over in an open label extension trial in which all subjects 
will be offered to receive FAB122.   
 
STUDY PARTICIPANTS:  
 Study Population  
ALS patients  
Inclusion Criteria  
In order to be eligible for participation in this trial, a subject must meet all of 
the following criteria:  
 
1. Age 18  80 years (both inclusive), male or female; 
2. Diagnosis of definite, probable, probable laboratory supported or 
possible ALS as based on the El Escorial and the revised Airlie 
House diagnostic criteria for ALS; 
3. Onset of first symptoms* no longer than 24 months prior to 
randomization; 
*Date of onset is the date the patient reported one or 
more of the following symptoms: 
 Muscle weakness in limbs 
 Speech/swallowing difficulties 
 Respiratory symptoms: dyspnea was noticed 
4. SVC equal to or more than 70% of the predicted normal value
for gender, height and age at screening visit; 
5. Change in ALSFRS-R score between 0.35 points and 1.5 points 
per month (both inclusive) in the period from onset of first 
symptoms to the Screening visit; 
6. Patients on riluzole sho
s prior to 
the baseline visit and this dose should be maintained during the 
entire trial. 
7. A female subject should not be able to become pregnant and 
needs to meet at least one of the following criteria: 
 
female subject who is not of reproductive potential is 
eligible without requiring the use of contraception.  A
woman is considered not having childbearing 
potential when becoming post-menopausal unless 
permanently sterile. Permanent sterilisation methods 
include hysterectomy, bilateral salpingectomy and 
bilateral oophorectomy. A postmenopausal state is 
defined as no menses for 12 months without an 
alternative medical cause. 
 
female who is of reproductive potential and has a 
negative pregnancy test at screening and at baseline 
and is non-lactating. A female subject who is of
reproductive potential agrees to use (or have their 
partner use) or practicing adequate birth control 
methods starting from the time of consent through 30 
days after the last dose of study therapy.  Longer 
periods of birth control may be required per local
requirements. Acceptable methods of birth control
include 
combined 
(estrogen 
and 
progestogen 
containing) hormonal contraception associated with 
inhibition 
of 
ovulation 
(oral, 
intravaginal, 
transdermal), 
progestogen-only 
hormonal 
contraception associated with inhibition of ovulation


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(oral, injectable, implantable), intrauterine device in 
ths, intrauterine hormone-releasing 
system, bilateral tubal occlusion or vasectomised 
partner.   
8. A male patient must: 
 
agree he will not donate sperm during the study and 
until 104 days after the last dose, AND 
 
use a condom during sexual intercourse with 
pregnant or non-pregnant women of childbearing 
potential 
(WOCBP) 
partner 
even 
if 
he 
is 
vasectomized 
 
in addition WOCBP partner of the male patient must 
use the following acceptable methods of birth control 
during the study and until 104 days after the last 
dose: 
combined 
(estrogen 
and 
progestogen 
containing) hormonal contraception associated with 
inhibition 
of 
ovulation 
(oral, 
intravaginal, 
transdermal), 
progestogen-only 
hormonal 
contraception associated with inhibition of ovulation 
(oral, injectable, implantable intrauterine device in 
place 
3 months, intrauterine hormone-releasing 
system, bilateral tubal occlusion or vasectomised 
partners; 
 
9. Capable of providing informed consent and complying with trial 
procedures.  
 
Exclusion Criteria  
A subject must not meet one or more of the following criteria: 
 
1. Diagnosis of Primary Lateral Sclerosis; 
2. Diagnosis of Frontotemporal Dementia; 
3. Diagnosis of other neurodegenerative diseases (e.g. 
Parkinson disease, Alzheimer disease); 
4. Diagnosis of polyneuropathy; 
5. Other causes of neuromuscular weakness; 
6. Have a significant pulmonary disorder not attributed to ALS 
and/or require treatment interfering with the evaluation of ALS 
on respiratory function; 
7. Use of intravenous (IV) edaravone within 6 months of the 
screening visit; 
8. Use of mechanical ventilation (invasive or non-invasive) at 
Screening; 
9. Renal impairment as indicated by a creatinine clearance of 
less than 50 mL/min; 
10. Subject has a history of clinically significant hepatic disease, 
hepatitis or biliary tract disease, ALT/AST levels 
, 
bilirubin levels 2xULN   or subject has a positive screening 
test for HIV, hepatitis B or C; 
11. Presence of any of the following clinical conditions: 
a. Unstable cardiac, pulmonary, endocrine, 
hematologic or active infectious disease 
b. Severe active psychiatric illness e.g. psychosis, 
untreated major depression within 90 days of the 
screening visitSignificant cognitive impairment, 


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clinical dementia or psychiatric illness 
c. Cancer that is currently under active treatment or is 
likely to require treatment during the trial that may 
alter the subject´s function and interfere with 
assessment of ALS disease progression.
 
 
12. Any comorbidity that may interfere with the functions as scored 
with the ALSFRS-R; 
13. History of known sensitivity or intolerability to edaravone, to 
any related compound, or to any of the excipients;  
14. Exposure to any investigational drug within 30 days of the 
screening visit or 5 half-lives, whichever is longer; 
15. Current substance or alcohol dependence. 
16. For patients undergoing optional CSF sampling: any condition 
that according to the investigator criteria is contraindicated for 
the procedure (e.g. space-occupying lesion with mass effect, 
increase of intracranial pressure due to increased CSF 
pressure; posterior fossa mass; Arnold-Chiari malformation; 
anticoagulant medication; coagulopathy; uncorrected bleeding 
diathesis; congenital spine abnormality; and skin infection at 
puncture site 
 
SAMPLE SIZE: 
Total of 300 ALS patients, randomized 2:1 to FAB122 100 mg and placebo, 
respectively 
PLANNED STUDY 
PERIOD: 
2 Years  
Double-blind treatment is planned to continue until the last randomized 
subject has reached 48 weeks of follow-up (or has reached an intercurrent 
event (IE)) AND the first one third of the subjects randomized (100) have
reached 72 weeks of follow-up (or has reached an intercurrent event).  The 
maximum treatment duration for a subject in this study is 72 weeks.   
PLANNED 
RECRUITMENT PERIOD: 
10 Months  
STUDY SITES  
 Approximately 30 sites  
OBJECTIVES AND OUTCOME MEASURES:  
PRIMARY OBJECTIVE: 
To assess the effect of treatment with 100 mg of FAB122 on disease 
progression in patients with ALS 
SECONDARY 
OBJECTIVES:  
1. 
To evaluate the effect of treatment with FAB122 on survival 
2. 
To evaluate the safety and tolerability of FAB122  
3. 
To evaluate the effect of treatment with FAB122 on quality of 
life (QoL) 
4. 
To evaluate the effect of treatment with FAB122 on cognitive 
functioning 
5. 
To evaluate the pharmacokinetics (PK) of FAB122 
 


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EXPLORATORY 
OBJECTIVES  
1. 
To evaluate the PK interaction of FAB122 and riluzole 
2. 
To explore and identify biomarkers that inform the scientific 
understanding of ALS and/or their therapeutic treatments 
 
 
PRIMARY ENDPOINT:  
Change from baseline in Amyotrophic Lateral Sclerosis Functional Rating 
Scale  Revised (ALSFRS-R) score after 48 weeks  
SECONDARY 
ENDPOINTS: 
Key secondary endpoints 
1. 
Combined assessment of function and survival (CAFS) at 48 
and 72* weeks;  
 
2. 
Survival time, i.e. time to death, tracheostomy or initiation of 
non-invasive ventilation for more than 20 hours a day for more 
than 10 consecutive days, over 72 weeks.  
 
Efficacy 
1. 
Change from baseline in ALSFRS-R score after 24 and 72* 
weeks; 
2. 
The slope of the decrease in ALSFRS-R score over time at 24, 48 
and 72* weeks; 
3. 
Change from baseline in ALSFRS-R score on Bulbar function 
(question 1-3 of the ALSFRS-R) after 24, 48 and 72* weeks; 
4. 
Change from baseline in ALSFRS-R score on Fine motor function 
(question 4-6 of the ALSFRS-R) after 24, 48 and 72* weeks; 
5. 
Change from baseline in ALSFRS-R score on Gross motor 
function (question 7-9 of the ALSFRS-R) after 24, 48 and 72* 
weeks; 
6. 
Change from baseline in ALSFRS-R score on Respiratory 
function (question 10-12 of the ALSFRS-R) after 24, 48 and 72* 
weeks; 
7. 
Time to a 3, 6, 9 and 12 points change or death from baseline in 
ALSFRS-R score, over 72* weeks;  
8. 
Proportion of subjects with change from baseline in ALSFRS-R 
score at 24, 48 and 72* weeks in categories: categories will 
include change 0, change between <0 and -1, change between 
<-1 and -2 etc.; 
9. 
Time to change in clinical staging or death (
staging system 
and MiToS) over 72* weeks;  
10. Overall survival: Proportion of subjects alive (survival rate) after 
24, 48 and 72* weeks; 
11. Proportion of subjects alive and no tracheostomy, or no initiation 
of non-invasive ventilation for more than 20 hours a day for more 
than 10 consecutive days after 24, 48 and 72* weeks; 
12. Change from baseline in slow vital capacity (SVC, liters) at 24, 48 
and 72* weeks;  
13. Change from baseline in the overall mega score for the hand-held 
dynamometer (HHD) at 24, 48 and 72 weeks.  
 
 
QoL 
1. Change from baseline in the total score on the ALS Assessment 
Questionnaire-40-Item (ALSAQ-40) Form at 24, 48 and 72* 
weeks; 


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2. Change from baseline in EuroQoL  5 Dimensions-5 Levels (EQ-
5D-5L) questionnaire score and health related QoL at 24, 48 and 
72* weeks. 
3. Change from baseline in Visual Analogue Scale (VAS) score at 
24, 48 and 72* weeks. 
Cognition 
 
1. Proportion of subjects with a chang
 
Specific, ALS Non-Specific, and ECAS (Edinburgh Cognitive and 
behavioural ALS Screen) total score; 
2. Change from baseline for ALS Specific, ALS Non-Specific, and 
ECAS total score at 24, 48 and 72* weeks; 
3. Time to 
8
an
Non-Specific, and ECAS total score. 
 
Pharmacokinetics 
 
(Population) PK parameters of FAB122 and riluzole  
 
 
*All secondary endpoints at 72 weeks will be analyzed for the subgroup 
of patients that reach 72 weeks (or IE). 
 
EXPLORATORY 
ENDPOINTS: 
Pharmacokinetics 
 
PK interaction between FAB122 and riluzole 
 
Biomarkers 
1. 
Change from baseline in the prognostic ALS biomarker neurofilament 
light (NFL)  
2. 
Change from baseline in the ALS biomarkers creatinine and 
creatinine kinase 
3. 
Change from baseline in the ALS biomarker Urinary extracellular 
domain of neurotrophin receptor p75 (Urinary P75ECD) 
4. 
Change 
from 
baseline 
of 
oxidative 
stress 
biomarker 
8-
hydroxyguanosine (8-OHdG) 
 
Health economics  
Cost-Utility analysis of treatment with FAB122 
 
SAFETY ENDPOINTS  
1. 
Nature, frequency and severity of Treatment Emergent Adverse 
Events; 
2. 
Parameters derived from in vital signs and 12-lead electrocardiogram 
(ECG); 
3. 
Parameters derived from laboratory tests (hematology, biochemistry, 
urinalysis); 
4. 
Proportion of patients that drop out due to adverse events.    
 


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INTERVENTION(S): 
IMP(S): 
FAB122:  
Fasted daily dose of 100 mg FAB122 granules for oral solution in single
sachets, which has to be dissolved in 100 mL water prior to administration, or 
matched placebo in a 2:1 ratio, respectively. 
nIMP(S): 
Riluzole:   
The use of riluzole is allowed as add-on therapy on top of other supportive
SOC treatments (such as symptomatic treatment of muscle spasms, pain, 
insomnia, dysphagia and emotional instability) during the study. Subjects 
taking riluzole must be on stable d
30 days prior to the baseline visit. 
The riluzole dose must not exceed the recommended dose of 100 mg/day.  
Riluzole will not be provided for the participating sites. 
COMPARATOR: 
Placebo  
 
STATISTICAL METHODS: 
 
The sample size estimation is based on the primary endpoint: the change 
from baseline in ALSFRS-R score after 48 weeks of follow up. A difference of 
3.0 points between FAB122 treatment arm and placebo is assumed with a 
(pooled) standard deviation of 7.5 and an allocation ratio of 2:1 (FAB122:
Placebo). With these assumptions, a total sample size of 300 (200 patients 
on FAB122 and 100 on placebo) is needed to achieve 90% power to detect 
the difference of 3.0 points between the two treatment groups at a 5% (2-
sided) level of significance.  
The primary analysis will be performed on the modified intent-to-treat 
population (mITTs), i.e. all randomized patients who had at least one 
treatment intake. The analysis of the primary endpoint will be also assessed 
with the PP and ITT populations as per sensitivity analysis. 


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2. 
INTRODUCTION 
2.1. 
Background and rationale  
Disease under investigation 
 
ALS is a devastating and fatal condition (Bruijn et al., 2004; Shook and Pioro, 2009) 
characterized by progressive degeneration of upper and lower motor neurons (Elbasiouny 
et al., 2012). Degeneration of lower motor neurons (LMN) results in loss of muscle 
strength, muscular atrophy, hyporeflexia, hypotonicity, fasciculations, flaccidity and or 
muscle cramps. If the upper motor neurons (UMN) degenerate, symptoms of spasticity and 
pathologic hyperreflexia may occur. ALS eventually results in death, usually due to 
respiratory failure (Brown and Al-Chalabi, 2017; Hardiman et al., 2017; Maurer, 2012; van 
Es et al., 2017)  
Average disease duration is 2-5 years from the first symptoms until death, but it may vary 
between a few months to over twenty years (Westeneng et al., 2018). About one-third of 
the patients present with speech and swallowing difficulties, whereas others report 
progressive weakness in the hands, arms or legs. Respiratory symptoms are the initial 
signs in 2-3% of the patients and are associated with a poorer prognosis (Gautier et al., 
2010; Shoesmith et al., 2007). Respiratory failure is the cause of death in 66-81% of the 
patients with ALS (Gil et al., 2008; Spataro et al., 2010; Yang et al., 2011).  
ALS is a rare disease with a relatively uniform estimated incidence and prevalence in 
Western countries of 1,89 per 100.000/year and 5,2 per 100.000, respectively (Wijesekera 
and Nigel Leigh, 2009; Worms, 2001). It occurs mostly in the range of 40-60 years, 
although ALS can occur at any adult age. Approximately 10% is classified as familial ALS 
(fALS) and 90% as sporadic ALS (sALS). For the familial form, over 20 genes have been 
identified, although the exact mechanism of the cause and the progression of ALS is 
unknown (Diamanti et al., 2013; Rossi et al., 2013). 
 
Aetiology 
ALS has been classified as either the sporadic or the familial form. In 5 15% of patients 
with ALS, the ALS runs in the family (Byrne et al., 2011; Swinnen and Robberecht, 2014; 
Wingo et al., 2011). In these cases, a single genetic defect is thought to cause disease. 
Examples of the most common mutations with a large effect (presumably pathogenic) are 
C9orf72 (40%), SOD1 (20%), FUS (1 5%), and TARBDP (gene for TDP-43 protein) (1
5%) (Renton et al., 2014). However, most patients do not have a family history of ALS, in 
which case the disease is thought to have sporadically resulted from both environmental 
and genetic risk factors. Multiple genetic risk factors for sporadic ALS have been identified. 
However, the environmental risk factors are less clear. Currently, only smoking is 
established to be a risk factor for sporadic ALS (Armon, 2009), but other environmental 
risk factors such as pesticides, organic toxins, electromagnetic radiation, and physical 
exercise have been suggested as well (Al-Chalabi and Hardiman, 2013; Harwood et al., 
2016; Lacorte et al., 2016). Patients with symptom onset before age 45 are more often 
related to a positive family history of ALS (Turner et al., 2012). 
 
Specific 
characteristics; 
pathophysiological, 
histopathological, 
clinical 
characteristics 
ALS is a clinically and genetically heterogeneous, multidomain neurodegenerative 
syndrome of motor and extra-motor systems with multiple underlying pathophysiological 


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mechanisms and different clinical subphenotypes (Swinnen and Robberecht, 2014). The 
mechanisms underlying neurodegeneration in ALS are still not fully understood. Many 
cellular and molecular processes have been implicated, including mitochondrial 
dysfunction, axonal transport, toxic protein aggregation, impaired protein degradation 
(involving the proteasome or autophagy, or both), prion-like spreading, excitotoxicity, 
decreased 
neurotrophic 
support 
from 
non-neuronal 
cells, 
oxidative 
stress, 
hypermetabolism, inflammation, RNA metabolism defects, and RNA toxicity (Robberecht 
and Philips, 2013). Defects in some of these pathways could be secondary phenomena, 
and genetics would be the logical initial approach to identifying the primary 
pathophysiological processes underlying ALS.  
Clinically, ALS is characterized by muscle weakness and functional decline. Disease onset 
is usually focal, but the disease eventually spreads to other body regions. The progression 
and spread of the disease appear to be both local (within the same region; eg, from hand 
to upper arm) and between neuro-anatomically linked regions (contra-lateral or rostral-
caudal) (Ravits and La Spada, 2009). In addition, muscle weakness and functional decline 
may be accompanied by significant reductions in weight and a poor nutritional status 
(Moglia et al., 2019). 
Moreover, extra-motor symptoms such as cognitive or behavorial impairments occur in up 
to 50% of the patients, whereas 5-15% fulfill the criteria for frontotemporal dementia (FTD) 
(Goldstein and Abrahams, 2013; Hardiman et al., 2017; van Es et al., 2017).  
 
Classification 
ALS is one of the Motor Neuron Diseases (MNDs), as it is a condition that affects both the 
UMN as well as the LMN. However, during the first stage of the disease only the UMN or 
the LMN is affected which can blur the diagnosis of the disease with regard to other 
MNDs. Example(s) of disease by which the LMN is affected is progressive spinal muscular 
atrophy and by which the UMN is affected are Primary Lateral Sclerosis (PLS) and 
Hereditary Spastic Paraparesis (HSP) (Ludolph et al., 2015; Shook and Pioro, 2009). ALS 
is classified as a neuromuscular disorder and is heterogeneous. 
 
Diagnosis and symptoms 
The diagnosis of ALS depends on the criteria-set developed by the World Federation of 
Neurology (WFN) and are also known as the El Escorial criteria. The criteria-set contains 
the requirement of both affected LMN and UMN. The clinical part of the diagnosis is made 
based on signs and symptoms of motor neuron dysfunction of both the lower and upper 
part of the body confirmed by electromyography (EMG) (Gordon, 2013). The El Escorial 
criteria have been updated and have been renamed into the Airlie House criteria in 2000 
(Brooks et al., 2000)(Brooks et al., 2000). The most widely used instrument to measure 
function in ALS clinical trials is the Amyotrophic Lateral Sclerosis Functional Rating Scale 
(ALSFRS) and the revised version that includes respiratory function (ALSFRS-
R)(Cedarbaum et al., 1999), which is a validated disease-specific questionnaire (see 
Annex 2). 


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Pharmacological and non-pharmacological treatment options 
There are limited pharmacological options in the treatment of ALS (an overview is provided 
in Annex 3); the mainstay of management is symptomatic treatment. ALS patients who 
receive care at a multidisciplinary clinic may have a better prognosis than patients 
attending a general neurology clinic. Median survival is up to 7.5 months longer for the 
patient group treated at a multidisciplinary clinic and was up to two months more for 
patients with bulbar dysfunction. The data suggest that active management enhances 
survival (Gordon, 2013).  
A variety of compounds have been investigated for their potential in the management of 
ALS (Zoccolella, 2009), but the only existing, authorised medicine for the treatment of ALS 
in the European Union is riluzole (INN: riluzole; chemical name: riluzole (2-amino-6-
(trifluoromethoxy) benzothiazole,)( Rilutek SmPC,  n.d.). Although riluzole reduces 
glutamate-induced excitotoxicity, its precise mechanism in ALS is unknown.  
All other pharmacological treatment options which are commonly used in the management 
of ALS in clinical practice are additional palliative treatments aiming at improving the 
quality of life and at reducing signs and symptoms associated with the disease but which 
on their own are not specifically indicated for ALS (e.g. treatment of muscle spasms, pain, 
insomnia, dysphagia and emotional instability; see below)(Hardiman et al., 2017) . In 
addition, supportive non-pharmacological treatments may be required, like mechanical 
ventilation for the management of respiratory insufficiency. 
Quinine sulphate 325 mg BID is the most effective treatment option for muscle spasms 
and cramps. Baclofen and tizanidine are used for excess muscle spasticity that causes 
incoordination and discomfort. Sialorrhea (excess salivation) may respond to amitriptyline, 
atropine, botulinum toxin injection, glycopyrronium or hyoscyamine. Insomnia should be 
managed by addressing underlying problems (e. g. depression, dyspnoea, dysphagia, 
pain). This may obviate the need to use sedatives. Pain management includes the use of 
non-steroidal anti-inflammatory agents, anti-convulsants (e.g. carbamazepine) and later 
opiates if/when the former treatments fail. 
Emotional lability is often treated with amitriptyline or fluvoxamine. A combination of 
dextromethorphan and quinidine (30 mg/30 mg) were assessed in a randomized, double-
blind, controlled trial. The combination was effective for reducing the frequency and 
severity of pathologic laughter and crying compared with either drug alone. It also resulted 
in improved quality of life. Longer-term studies regarding side effects of this combination 
are awaited (Phukan and Hardiman, 2009; Pioro et al., 2010). 
Management of respiratory insufficiency in ALS is guided by the American Academy 
Practice Parameter (Miller et al., 2009). Deciding when to initiate non-invasive mechanical 
ventilation is critical because of the risk of either sudden death or ventilator dependence 
without proper advance planning. The recommendations are as follows:  
1. Be vigilant for symptoms indicating hypoventilation. Serial measures 
of pulmonary function (especially vital capacity) are recommended 
to guide management and to determine prognosis with the 
understanding that no single test can detect hypoventilation reliably. 
2. Offer non-invasive ventilatory support as an effective initial therapy 
for symptomatic chronic hypoventilation and to prolong survival in 
patients with ALS.  
3. When long-term survival is the goal, offer invasive ventilation and 
fully inform patient and family of burdens and benefits. 


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4. In accordance with the principle of patient autonomy, physicians 
should respect the right of the patient with ALS to refuse or withdraw 
any treatment, including mechanical ventilation. 
5. When withdrawing ventilation, use adequate opiates and anxiolytics 
to relieve dyspnoea and anxiety.  
Non-invasive positive pressure ventilation (NIPPV) is particularly useful if patients have 
nocturnal respiratory symptoms but also can be used during waking hours as the disease 
progresses (Gordon, 2013; Phukan and Hardiman, 2009).  
NIPPV has been shown to extend survival, particularly in those compliant 
 4 hours 
use each day and those without severe bulbar dysfunction. It also improves quality of life 
in patients without increasing caregiver burden or stress. In some studies, it improves 
cognitive impairment due to sleep disruption (Lo Coco et al., 2012). 
Management of dysphagia includes modification of food and fluid consistency, postural 
advice (e.g. chin tuck: flexing the neck forward on swallowing to protect the airway), and 
parenteral feeding. A PEG (percutaneous endoscopic gastrostomy) placement is indicated 
for those who have symptomatic dysphagia or significant weight loss. Patients and their 
families should be suitably counselled regarding the benefits and risks of the procedure 
(Phukan and Hardiman, 2009). 
 
Product under investigation (edaravone) 
 
As described above, ALS is a progressive neurodegenerative disease with multiple 
underlying pathological mechanisms of neuronal cell death, and most of the possible 
current therapeutic interventions were developed basically against a specific route of ALS 
disease progression. From the various published non-clinical and clinical studies described 
below, the mechanism of action of edaravone in the treatment of ALS is thought to be 
multifactorial, comprising, but not limited to, inhibition of oxidative damage of motor 
neurons, inhibition of motor neuron death caused by inflammatory processes, the inhibition 
of neuronal damage caused by the accumulation of aggregated SOD1 particles, and the 
inhibition of apoptosis induced protein aggregation (Shin and Lee, 2013). (See Figure 1). 
 
Edaravone is one of three metabolites resulting from antipyrine biotransformation in 
mammals, and is also referred to as norphenazone or norantipyrine. It exerts anti-
ischaemic actions and is capable of reducing oedema in the brain following 
ischaemia/reperfusion injury (Lapchak, 2010; Tabrizchi, 2000). In 2001, Mitsubishi Tanabe 
Pharma received a marketing approval in Japan for the intravenous (slow drip infusions) 
use of edaravone under the trade name Radicut® for improvement of neurological 
symptoms, disorder of activities of daily living, and functional disorder associated with 
acute ischaemic stroke (AIS) (Mitsubishi Tanabe Pharma Corporation, 2015) . 
Edaravo
 potential in the treatment of cerebrovascular ischaemia and cerebral oedema 
appears to be at least partly due to its action to reduce oxidative stress as a free radical 
scavenger and its capability to reduce the disintegration of the membrane lipid bilayer 
which is associated with neurodegeneration (Fujisawa and Yamamoto, 2016; Kamat et al., 
2008; Kikuchi et al., 2013, 2012, 2011; Tabrizchi, 2000; Watanabe et al., 1997). In 
addition, edaravone was found to counteract oxidative neurotoxicity and neuronal cell 
death arising from activated microgli
neurodegenerative disorders of the central nervous system (CNS) (Banno et al., 2005). 
Therefore, edaravone was also considered to be a possible candidate drug for the 
treatment of ALS, since oxidative stress and inflammation-induced neuronal cell death are 


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part of the underlying multifactorial pathogenic mechanisms of ALS (Franco et al., 2013; 
Rossi et al., 2013; Zoccolella, 2009). 
To investigate e
ential in the treatment of ALS, additional studies were 
performed by the Mitsubishi Tanabe Pharma, including an extensive pharmacology study 
in an ALS mouse model (Aoki et al., 2011; Ikeda and Iwasaki, 2015; Ito et al., 2008), an 
open label Phase II study (Yoshino and Kimura, 2006), two double-blind, placebo 
controlled Phase III studies in ALS patients (Abe et al., 2014; Takei et al., 2017; The 
Writing Group on behalf of the Edaravone (MCI-186) ALS 17 Study Group. 2017 a, 2017; 
The Writing Group on behalf of the Edaravone (MCI-186) ALS 19 Study Group. 2017 b, 
2017; The Writing Group on behalf of the Edaravone (MCI-186) ALS 19 Study Group. 
2017 c, 2017) and an explorative study in severe ALS patients (The Writing Group on 
behalf of the Edaravone (MCI-186) ALS 18 Study Group., 2017). This resulted in approval 
of edaravone for the inhibition of progression of functional disorder in ALS in Japan and 
South-Korea in June and December 2015 (Radicut®) (Mitsubishi Tanabe Pharma 
Corporation, 2015), respectively and more recently also for the treatment of ALS in the US 
(Radicava®) (Mitsubishi Tanabe Pharma Corporation, 2017) (April 2017), Canada (October 
2018), Switzerland (January 2019) and China (August 2019). Based on the initial results 
achieved with the intravenous edaravone formulation in ALS patients, Treeway started its 
own clinical development program 
nt of 
with a newly developed oral edaravone formulation. 
 
 
 
 
 
 


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Figure 1: Posible mechanism of action of edaravone 
(1)increased Ca 2+ in the motor neuron: dysfunction or downregulation of glutamate transporters; (2) 
oxidative damage of the motor neuron; (3) apoptosis in the motor neuron: including alteration and 
aggregation of proteins via mitochondrial interaction with mSOD1; (4) inflammation: non-cell-
autonomous motor neuron death (the disease progression is coordinated by mSOD1 expression in all 
neuronal and non-neuronal cells) and concurrent activation of the innate immune system and 
systemic inflammation; and (5) autophagy: increased auto-phagosome formation. 
Please see FAB122 in
rochure (IB) for more details on intravenous edaravone 
and FAB122 (Nonclinical pharmacology; Toxicology and toxicokinetics; Pharmacokinetics 
and metabolism; Clinical data for edaravone administered via the intravenous route; and 
Phase 1 clinical data for FAB122 administered via the oral route). 
 
 
 
 
 
 
 
 
 
 
 


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Rationale for the Current Study 
 
This is a multicenter, multinational, double-blind, randomized, placebo-controlled Phase III 
study to investigate the efficacy and safety of 100 mg FAB122 once daily as oral 
formulation in ALS patients.  
Results from previous Phase II (Yoshino and Kimura, 2006) and III clinical trials (Abe et 
al., 2014; Takei et al., 2017; The Writing Group on behalf of the Edaravone (MCI-186) ALS 
17 Study Group. 2017 a, 2017; The Writing Group on behalf of the Edaravone (MCI-186) 
ALS 18 Study Group., 2017; The Writing Group on behalf of the Edaravone (MCI-186) 
ALS 19 Study Group. 2017 b, 2017; The Writing Group on behalf of the Edaravone (MCI-
186) ALS 19 Study Group. 2017 c, 2017) in ALS patients with IV administered edaravone 
showed the potential of edaravone for the treatment of ALS. The data from these trials led 
to the approval of IV administered edaravone (Radicut
 or Radicava ) for the inhibition of 
ALS disease progression in Japan, the USA, Canada and Switzerland. In these studies, 
edaravone was administered in repeated cycles of 28 days consisting of daily IV infusions 
of 60 mg edaravone for 60 minutes for 10 out of 14 days followed by 14 days without IV 
infusions of edaravone. Chronic IV administration has important drawbacks including the 
risk of both local and systemic side effects. Also, the involvement of medical personnel at 
home or daily attendance to the hospital for drug administration impedes compliance. In 
addition, no exposure to the drug is obtained during the treatment holidays of 14 days per 
month. These drawbacks could be overcome using administration of the oral FAB122 
formulation as proposed in this trial and given the exposure-based efficacy of edaravone, a 
more sustained exposure profile may further increase the efficacy of edaravone in ALS. 
This may be achieved by once daily dosing of orally administered FAB122 (elimination 
half-life of FAB122 ~ 5 h) without drug holidays.   
 
Rationale for dose 
In a Phase III pivotal trial, a statistically significant reduction in ALSFRS-R decline was 
shown after 24 weeks of treatment with 60 mg edaravone administered as a 60-minute 
drip infusion as compared to placebo (The Writing Group on behalf of the Edaravone 
(MCI-186) ALS 19 Study Group. 2017 c, 2017). Therefore, the exposure and plasma levels 
associated with a 60 mg IV infusion of edaravone are correlated with efficacy in ALS 
patients. In three phase I studies, in both healthy volunteers and ALS patients, the 
exposure and plasma levels of oral intake FAB122 at different dose regimens were studied 
(Treeway, 2019, 2017a, 2017b). In addition, the bioavailability of oral intake of FAB122 
was compared to 60 mg edaravone administered as a 60-minute drip infusion (Treeway, 
2019), (Treeway, 2019). Recently, Ferrer has conducted two Phase I studies to confirm 
the selected dose for the current trial. The first study was a single center, randomized, 
double-blind, 
placebo-controlled 
study 
investigating 
the safety, 
tolerability, 
and 
pharmacokinetics of single ascending doses of 50, 100 and 200 mg FAB122 in healthy 
volunteers (Study EDV-PBA-01-FRI/20). The indirect comparative PK data with IV 
edaravone has demonstrated the selection of 100mg dose of FAB122 which has been 
confirmed by the second study, a single center, randomized, open label, two-treatment, 
three-period, crossover, single dose study to comparatively assess the bioavailability of 
100 mg FAB122 administered under fasting and fed conditions versus Radicava 60 mg in 
healthy volunteers (Study EDV-BEFI-02-FRI/20). 


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Based on these data and literature data, a dose regimen of 100 mg FAB122 once daily 
has been chosen for this study according to the following considerations: 
1. that all subjects treated with oral FAB122 should have an adequate AUC, that is at 
least equal to than the mean AUC of RadicavaTM. Oral dosing may have slightly 
higher variability than IV dosing. However, the differences in standard deviations 
between IV Radicava and oral FAB122 are small (23% for IV versus 28% for 
FAB122). 
2. that FAB122 will be dosed continuously instead of intermittently. For this regimen a 
safety margin of 6.0 and 2.1 was established in rats and dogs respectively, in the 
chronic toxicity studies (FDA, 2017; Schoenmakers A., 2019; Stegeman H., 2020) 
and that  due to the continuous dosing  slight increases in variability, resulting in 
a slightly lower target exposure for subjects at the lower end of the distribution 
curve, will be largely compensated for as compared to the intermittent schedule for 
IV Radicava . 
 
The bioavailability of FAB122 after oral administration has been shown to decrease with 
~40% when concomitantly given with food (Treeway, 2017a, EDV-BEFI-02-FRI/20). 
Therefore, FAB122 is to be administered under fasted conditions in this trial. 
 
Rationale for dosing schedule  
In the Phase III studies with IV edaravone, a dose of 60 mg was applied via IV infusion 
using 28-day treatment cycles (Abe et al., 2014; Takei et al., 2017; The Writing Group on 
behalf of the Edaravone (MCI-186) ALS 17 Study Group. 2017 a, 2017; The Writing Group 
on behalf of the Edaravone (MCI-186) ALS 18 Study Group., 2017; The Writing Group on 
behalf of the Edaravone (MCI-186) ALS 19 Study Group. 2017 b, 2017; The Writing Group 
on behalf of the Edaravone (MCI-186) ALS 19 Study Group. 2017 c, 2017). The first cycle 
of treatment consisted of a 2-week, once-daily treatment period, followed by a 2-week 
drug-free period. Subsequent cycles consisted of a 2-week treatment period during which 
a total of 10 doses of edaravone (5 doses/week) were administered, followed by a 2-week 
drug-free period. The once daily dosing and 14-day drug holiday were merely included to 
reduce the burden of the patient. Given the exposure-based efficacy of edaravone, a more 
sustained exposure profile may further increase the efficacy of edaravone in ALS. This 
may be achieved by once daily dosing of orally administered FAB122 (elimination half-life 
of FAB122 ~ 5 h) without drug holidays.  
 
Rationale for trial duration 
Double-blind treatment is planned to continue until the last enrolled subject reaches 48 
weeks of participation (or has reached an intercurrent event) and the first one third of the 
subjects randomised (100) has reached 72 weeks of follow up (or has reached an 
intercurrent event). Thus, all patients will have at least a 48-week treatment duration which 
is considered to provide a reliable assessment of disease modifying effects in the ALS 
patients included in this study (EMA, 2015)( Continuation of the study for up to 72 weeks 
for the first one third of the subjects (100) allows collection of longer-term data on disease 
progression and survival.   
 
Rationale for efficacy endpoints 


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Based on 
 and the results of the Phase II and III clinical trials 
on IV administered edaravone, FAB122 is expected to slow down disease progression in 
ALS patients. The most widely used instrument to measure the progressive decline in 
functional capabilities in ALS clinical trials is the ALSFRS-R score, which is a validated 
disease-specific questionnaire (Cedarbaum et al., 1999). The primary analysis is therefore 
based on the change from baseline in ALSFRS-R score after 48 weeks. The effect of 
FAB122 on survival will be assessed using the key secondary endpoints including the 
CAFS score and overall survival, defined as time to death from any cause or respiratory 
insufficiency (DRI; defined as tracheostomy or the use of non-invasive ventilation for more 
than 20 h per day for more than 10 consecutive days).  
These primary and key secondary endpoints are in line with the EMA guideline on clinical 
investigation of medicinal products for the treatment of ALS (EMA, 2015). To support the 
outcomes of the primary and key secondary endpoints, additional measures of disease 
progression are included such as the assessment of muscle strength by hand-held 
dynamometer (HHD)(Shefner, 2017), respiratory function by SVC (Pinto and de Carvalho, 
2019) as well as additional analysis on the (sub)scores of the ALSFRS-R questionnaire.  
QoL will be measured both with an ALS-specific questionnaire, the ALSAQ-40 (Jenkinson 
et al., 1999), as well as with a more general QoL measure, the EQ-5D-5L questionnaire 
score and health-related QoL VAS score (Herdman et al., 2011). Potential cognitive effects 
will be measured by ECAS (Abrahams et al., 2014). 
 
Rationale for vitamin B6 monitoring and Nerve Conduction Study 
Axonal degeneration as observed in non-clinical studies (Schoenmakers A., 2019) are 
possibly related to reduced levels of 
-phosphate (PLP) in plasma, the active 
form of vitamin B6 (CHMP EMA, 2019). In the clinic similar axonal damage has been 
associated with a decrease of vitamin B6. This was observed with tuberculosis therapy 
with the antibiotic isoniazid. Accordingly, supplementation with vitamin B6 is generally 
recommended during isoniazid therapy. The scientific rationale for reduction of vitamin B6 
with edaravone treatment has been established (CHMP EMA, 2019), and therefore, during 
this study vitamin B6 levels will be monitored and, if necessary, supplementation of vitamin 
B6 with pyridoxine (maximal 100 mg/day) will be prescribed.  
 
In addition, to allow early detection of neurotoxicity during treatment with FAB122, Nerve 
Conduction Study (NCS) will be performed at screening, week 4, week 12, and week 24, 
and DSMB interim assessment on vitamin B6, clinical signs, ALSFRS-R questions related 
to leg functioning (8. walking and 9. climbing stairs) and NCS data when 60 subjects 
(about 40 active and 20 placebo) have been treated for 24 weeks: 
a. If no neurological concerns are observed, the study will continue with one additional 
NCS at week 48;  
b. If NCS show signs of neurological damage, intensive NCS monitoring will continue 
every 12 weeks for all patients. All NCS measurements will be centrally analysed by an 
independent neurophysiologist from the Neuromuscular center, UMC Utrecht, The 
Netherlands.  
Rationale for pharmacokinetic endpoints 
FAB122 plasma concentrations will be used to further establish the concentration-time 
profiles. These and results of population PK analyses will be used to study the relation 
between PK and pharmacodynamics (PD) effects including retrospective assessment of 
possible dose/exposure-treatment response correlations.  


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Riluzole is allowed as add-on therapy in the present clinical trial. Riluzole and FAB122 
have non-overlapping primary metabolic pathways i.e. phase 1 metabolism for riluzole by 
mainly CYP1A2 (CHMP EMA, 2005) and glucuronidation and sulfation for FAB122 
(PMDA, 2015; Tabrizchi, 2000). Therefore, no relevant drug interaction between FAB122 
and riluzole is anticipated within the proposed dose range. This was confirmed in the 
Phase II and Phase III studies with IV administered edaravone in which no interaction 
between FAB122 and riluzole was reported: most patients in studies MCI186-16 
(n=182/205) and MCI186-19 (n=112/123) and the extension study MCI186-17 (n=161/180) 
received concomitantly riluzole (Abe et al., 2014; The Writing Group on behalf of the 
Edaravone (MCI-186) ALS 17 Study Group. 2017 a, 2017; The Writing Group on behalf of 
the Edaravone (MCI-186) ALS 19 Study Group. 2017 b, 2017; The Writing Group on 
behalf of the Edaravone (MCI-186) ALS 19 Study Group. 2017 c, 2017). Additional 
monitoring is included in the present trial in which the data obtained as part of the FAB122 
PK analysis, as well as peak and trough levels from riluzole will be used to evaluate the 
PK interaction between riluzole and FAB122.  
 
Rationale for Future Biomedical Research 
This research may include genetic analyses (DNA and/or RNA) and/or the measurement 
of blood derived analytes. The objective of collecting specimens for Future Biomedical 
Research (FBR) is to explore and identify additional biomarkers which can improve our 
current understanding of diseases and/or their therapeutic treatments. In particular, the 
information gathered may be used to aid diagnosis and/or prognosis of ALS, to develop 
safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the 
correct drug at the correct time. Exploratory pharmacogenetic (PGt) studies may be 
performed if significant PK/PD relationships are observed or adverse events are identified. 
Genomic 
markers 
of 
disease 
may 
also 
be 
investigated. 
Such 
retrospective 
pharmacogenetic studies will be conducted with appropriate statistical design and analysis 
and compared to PK/PD results or clinical outcomes. Any significant PGt relationships to 
outcome would require validation in future clinical trials.  
Collection of FBR samples is optional to the patient and blood samples for FBR can only 
be collected after the patient has reviewed and signed the FBR Informed Consent Form 
(ICF). Samples will be stored in a biobank. The patients will have the right to always 
withdraw their samples from the biobank. 
 
Rationale for biomarkers 
NFL is a biomarker correlated with prognosis and remain relatively stable over time. A 
change in the expression of NFL may, therefore, be considered as a potential disease 
amelioration in ALS (Verber et al., 2019).  Plasma creatinine is a surrogate ALS biomarker 
of muscle mass and is decreased in ALS patients. Serum creatine kinase (CK) is 
increased in ALS patients and correlates with survival in some studies. Both are 
considered muscle denervation biomarkers in ALS. Urinary P75ECD is a surrogate ALS 
biomarker and is elevated in ALS patients. The three biomarkers are associated with 
disease progression (Verber et al., 2019). To measure the pharmacological effect (target 
engagement) of edaravone, oxidative stress biomarkers, like 8-OHdG, will be measured 
(Verber et al., 2019). 
 


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2.2. 
Risk-Benefit Assessment 
ALS is a devastating neurological disease for which there is no cure and an urgent unmet 
need persists for effective therapies. The main aims in the care of these patients are to 
minimize morbidity and maximize quality of life. Riluzole (Europe and USA) and iv 
edaravone (USA) are the only current approved drugs for ALS.  
 
In general, long-term treatment with intravenously administered edaravone showed clinical 
benefit and an acceptable safety profile in ALS patients. As well, single- and multiple dose 
of FAB122 was safe and well tolerated in ALS patients and healthy volunteers.  
 
The animal toxicology studies revealed neurologic adverse findings (e.g. abnormal gait, 
decreased activity, prostration, reduced function of the hind limbs) with prolonged 
exposure to edaravone at relatively low safety margins compared to the anticipated human 
exposure levels. Analysis of the non-clinical data indicated that the neurotoxic effects seen 
after edaravone administration resulted from demyelination (primary effect) followed by 
axonal degeneration (secondary effect). Therefore, special monitoring of potential 
neurotoxicity will be performed by NCS during the conduct of the current study (For more 
details, see FAB122 IB).  
 
In trial C1.02, an oral dose of 180 mg BID FAB122 was given to 12 healthy male 
volunteers for 9 days (Day 1 and 9 once daily dosing) and was shown safe and well 
tolerated. Eight (8) of the 12 subjects (66.7%) reported a total of 9 adverse events (AEs). 
All of the AEs were transient in nature and mild in intensity. Six (6) of the AEs were 
considered to be possibly drug related i.e. 4 events of headache, one event of oral herpes 
infection and one event of transiently increased aspartate aminotransferase (AST) levels 
at Day 5 (79 U/L; normal range 0-40 U/L). There were no discontinuations due to adverse 
events. No clinically significant abnormal values were observed for vital signs (blood 
pressure, heart rate, temperature) and 12-lead ECG. Also, no clinically significant 
abnormal values were observed in laboratory safety tests (haematology, biochemistry) 
except for the one case of transiently increased AST, nor were trends observed in mean 
safety analyses. In trial C1.04, a single oral dose of 140 mg FAB122 was administered to 
36 healthy volunteers. The safety results showed that the oral administration was safe and 
well tolerated. In total 11 adverse events were reported of which headache (n=7) was most 
frequent. There were no discontinuations due to adverse events. No clinically significant 
abnormal values were observed for vital signs (blood pressure, heart rate, temperature) 
and 12-lead ECG. Also, no clinically significant abnormal values were observed in 
laboratory safety tests (hematology, biochemistry). In trial C1.01, 8 patients were dosed 
twice with a single dose of 90 mg FAB122, once under fed conditions and once under 
fasted conditions. Six (6) of the 8 patients (75%) reported a total of 21 AEs, all of mild 
intensity. None of them were deemed to be drug related by the investigator.  No clinically 
significant abnormal values were observed in laboratory safety tests (haematology, 
biochemistry). No clinically significant abnormal values were observed for 12-lead ECG 
and vital signs (blood pressure, heart rate, temperature), except for one subject with high 
blood pressure starting pre-dose in the second dosing period. In the trial EDV-PBA-01-
FRI/20 a single oral dose of 50mg, 100mg, and 200mg FAB122 (three cohorts ascending 
dose) was administered to 60 healthy volunteers. The safety results showed that the oral 
administration was safe and well tolerated. 
 notified for 
cohort 1 (50mg), the AE was mild and transient in nature and was evaluated as related to 


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the study drug. No clinically significant abnormal values were observed for vital signs 
(blood pressure, heart rate, temperature) and 12-lead ECG. Also, no clinically significant 
abnormal values were observed in laboratory safety tests (hematology, biochemistry, urine 
analysis), except for one subject who has transient elevation of AST, ALT, and GGT in 
cohort 3 group (200mg FAB122). In the trial EDV-BEFI-02-FRI/20, two AEs of 
 
in two subjects have been notified, the AEs were mild and transient in nature and were 
evaluated as related to the study drug. No clinically significant abnormal values were 
observed for vital signs (blood pressure, heart rate, temperature) and 12-lead ECG. Also, 
no clinically significant abnormal values were observed in laboratory safety tests 
(hematology, biochemistry, urine analysis). (For more details, see FAB122 IB). 
 
Overall, the preclinical toxicity profile as well as the clinical safety and efficacy profile of 
FAB122/edaravone administered by the oral and intravenous route support evaluation of 
FAB122 in an oral formulation in clinical trials in ALS patients and the expected clinical 
benefits overcome the potential risks.   


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3. 
OBJECTIVES AND OUTCOME MEASURES  
 
3.1. 
Objectives  
3.1.1. 
Primary Objective  
To assess the effect of treatment with 100 mg of FAB122 on disease progression in 
patients with ALS 
 
3.1.2. 
Secondary Objectives  
1. To evaluate the effect of treatment with FAB122 on survival 
2. To evaluate the safety and tolerability of FAB122  
3. To evaluate the effect of treatment with FAB122 on quality of 
life (QoL) 
4. To evaluate the effect of treatment with FAB122 on cognitive 
functioning 
5. To evaluate the pharmacokinetics (PK) of FAB122 
 
3.1.3. 
Exploratory Objectives  
1. To evaluate the PK interaction of FAB122 and riluzole 
2. To explore and identify biomarkers that inform the scientific 
understanding of ALS and/or their therapeutic treatments 
 
3.2. 
Endpoints  
3.2.1. 
Primary Endpoint  
Change from baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale  Revised 
(ALSFRS-R) score after 48 weeks.  
3.2.2. 
Secondary Endpoints  
Key secondary endpoints 
 
1. Combined assessment of function and survival (CAFS) at 
48 and 72* weeks;  
2. Survival time, i.e. time to death, tracheostomy or initiation of 
non-invasive ventilation for more than 20 hours a day for 
more than 10 consecutive days, over 72 weeks. 
 
Efficacy 
 
1. Change from baseline in ALSFRS-R score after 24 and 72* 
weeks; 


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2. The slope of the decrease in ALSFRS-R score over time at 
24, 48 and 72* weeks; 
3. Change from baseline in ALSFRS-R score on Bulbar function 
(question 1-3 of the ALSFRS-R) after 24, 48 and 72* weeks; 
4. Change from baseline in ALSFRS-R score on Fine motor 
function (question 4-6 of the ALSFRS-R) after, 24, 48 and 
72* weeks; 
5. Change from baseline in ALSFRS-R score on Gross motor 
function (question 7-9 of the ALSFRS-R) after, 24, 48 and 
72* weeks; 
6. Change from baseline in ALSFRS-R score on Respiratory 
function (question 10-12 of the ALSFRS-R) after 24, 48 and 
72* weeks; 
7. Time to a 3, 6, 9 and 12 points change or death from baseline 
in ALSFRS-R score over 72* weeks;  
8. Proportion of subjects with change from baseline in ALSFRS-
R score at 24, 48, and 72* weeks in categories: categories 
will include change 
 change between <0 and -1, change 
between <-
-2 etc.; 
9. Time to change in clinical stage or death 
staging 
system and MiToS) over 72* weeks; 
10. Overall survival: Proportion of subjects alive (survival rate) 
after 24, 48 and 72* weeks; 
11. Proportion of subjects alive and no tracheostomy, or no 
initiation of non-invasive ventilation for more than 20 hours a 
day for more than 10 consecutive days after 24, 48 and 72* 
weeks; 
12. Change from baseline in slow vital capacity (SVC, liters) at 
24, 48 and 72* weeks;  
13. Change from baseline in the overall mega score for the hand-
held dynamometer (HHD) at 24, 48 and 72* weeks.  
 
QoL 
1. Change from baseline in the total score on the ALS 
Assessment Questionnaire-40-Item (ALSAQ-40) Form at 24, 
48 and 72* weeks; 
2. Change from baseline in EuroQoL  5 Dimensions-5 Levels 
(EQ-5D-5L) questionnaire score at 24, 48 and 72* weeks. 
3.  Change from baseline in Health related QoL Visual Analogue 
Scale (VAS) score at 24, 48 and 72 weeks. 
 
 
Cognition 
 
1. Proportion of 
ALS Specific, ALS Non-Specific, and ECAS (Edinburgh 
Cognitive and behavioural ALS Screen) total score; 
2. Change from baseline for ALS Specific, ALS Non-Specific, 
and ECAS total score at 24, 48 and 72* weeks; 


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3. 
 
for ALS Specific, 
ALS Non-Specific, and ECAS total score. 
 
Pharmacokinetics 
 
(Population) PK parameters of FAB122 and riluzole  
 
 
*All secondary endpoints at 72 weeks will be analyzed for the 
subgroup of patients that reach 72 weeks (or IE) 
 
3.2.3. 
Safety Endpoints 
 
1. Nature, frequency and severity of Treatment Emergent 
Adverse Events; 
2. Parameters derived from in vital signs and 12-lead 
electrocardiogram (ECG); 
3. Parameters derived from laboratory tests (hematology, 
biochemistry, urinalysis); 
4. Proportion of patients that drop out due to adverse events.    
 
3.2.4. 
Exploratory Endpoints 
Pharmacokinetics 
 
PK interaction between FAB122 and riluzole 
 
Biomarkers 
 
1. Change from baseline in the prognostic ALS biomarker 
neurofilament light (NFL)  
2. Change from baseline in the ALS biomarkers creatinine and 
creatinine kinase 
3. Change from baseline in the ALS biomarker Urinary 
extracellular domain of neurotrophin receptor p75 (Urinary 
P75ECD) 
4. Change from baseline of oxidative stress biomarker 8-
hydroxyguanosine (8-OHdG) 
 
 
Health economics  
Cost-Utility analysis of treatment with FAB122 


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4. 
STUDY DESIGN  
Multicenter, multinational, double-blind, randomized (2:1), placebo-controlled Phase III 
study to investigate the efficacy and safety of 100 mg FAB122 (former TW001) once daily 
as oral formulation in ALS patients. 
 
Subjects will be screened to assess whether they comply with all enrolment criteria.  
Approximately 300 patients will be randomized to 100 mg FAB122 or matched placebo in 
a 2:1 ratio.  Patients will be stratified by;    
1) their ALS progression rate at the start of the study (the slope ALSFRS-R score from 
time of first symptoms till Screening <1
1.0), 
2) additional co-medication for ALS (a. riluzole, b. no riluzole). 
 
Riluzole (100 mg/day or less) may be used as background (add-on) therapy. Patients on 
riluzole should be on stable doses at the start of the trial and for at least 30 days before 
the initiation of the study drug. It will not be allowed to initiate riluzole therapy during the 
trial. Additional supportive Standard Of Care (SOC) treatments will be allowed in all 
patients and will be standardized as much as possible. 
 
Subjects will receive double-blind treatment up to a maximum of 72 weeks.  The study is 
planned to continue until the last randomized subject has reached 48 weeks of follow up 
(or has reached an intercurrent event) AND the first one third of the subjects randomized 
(100) have reached 72 weeks of follow up (or has reached an intercurrent event). Subjects 
who discontinue treatment before week 72 will be followed as much as possible according 
to the planned visit schedule. In case of sanitary restrictions due to COVID-19 pandemic, 
home visits might be performed (for more details, see annex 4).  
 
Subjects will visit the clinic at Screening, Baseline, Week 4, Week 12, and every 12 weeks 
thereafter. Monthly telephone visits are performed in between the visits to the clinic until 
Week 48.   
 
Blood sampling for FAB122 plasma concentrations will be done in ~90 subjects treated 
with the study drug.  
 
After a subject completed the study (max at 72 weeks), he/she will be offered the 
possibility to roll over in an open label extension trial in which all subjects will be offered to 
receive FAB122. 
 
The end of the trial will correspond to the last subject last visit per the trial schedule. 
 
The study flowchart is presented in the Figure 2.  
 
 


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Figure 2: Study flowchart  


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5. 
STUDY POPULATION 
5.1. 
Study Participants   
ALS patients  
5.2. 
Inclusion Criteria 
In order to be eligible for participation in this trial, a subject must meet all of the following 
criteria:  
 
1. Age 18  80 years (both inclusive), male or female; 
2. Diagnosis 
of 
definite, 
probable, 
probable 
laboratory 
supported or possible ALS as based on the El Escorial and 
the revised Airlie House diagnostic criteria for ALS; 
3. Onset of first symptoms* no longer than 24 months prior to 
randomization; 
*Date of onset is the date the patient reported one or more of 
the following symptoms: 
 
Muscle weakness in limbs 
 
Speech/swallowing difficulties 
 
Respiratory symptoms: dyspnea was noticed 
 
4. SVC equal to or more than 70% of the predicted normal value 
for gender, height and age at screening visit; 
5. Change in ALSFRS-R score between 0.35 points and 1.5 
points per month (both inclusive) in the period from onset of 
first symptoms to the Screening visit; 
6. Patien
30 days prior 
to the baseline visit and this dose should be maintained 
during the entire trial. 
7. A female subject should not be able to become pregnant and 
needs to meet at least one of the following criteria: 
 
female subject who is not of 
reproductive potential is eligible without requiring the 
use of contraception.  A woman is considered not 
having childbearing potential when becoming post-
menopausal unless permanently sterile. Permanent 
sterilisation methods include hysterectomy, bilateral 
salpingectomy 
and 
bilateral 
oophorectomy. 
A 
postmenopausal state is defined as no menses for 
12 months without an alternative medical cause  
 
female who is of reproductive 
potential and has a negative pregnancy test at 
screening and at baseline and is non-lactating. A 
female subject who is of reproductive potential 
agrees to use (or have their partner use) adequate 
birth control methods starting from the time of 


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consent through 30 days after the last dose of study 
therapy.  Longer periods of birth control may be 
required 
per 
local 
requirements. 
Acceptable 
methods of birth control include combined (estrogen 
and 
progestogen 
containing) 
hormonal 
contraception associated with inhibition of ovulation 
(oral, intravaginal, transdermal), progestogen-only 
hormonal contraception associated with inhibition of 
ovulation 
(oral, 
injectable, 
implantable), 
 
, 
intrauterine device in place for 
nths, 
intrauterine hormone-releasing system, bilateral 
tubal occlusion or vasectomised partner.  
8. A male patient must: 
 
agree he will not donate sperm 
during the study and until 104 days after the last 
dose, AND 
 
use a condom during sexual 
intercourse with pregnant or non-pregnant women of 
childbearing potential (WOCBP) partner even if he is 
vasectomized 
 
 in addition WOCBP partner of 
the male patient must use the following acceptable 
methods of birth control during the study and until 
104 days after the last dose: combined (estrogen 
and 
progestogen 
containing) 
hormonal 
contraception associated with inhibition of ovulation 
(oral, intravaginal, transdermal), progestogen-only 
hormonal contraception associated with inhibition of 
ovulation 
(oral, 
injectable, 
implantable), 
 
, 
intrauterine hormone-releasing system, bilateral 
tubal occlusion or vasectomised partner; 
9. providing informed consent and complying with trial 
procedures.  
 
5.3. 
Exclusion Criteria 
A subject must not meet one or more of the following criteria: 
 
1. Diagnosis of Primary Lateral Sclerosis; 
2. Diagnosis of Frontotemporal Dementia; 
3. Diagnosis 
of 
other 
neurodegenerative 
diseases 
(e.g. 
Parkinson disease, Alzheimer disease); 
4. Diagnosis of polyneuropathy; 
5. Other causes of neuromuscular weakness; 


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6. Have a significant pulmonary disorder not attributed to ALS 
and/or require treatment interfering with the evaluation of 
ALS on respiratory function; 
7. Use of intravenous (IV) edaravone within 6 months of the 
screening visit; 
8. Use of mechanical ventilation (invasive or non-invasive) at 
Screening; 
9. Renal impairement as indicated by a creatinine clearane of 
less than 50 mL/min  
10. Subject has a history of clinically significant hepatic disease, 
hepatitis or biliary tract disease, 
or subject has a positive screening 
test for HIV, hepatitis B or C; 
11. Presence of any of the following clinical conditions: 
 
unstable 
cardiac, 
pulmonary, 
endocrine, 
hematologic or active infectious disease 
 
Severe active psychiatric illness e.g. psychosis, 
untreated major depression within 90 days of the 
screening visit 
 
significant cognitive impairment, clinical dementia 
or psychiatric illness 
 
Cancer that is currently under active treatment or 
is likely to require treatment during the trial that 
may alter the subject´s function and interfere with 
assessment of ALS disease progression. 
 
12. Any comorbidity that may interfere with the functions as 
scored with the ALSFRS-R; 
13. History of known sensitivity or intolerability to edaravone, to 
any related compound, or to any of the excipients;  
14. Exposure to any investigational drug within 30 days of the 
screening visit or 5 half-lives, whichever is longer; 
15. Current substance or alcohol dependence. 
16. For patients undergoing optional CSF sampling: any 
condition that according to the investigator criteria is 
contraindicated for the procedure (e.g. space-occupying 
lesion with mass effect, increase of intracranial pressure due 
to increased CSF pressure; posterior fossa mass; Arnold-
Chiari malformation; anticoagulant medication; coagulopathy; 
uncorrected bleeding diathesis; congenital spine abnormality; 
and skin infection at puncture site. 
 
This study permits the re-screening of a subject that has been deemed as ineligible 
(screen failure) during the Screening Period (ie, subject has not been randomized/has not 
been treated). Reasons that may qualify for a re-screening include medication stabilizing 
or ending, an acute event that has now resolved or any circumstance that is deemed 
appropriate by a medical monitor. If re-screened, the subject must be re-consented. Only 
one 
re-screening 
per 
subject 
is 
permitted.










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In case that, due to ALS progression, the subject is not able to attend the clinic or perform 
specific testing such as HHD or SVC, at least ALSFRS score, adverse events and 
concomitant medication use will be collected (if necessary by telephone). For safety 
assessments, the on-site visits are key for the study. In case a subject is not able to attend 
the site for two consecutive visits IMP must be discontinued at the second missed visit. 
The patient can continue its participation in the trial, via telephonic visits to collect 
ALSFRS-R, Adverse Events and Concomitant Medication, as long as the subject does not 
withdraw consent. 
The following sections provide details regarding the procedures to be performed at each 
study visit: 
 
6.1. 
Screening and Eligibility Assessment 
Subjects will report to the clinical site for a screening examination between Day -12 and 
Day -2. 
Prior to performing any study-related activities or evaluations, the patient must be 
thoroughly informed about all aspects of the study, including scheduled visits and 
activities. Patients will sign the study-specific consent form prior to any screening 
procedure. A signed copy of the informed consent form (ICF) should be provided to each 
consenting subject and with the original to be 
 
Depending on local regulations an independent ICF for Future Biomedical Research (FBR) 
should also be signed.  
The following information and procedures will be performed and documented as part of the 
screening assessment: 
 
Assessment of eligibility according to inclusion/exclusion criteria 
 
Demographics, including sex, ethnic origin, date of birth 
 
Medical history including query for baseline signs/symptoms 
 
Review of prior and ongoing concomitant medications (taken in previous 30 
days) 
 
Complete physical examination  
 
Neurological examination  
 
Height, weight and calculated BMI 
 
Vital signs measured with the subject in a supine/semi-supine position (for at 
least 5 minutes prior), including blood pressure, pulse rate, pulse oximetry and 
temperature 


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Standard 12-lead ECG (subject should be in a supine/semi-supine position for 
at least 5 minutes prior to assessment) 
 
Nerve Conduction Study (NCS)  
 
Fasting blood samples for routine clinical labs (clinical chemistry, haematology). 
See table 2 for lab assessments.  
 
Blood samples for serology (HIV, and hepatitis B and C evaluations) 
 
Urine samples for urinalysis  
 
-hCG in plasma and urine pregnancy test only in women of childbearing 
potential 
 
ALS evaluation procedures: ALSFRS-R and Slow Vital Capacity (SVC)  
 
Plasma vitamin B6 levels, and, if necessary, vitamin B6 supplements 
(pyridoxine (100 mg/day)) will be prescribed 
Compliance with inclusion criteria and exclusion criteria will be verified against information 
collected and documented in the database. 
Once all inclusion criteria are met, exclusion criteria ruled out, and safety* laboratory 
measurements obtained and reviewed, consenting subjects are eligible for randomization 
into the study.  
*Vit B6 is not considered a safety assessment at screening 
6.2. 
Baseline Assessments 
Baseline (Visit 1) Week 0 (Day 1) 
 
The following procedures will be performed: 
 
 
Assessment of eligibility according to inclusion/exclusion criteria 
 
Randomization  
Eligible patients will be randomized strictly sequentially, according to a 
randomization list prepared by the Biostatistician  
All patients will receive a unique patient identification number at screening visit 
when signing the informed consent and before any study procedures are 
performed. Three hundred patients will be randomized 2:1 in the following 2 
groups: 


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1. 200 patients will receive FAB122 100mg/d + SOC 
2. 100 patients will receive placebo + SOC 
The investigators will randomize patients directly online. In case of 
discontinuation from the study, the randomization number will not be reused. 
 
Review of prior and ongoing concomitant medications  
 
Complete physical examination  
 
Neurological examination  
 
Weight  
 
Vital signs measured with the subject in a supine/semi-supine position (for at 
least 5 minutes prior), including blood pressure, pulse rate, pulse oximetry and 
temperature 
 
Standard 12-lead ECG (subject should be in a supine/semi-supine position for 
at least 5 minutes prior to assessment) 
 
Fasting blood samples for routine clinical labs (clinical chemistry, haematology). 
See table 2 for lab assessments.  
* Only labs parameters that are abnormal in the screening visit will be re-
evaluated in baseline visit. 
 
Urine samples for urinalysis  
 
Urine pregnancy test only in women of childbearing potential 
 
Plasma vitamin B6 levels, and, if necessary, vitamin B6 supplements 
(pyridoxine (100 mg/day)) will be prescribed. 
 
ALS evaluation procedures: ALSFRS-R, Slow Vital Capacity (SVC), Hand-Held 
Dynamometry, ALSAQ-40, Edinburgh Cognitive and Behavioural ALS Screen 
(ECAS), EQ-5D-5L, VAS, King
staging system and MiToS. 
 
Blood sampling for biomarker: neurofilament light (NFL). Creatinine and 
creatine kinase will be measured in routine biochemistry lab testing. 
 
Urine collection for biomarkers: urinary extracellular domain of neurotrophin 
receptor 
p75 
(Urinary 
P75ECD) 
and 
oxidative 
stress 
biomarker 
8-
hydroxyguanosine (8-OHdG) 
 
Blood sampling for genotyping for Future Biomedical Research (FBR) (if 
consented) 


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Blood sampling for RNA and serum collection for FBR (if consented) 
 
Cerebrospinal fluid (CSF) sampling for Future Biomedical Research (if 
consented) 
 
Dispensing study Medication: Instructions for dosing FAB122 and first dosing 
 
Blood sampling for FAB122, in selected sites if consented. Specific ICF will be 
provided.  
 
Blood sampling for riluzole, in selected sites if consented. Specific ICF will be 
provided.  
 
Adverse Events monitoring 
 
Cost questionnaire 
 
6.3. 
Subsequent Visits 
Visit 2 Week 4 (Day 28 ±3Days) 
 
The following procedures will be performed: 
 
 
Review ongoing concomitant medications  
 
Neurological examination  
 
Vital signs measured with the subject in a supine/semi-supine position (for at 
least 5 minutes prior), including blood pressure, pulse rate, pulse oximetry and 
temperature 
 
Fasting blood samples for routine clinical labs (clinical chemistry, haematology). 
See table 2 for lab assessments 
 
Urine samples for urinalysis 
 
Plasma vitamin B6 levels, and, if necessary, vitamin B6 supplements 
(pyridoxine (100 mg/day)) will be prescribed. 
 
ALS evaluation procedures: ALSFRS-R  
 
Blood sampling for biomarker: neurofilament light (NFL). Creatinine and 
creatine kinase will be measured in routine biochemistry lab testing. 


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Urine collection for biomarkers: urinary extracellular domain of neurotrophin 
receptor 
p75 
(Urinary 
P75ECD) 
and 
oxidative 
stress 
biomarker 
8-
hydroxyguanosine (8-OHdG) 
 
Blood sampling for FAB122, in selected sites if consented  
 
Blood sampling for riluzole, in selected sites if consented 
 
 Nerve Conduction Study (NCS)  
 
Adverse Events monitoring 
 
Compliance check 
 
Visit 3 Week 12 (Day 84 ±3Days) 
 
The following procedures will be performed: 
 
 
Review ongoing concomitant medications  
 
Neurological examination  
 
Vital signs measured with the subject in a supine/semi-supine position (for at 
least 5 minutes prior), including blood pressure, pulse rate, pulse oximetry and 
temperature 
 
Fasting blood samples for routine clinical labs (clinical chemistry, haematology). 
See table 2 for lab assessments  
 
Urine samples for urinalysis  
 
Urine pregnancy test only in women of childbearing potential 
 
Plasma vitamin B6 levels, and, if necessary, vitamin B6 supplements 
(pyridoxine (100 mg/day)) will be prescribed 
 
ALS evaluation procedures: ALSFRS-R, Slow Vital Capacity (SVC), Hand-Held 
Dynamometry, King s staging system and MiToS, EQ-5D-5L and VAS 
 
Blood sampling for RNA and serum collection for FBR (if consented) 
 
Blood sampling for biomarker: neurofilament light (NFL). Creatinine and 
creatine kinase will be measured in routine biochemistry lab testing. 


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Urine collection for biomarkers: urinary extracellular domain of neurotrophin 
receptor 
p75 
(Urinary 
P75ECD) 
and 
oxidative 
stress 
biomarker 
8-
hydroxyguanosine (8-OHdG) 
 
Cerebrospinal fluid (CSF) sampling for Future Biomedical Research (if 
consented) 
 
Nerve Conduction Study (NCS)  
 
Adverse Events monitoring 
 
Cost questionnaire 
 
Dispensing study medication 
 
Compliance check 
 
Visit 4 Week 24 (Day 168 ±7Days) 
 
The following procedures will be performed: 
 
Review ongoing concomitant medications  
 
Complete physical examination  
 
Neurological examination  
 
Weight  
 
Vital signs measured with the subject in a supine/semi-supine position (for at 
least 5 minutes prior), including blood pressure, pulse rate, pulse oximetry and 
temperature 
 
Standard 12-lead ECG (subject should be in a supine/semi-supine position for 
at least 5 minutes prior to assessment) 
 
Fasting blood samples for routine clinical labs (clinical chemistry, haematology). 
See table 2 for lab assessments 
 
Urine samples for urinalysis  
 
Urine pregnancy test only in women of childbearing potential 
 
Plasma vitamin B6 levels, and, if necessary, vitamin B6 supplements 
(pyridoxine (100 mg/day)) will be prescribed 


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ALS evaluation procedures: ALSFRS-R, Slow Vital Capacity (SVC), Hand-Held 
Dynamometry, ALSAQ-40, Edinburgh Cognitive and Behavioural ALS Screen 
(ECAS), EQ-5D-5L, VAS, King
staging system and MiToS 
 
Blood sampling for biomarker: neurofilament light (NFL) Creatinine and creatine 
kinase will be measured in routine biochemistry lab testing. 
 
Urine collection for biomarkers: urinary extracellular domain of neurotrophin 
receptor 
p75 
(Urinary 
P75ECD) 
and 
oxidative 
stress 
biomarker 
8-
hydroxyguanosine (8-OHdG) 
 
Blood sampling for RNA and serum collection for FBR (if consented) 
 
Cerebrospinal fluid (CSF) sampling for Future Biomedical Research (if 
consented) 
 
 Nerve Conduction Study (NCS)  
 
Adverse Events monitoring 
 
Cost questionnaire 
 
Dispensing study medication 
 
Compliance check 
 
 
Visit 5 Week 36 (Day 252 ±7Days) 
 
The following procedures will be performed: 
 
 
Review ongoing concomitant medications  
 
Neurological examination  
 
Vital signs measured with the subject in a supine/semi-supine position (for at 
least 5 minutes prior), including blood pressure, pulse rate, pulse oximetry and 
temperature 
 
Fasting blood samples for routine clinical labs (clinical chemistry, haematology). 
See table 2 for lab assessments  
 
Urine samples for urinalysis  
 
Urine pregnancy test only in women of childbearing potential 


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Plasma vitamin B6 levels, and, if necessary, vitamin B6 supplements 
(pyridoxine (100 mg/day)) will be prescribed. 
 
ALS evaluation procedures: ALSFRS-R, Slow Vital Capacity (SVC), Hand-Held 
Dynamometry, King
staging system and MiToS, EQ-5D-5L and VAS. 
 
Blood sampling for biomarker: neurofilament light (NFL). Creatinine and 
creatine kinase will be measured in routine biochemistry lab testing. 
 
Urine collection for biomarkers: urinary extracellular domain of neurotrophin 
receptor 
p75 
(Urinary 
P75ECD) 
and 
oxidative 
stress 
biomarker 
8-
hydroxyguanosine (8-OHdG) 
 
Blood sampling for RNA and serum collection for FBR (if consented) 
 
Nerve Conduction Study (NCS) (if required) 
 
 Adverse Events monitoring 
 
Cost questionnaire 
 
Dispensing study medication 
 
Compliance check 
 
Visit 6 Week 48 (Day 336 ±7Days)-End of Trial 
 
The following procedures will be performed: 
 
Review ongoing concomitant medications  
 
Complete physical examination  
 
Neurological examination  
 
Weight  
 
Vital signs measured with the subject in a supine/semi-supine position (for at 
least 5 minutes prior), including blood pressure, pulse rate, pulse oximetry and 
temperature 
 
Standard 12-lead ECG (subject should be in a supine/semi-supine position for 
at least 5 minutes prior to assessment) 
 
Fasting blood samples for routine clinical labs (clinical chemistry, haematology). 
See table 2 for lab assessments 
 
Urine samples for urinalysis  


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Urine pregnancy test only in women of childbearing potential 
 
Plasma vitamin B6 levels, and, if necessary, vitamin B6 supplements 
(pyridoxine (100 mg/day)) will be prescribed. 
 
ALS evaluation procedures: ALSFRS-R, Slow Vital Capacity (SVC), Hand-Held 
Dynamometry, ALSAQ-40, Edinburgh Cognitive and Behavioural ALS Screen 
(ECAS), EQ-5D-5L, VAS, King
staging system and MiToS  
 
Blood sampling for biomarker: neurofilament light (NFL). Creatinine and 
creatine kinase will be measured in routine biochemistry lab testing. 
 
Urine collection for biomarkers: urinary extracellular domain of neurotrophin 
receptor 
p75 
(Urinary 
P75ECD) 
and 
oxidative 
stress 
biomarker 
8-
hydroxyguanosine (8-OHdG) 
 
Blood sampling for RNA and serum collection for FBR (if consented) 
 
Blood sampling for FAB122 
 
Nerve Conduction Study (NCS) (if required) 
 
 Adverse Events monitoring 
 
Cost questionnaire 
 
Dispensing study medication 
 
Compliance check 
 
Visit 7 Week 60 (Day 420 ±7Days) 
 
The following procedures will be performed: 
 
 
Review ongoing concomitant medications  
 
Neurological examination  
 
Vital signs measured with the subject in a supine/semi-supine position (for at 
least 5 minutes prior), including blood pressure, pulse rate, pulse oximetry and 
temperature 
 
Fasting blood samples for routine clinical labs (clinical chemistry, haematology). 
See table 2 for lab assessments 
 
Urine samples for urinalysis  


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Urine pregnancy test only in women of childbearing potential 
 
Plasma vitamin B6 levels, and, if necessary, vitamin B6 supplements 
(pyridoxine (100 mg/day)) will be prescribed 
 
ALS evaluation procedures: ALSFRS-R, Slow Vital Capacity (SVC), Hand-Held 
Dynamometry, King
staging system and MiToS, EQ-5D-5L and VAS 
 
Blood sampling for biomarker: neurofilament light (NFL). Creatinine and 
creatine kinase will be measured in routine biochemistry lab testing. 
 
Urine collection for biomarkers: urinary extracellular domain of neurotrophin 
receptor 
p75 
(Urinary 
P75ECD) 
and 
oxidative 
stress 
biomarker 
8-
hydroxyguanosine (8-OHdG) 
 
Blood sampling for RNA and serum collection for FBR (if consented) 
 
Nerve Conduction Study (NCS) (if required) 
 
 Adverse Events monitoring 
 
Cost questionnaire 
 
Dispensing study medication 
 
Compliance check 
 
Visit 8 Week 72 (Day 504 ±7Days)-End of Trial visit (first 100 patients enrolled) 
 
The following procedures will be performed: 
 
Review ongoing concomitant medications  
 
Complete physical examination  
 
Neurological examination  
 
Weight  
 
Vital signs measured with the subject in a supine/semi-supine position (for at 
least 5 minutes prior), including blood pressure, pulse rate, pulse oximetry and 
temperature 
 
Standard 12-lead ECG (subject should be in a supine/semi-supine position for 
at least 5 minutes prior to assessment) 


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Fasting blood samples for routine clinical labs (clinical chemistry, haematology). 
See table 2 for lab assessments 
 
Urine samples for urinalysis  
 
Urine pregnancy test only in women of childbearing potential 
 
Plasma vitamin B6 levels, and, if necessary, vitamin B6 supplements 
(pyridoxine (100 mg/day)) will be prescribed 
 
ALS evaluation procedures: ALSFRS-R, Slow Vital Capacity (SVC), Hand-Held 
Dynamometry, ALSAQ-40, Edinburgh Cognitive and Behavioural ALS Screen 
(ECAS), EQ-5D-5L, VAS, and King s staging system and MiToS  
 
Blood sampling for biomarker: neurofilament light (NFL). Creatinine and 
creatine kinase will be measured in routine biochemistry lab testing. 
 
Urine collection for biomarkers: urinary extracellular domain of neurotrophin 
receptor 
p75 
(Urinary 
P75ECD) 
and 
oxidative 
stress 
biomarker 
8-
hydroxyguanosine (8-OHdG) 
 
Blood sampling for RNA and serum collection for FBR (if consented) 
 
Blood sampling for FAB122 (if early withdrawal) 
 
Nerve Conduction Study (NCS) (if required) 
 
Adverse Events monitoring 
 
Cost questionnaire 
 
Compliance check 
 
Table 2: Overview of laboratory assessments 
Haematology 
Biochemistry 
Urinalysis 
Other 
Biomarkers 
Haematocrit 
Bilirubin (direct) and 
Bilirubin (total) 
Blood 
Seru
-human 
chorionic 
gonadotropin 
( -hCG) 
Urinary P75ECD 
Haemoglobin 
Alkaline phosphatase 
Glucose 
Hepatitis 
B 
surface 
antigen (HBsAg) 
Urinary 8-OHdG 
RBC 
Alanine 
aminotransferase 
(ALT) 
Protein 
Hepatitis 
C 
virus 
antibody (HCV-Ab) 
Blood neurofilament 
light (NFL) 
Platelet count 
Aspartate 
aminotransferase 
(AST) 
Specific 
gravity  
HIV antibody (HIV-Ab) 
 
 


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Haematology 
Biochemistry 
Urinalysis 
Other 
Biomarkers 
WBC 
Bicarbonate 
Microscopic 
exam, 
if
abnormal 
results 
are 
noted  
Plasma 
vitamin 
B6
levels 
 
Differential count:  
Calcium 
Ketone 
Cystatin C 
 
 Basophils 
Chloride 
PH 
 
 
 Eosinophils 
Creatinine 
Nitrite 
 
 
 Lymphocytes 
gammaGT (GGT) 
Leukocytes 
 
 
 Monocytes 
Fasting Glucose 
Bilirubin 
 
 
 Neutrophils 
Potassium 
Urobilinogen 
  
 
 
Sodium 
 
  
 
 
Uric Acid 
 
  
 
 
Total protein 
 
  
 
 
Urea (BUN) 
 
  
 
 
eGFR 
 
  
 
 
Activated 
partial 
thromboplastin 
time
(aPTT) 
 
 
 
 
Protrombin 
Time 
(PTT) 
 
  
 
 
Fibrinogen 
 
 
  
 
 
Lactate 
dehyrdognease (LDH)
 
  
 
 
Creatinine kinase 
(CK) 
 
 
 
 
 
 
 
 
 
6.4. 
Telephonic visits  
Seven telephone calls will be performed throughout the study by the study team. These 
calls will be done in the following time points: Week 8, 16, 20, 28, 32, 40, and 44. The 
following activities will be performed in each call: 
 
 
ALSFRS-R questionnaire 
 
Adverse Events monitoring  
 
Review prior and ongoing concomitant medications  
 
6.5. 
Early Discontinuation/Withdrawal of Participants 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at 
the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be withdrawn by the investigator or the Sponsor if enrolment into the trial is 
inappropriate, the trial plan is violated, or for administrative and/or safety reasons.   


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In this trial, a subject may discontinue from treatment but continue to participate in the 
regularly scheduled activities, as long as the subject does not withdraw consent.  Once a 
subject has discontinued treatment, he/she may be allowed to start treatment again after 
consultation with the investigator, if discontinuation of treatment is  2 weeks. 
 
A subject must be discontinued from the trial for any of the following reasons: 
 
 
The subject withdraws consent. 
 
The subject has a medical condition or personal circumstances which, in the 
opinion of the investigator and/or Sponsor, places the subject at unnecessary 
risk if participation in the trial is continued.   
 
The subject reaches the criteria for respiratory insufficiency (tracheostomy or 
the use of non-invasive ventilation for >20 hours per day for >10 consecutive 
days), 
 
A subject must be discontinued from study treatment (but should continue to be monitored 
in the study) for any of the following reasons: 
 
1-The subject becomes pregnant during the study. 
2-
nsiders it is in the best interest of the subject to discontinue 
including worsening or disease progression if the investigator considers that it is in the 
 of care treatment prohibited in the study 
3-Serious adverse event considered related to the IMP 
4-Severe Neurotoxicity considered related to the IMP 
5-Any other severe adverse event considered related to the IMP at the discretion of the 
investigator. 
6-Acute renal failure (creatinine clearance of less than 30 mL/min as calculated by the 
Cockcroft Gault equation) 
7-Severe liver disorder defined as:  
 ALT/AST 
rect bilirubin) 
 ALT/AST  8xULN 
 ALT/AST 
th symptoms believed to be related to liver injury or 
hypersensitivity.  
 ALT/AST 
line ALT/AST and with symptoms believed to be related to liver 
injury or hypersensitivity. 
 ALT/AST 
/AST < 8xULN that persists more than two weeks 
8-Acute lung injury with pyrexia, cough, dyspnoea and chest X-ray abnormality 
9-Rhabdomyolysis  
10-Disseminated intravascular coagulation (DIC) 
11-Hypersensitivity reaction 
12- Anaphylactic reaction/shock 
13- Thrombocytopenia 
14- Neutropenia 
15-Introduction of riluzole 
16-The subject cannot attend two consecutive study visits and key safety assessment 
cannot be performed 
 
 
 


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If a subject discontinues the trial for safety reasons, a PK sample is to be taken (with the 
time of sampling after last dosing clearly documented) in those sites participating in the PK 
sub study.  
In case a subject withdraws FBR consent, the blood samples taken for FBR will be 
destroyed (when not analysed yet). 
The sponsor reserves the right to terminate the study at any time if continuation of the 
protocol would present a potential safety risk to the subjects. 
Every effort will be made to ensure that patients who do not complete all study 
requirements return to the site for the End-of-Trial Visit. Patients who withdraw due to an 
Adverse Event (AE) or Serious Adverse Event (SAE) will be given appropriate care under 
medical supervision until the symptoms resolve or the patie
ition becomes stable. 
The End-of-Trial Visit will be performed 7-14 days after withdrawal and the same 
procedures as Visit 8 will be performed. 
 
6.6. 
Sample Handling 
To minimise variability between centres in this multicentre study all clinical laboratory 
assays will be performed by a central laboratory (see details on Study Contacts Section). 
Blood samples are to be handled, shipped and stored according to the instructions 
provided by the laboratory. Laboratory kits, shipment material and a comprehensive 
laboratory manual will be provided to all sites. 
Instructions for handling, shipment and storing of blood and urine samples for Biomarkers 
testing will be described in a separate laboratory manual. 
Samples for future Biomedical Research of those patients providing consent, will be 
appropriately stored in the central laboratory facilities. Details will be included in the 
laboratory manual. 
6.7. 
PK Samples   
Blood Sampling FAB122  
 
Blood sampling for FAB122 PK analysis will be done in ~90 subjects in selected sites. Of 
those ~30 subjects will participate in a PK profiling sampling schedule and the additional 
~60 subjects will participate in a population PK sampling schedule, both at baseline, week 
4 and week 48 (or Early Termination).  
 
Sampling schedule for PK profiling: pre-dose and 15 min, 30 min, 1, 1.5, 2, 4 hrs., and 
6hrs. after the FAB122 morning dose. The pre-dose sample may be collected within 30 
minutes prior to dosing. 15 and 30 min post dosing samples should be taken within ±2 
minutes of the scheduled time, the 1 hr. post dosing sample within ±5 minutes, the 1.5 and 
2-hour sample within ±10 minutes and the 4 hr. and 6hr. sample within ±20 minutes of the 
scheduled time. The time of sampling will be accurately recorded.  
 
Sampling schedule for population PK: (1) pre-dose (within 1 hour prior to dosing), (2) 
within 5- and 30-minutes post dosing, (3) 1 hour and (4) 1.5 hour after the second PK 
sample was taken. The time of sampling will be accurately recorded. 
 
Patient should come fasted and will take the IMP dose in the clinic. 


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Patients participating in the PK profiling will not be allowed to eat until 4 hours post dose. 
 
Blood Sampling Riluzole  
 
Blood sampling for the determination of riluzole concentration will be done in the subjects 
included in FAB122 PK sampling in baseline and week 4 (~90 subjects) at (1) pre-dose 
(within 1 hour prior to dosing).(2) within 5- and 30-minutes post dosing,  (3) 1 hour and (4) 
1.5 hour after the second PK sample was taken. The time of sampling will be accurately 
recorded. 
 
Patient should come fasted and will take the riluzole dose in the clinic, at the same time 
that the IMP dose. 


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Table 3: Overview of PK sampling 
 
 
Baseline (V1)
Week 4 (V2) 
Week 48 (V6)* 
Early Termination** 
30 subjects 
FAB122 PK profiling 
Riluzole PK*** 
pre-dose and 0.25, 0.5, 1, 1.5, 2, 
4 hrs., and 6hrs after 
FAB122/riluzole morning dose 
30 subjects 
FAB122 PK profiling 
Riluzole PK*** 
pre-dose and 0.25, 0.5, 1, 1.5, 2, 
4 hrs., and 6hrs after 
FAB122/riluzole morning dose
30 subjects 
FAB122 PK profiling 
 
pre-dose and 0.25, 0.5, 1, 1.5, 2, 
4 hrs., and 6hrs after FAB122 
morning dose
30 subjects 
FAB122 PK profiling 
 
pre-dose and 0.25, 0.5, 1, 1.5, 2, 
4 hrs., and 6hrs after FAB122 
morning dose
60 subjects 
FAB122 PK population 
Riluzole PK 
pre-dose (within 1 hour prior to 
dosing), (2) within 5- and 30-
minutes post dosing, and (3) 1 
hour and (4) 1.5 hour after the 
second PK sample was taken
60 subjects 
FAB122 PK population 
Riluzole PK 
pre-dose (within 1 hour prior to 
dosing), (2) within 5- and 30-
minutes post dosing, and (3) 1 
hour and (4) 1.5 hour after the 
second PK sample was taken
60 subjects 
FAB122 PK population 
 
pre-dose (within 1 hour prior to 
dosing), (2) within 5- and 30-
minutes post dosing, and (3) 1 
hour and (4) 1.5h after the 
second PK sample was taken
60 subjects 
FAB122 PK population 
 
pre-dose (within 1 hour prior to 
dosing), (2) within 5- and 30-
minutes post dosing, and (3) 1 
hour and (4) 1.5h after the 
second PK sample was taken
*If feasible (if patients continue up to week 48) 
**Only for patients included in the FAB122 profiling PK and FAB122 population PK and who discontinue 
treatment before week 48  
***Riluzole will only be analyzed in pre-dose, 0.5, 1.5 and 2h samples. 
 
PK Samples Handling  
 
Plasma will be prepared from the blood samples and split into two aliquots (one for 
backup) for analysis of plasma concentrations of FAB122 and riluzole using a validated 
LC/MS/MS assay method. Instructions for handling, shipment and storing of the PK 
samples will be described in a separate study PK laboratory manual. Plasma 
concentrations will be measured using validated bioanalytical methods and according to 
the 
bioanalytical 
rating 
Procedures 
(SOP). 
Qualitative/comparative assessments of metabolite profiles will be performed. 
 
 
 
 
 


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7. 
STUDY INTERVENTIONS 
7.1. 
Investigational Medicinal Product(s) (IMP) Description 
Compound name: 
FAB122 
INN/generic name:  
edaravone 
Synonyms:  
norphenazone; methylphenylpyrazolone; norantipyrine 
IUPAC name: 
3-methyl-1-phenyl-4, 5-dihydro-1H-pyrazol-5-one 
CAS name:  
5-Methyl-2-phenyl-1, 2-dihydropyrazol-3-one (CAS Registry 
No. 89-25-8) 
Molecular formula: 
C10H10N2O 
Chirality: 
FAB122 has no chiral centre 
 
Structural formula: 
 
 
Molecular weight: 
174.20 g/mol 
Appearance: 
off-white to white powder 
Solubility: 
 
sparingly soluble in water, soluble in acetic acid and 
methanol, limited solubility in ethanol 
Hygroscopicity: 
FAB122 is not hygroscopic 
 
 
 
 
 
 
 
 
 


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Each sachet of the active treatment contains the following composition given in the table 4:  
 
Table 4: The theoretical quantitative composition of FAB122 granules for oral 
solution in sachet 
 
Component 
Amount/sachet 
FAB122 
100.0 mg 
Spray dried mannitol 200 
621.8 mg  
Disodium 
hydrogen 
phosphate 
dihydrate 
363.6 mg  
Sodium Laurilsulfate (SLS) 
5.5 mg 
Total 
1090.9 mg 
 
The active ingredient and the investigational drug have been produced complying the 
Good Manufacturing Practices of the European Union for active pharmaceutical 
ingredients and ICH Q7A guidelines. 
 
Study treatment is supplied as granules for oral solution, 100 mg FAB122 or placebo per 
sachet, to be dissolved in about 100 ml water approximately and stirred slightly by a 
teaspoonful. Study treatment must be administered immediately after its dissolution. 
 
First dosing will be administered at the study site and patients will be instructed about 
study treatment administration. 
 
Study treatment should be administered once a day at about the same time each day. 
Dosing needs to be done each morning under fasting conditions. This implies taking the 
dose: at least two (2) hours after a meal or snack and 30 min after a drink AND no eating 
or drinking for at least one hour post dosing. If a subject misses a dose, the missed dose 
should be taken as soon as possible taking the fasted conditions into account if feasible.  If 
the time period until the regular dosing time for the next dose is less than 4 hours, then the 
missed dose should be skipped, and the normal dosing schedule should be resumed.  The 
next dose should not be doubled in order to make up for the missed dose. 
The study medication is to be stored in the refrigerator at a temperature between 2 - 
. 
Temperature excursions are permitted at 8-25ºC not exceeding 72 hours. Please contact 
the sponsor in case the temperature excursion is on different conditions from the ones 
mentioned before.  
 
Study treatment could be given via gastric gavage and feeding tube if applicable.  
 
 
 


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7.1.1. 
Packaging and Labelling  
The label(s) for the investigational product and placebo will include all information 
according to GMP Annex 13. Additional information may be included on the label as 
applicable per local regulations. 
 
7.1.2. 
Blinding of IMP 
Verum and placebo are identical and unrecognizable sachets by form size, weight, and 
colour, and will be indistinguishable to patients and investigators. 
 
7.1.3. 
Compliance with Trial Treatment 
Patients will be instructed to return all used an unused medication at each study visit. The 
number of sachets dispensed and returned will be registered by the investigator at each 
visit to obtain information on patients' compliance. The patient will be considered complaint 
with treatment when 80%-120% of the total scheduled doses since the last clinic visit are 
administered. 
All investigational products used in this study will be monitored for compliant usage 
throughout the trial by the sponsor or their designee. 
 
7.1.4. 
Accountability of the Trial Treatment 
 Adequate supplies of the IMP will be provided to the site. Study drug should be stored in 
the original package under conditions as stated on the product label, in a secure, 
temperature-monitored, locked area, under the responsibility of the Investigator or other 
authorized individual until dispensed to the subjects.  
 
The pharmacy of the site must maintain accurate records of the receipt of all study drug, 
including date received, lot number, expiration date if applicable, amount received, 
condition of the package, and the disposition of all study drug. 
 
Current dispensing records will also be maintained, including the date and amount of 
medication dispensed and the identity of the subject receiving the medication.  
 
At the end of the study, it must be possible to reconcile delivery records with those of 
used, partially used and returned stocks. 
 
All used and unused IMP must be returned to the storage/distribution facility after the study 
is completed. 
In case of sanitary restrictions or if a patient cannot attend one study visit, following local 
regulation, IMP can be delivered directly to patient s home, as per site internal procedure 
or through a validated direct to patient service provided by the sponsor. For more details, 
please refer to the IP Manual.  
 


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7.1.5. 
Concomitant Medication 
The permitted concomitant medication for ALS 
 management (such as 
symptomatic treatment of muscle spasms, pain, insomnia, dysphagia and emotional 
instability) are listed in the Annex 3.  
Treatment of ALS impairments (nutrition, respiration, motricity, communication) will be 
done with a multidisciplinary approach and accordingly to European Federation of 
Neurological Societies (EFNS) Guidelines for ALS patient  management.  
7.1.6. 
Post-trial Treatment 
Once patients have completed the study (max week 72) and if potential clinical benefit is 
achieved, patients could be enrolled in an open-label one group extension study and 
FAB122 will be given for all included patients. 
7.2. 
Other Treatments (non-IMPS) 
Riluzole (100 mg/day or less) may be used as background (add-on) therapy. Patients on 
riluzole should be on stable doses 
ys prior to the baseline visit and this dose should 
be maintained during the entire trial. It will not be allowed to initiate riluzole therapy during 
the trial.  
 
 
 


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8. 
PARAMETERS AND METHODS OF ASSESSMENT 
8.1. 
 Parameters 
8.1.1. 
ALSFRS-R  
The ALSFRS-R is a validated 12-item questionnaire designed to evaluate the functioning 
of respiratory, bulbar, fine and gross motor function in ALS patients. The total score ranges 
from 48 (no limitation in daily activities) to 0 (total inability). The patients will be asked to 
complete the ALSFRS-R questionnaire at each in-clinic visit on Screening, Baseline, and 
weeks 4, 12, 24, 36, 48, 60, and 72, as well on each phone call on weeks 8, 16, 20, 28, 
32, 40, and 44. The total score of the ALSFRS-R and the score of each subdomain will be 
recorded in the eCRF by the investigator or designee.  
8.1.2. 
Survival Time  
If a patient dies during the 72 weeks of  participation, the date of death will be recorded in 
the eCRF. If a patient reaches the criteria for respiratory insufficiency (tracheostomy or the 
use of non-invasive ventilation for >20 hours per day for >10 consecutive days), the date 
this criterion was met will be recorded in the eCRF and the patient will no longer be part of 
the study. 
8.1.3. 
Lung Function  
Lung function is evaluated by using a non-invasive spirometer to determine the Slow Vital 
Capacity (SVC). During the test, the patient inspires fully and then slowly expires all the air 
in his/her lungs. The test will be done using a facemask. This procedure is repeated 3 
times minimally until a steady recording is obtained; the highest score is recorded. A digital 
spirometer is used to determine SVC values. The SVC will be assessed at Screening, 
Baseline, and weeks, 12, 24, 36, 48, 60, and 72. The results of SVC in liters will be 
recorded in the eCRF by the investigator or designee. 
8.1.4. 
Staging of Disease Progression  
The K
 staging system is a simple clinical staging system, which defines four stages of 
ALS. The first three stages are defined by functional involvement of a region: bulbar, upper 
limbs and lower limbs. The number of regions involved gives the stage. Stage 4 is reached 
if swallowing (4A) or respiratory (4B) difficulty is severe enough to require intervention. 
MiToS is a similar clinical staging system, in which the stages are defined as loss of 
independence on the four domains of the ALSFRS-R: swallowing, walking/self-care, 
communicating and breathing. The investigator will assess both staging systems for each 
patient and will record the results in the eCRF. The assessments will be performed at 
Baseline and weeks 12, 24, 36, 48, 60, and 72. 
8.1.5. 
Strength Test  
Handheld dynamometry (HHD) is a procedure for quantitative strength testing. This testing 
will be conducted by the Investigator or any designee who has been properly trained for 
the quantitative muscle strength evaluation. When possible, it is highly recommended that 


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all assessments be performed by the same assessor. Muscle strength testing will be 
performed on prespecified muscles in the upper and lower extremities bilaterally and the 
force measurement recorded. HHD will be assessed at Baseline and weeks 12, 24, 36, 48, 
60, and 72. The results of the HHD will be recorded in the eCRF by the investigator or 
designee. 
8.1.6. 
Health Status  
ALSAQ40: The Amyotrophic Lateral Sclerosis Assessment Questionnaire is a patient 
reported outcome (PRO) designed to determine the pat
ealth status. The ALSAQ40 
is specifically used to measure the subjective well-being of patients with ALS. There are 40 
items/questions in the long form, the ALSAQ40, with 5 discrete scales: physical mobility 
(10 items), activities of daily living and independence (10 items), eating and drinking (3 
items), communication (7 items), emotional reactions (10 items). During the study the 
questionnaire will be provided in the local language of the patient. The ALSAQ40 
questionnaire will be completed by the patient at Baseline and weeks 24, 48, and 72 via a 
study App or online questionnaire. In case of technical issues with the ePRO device these 
questionnaires can be completed on a paper version as a backup. 
EQ-5D-5L is a is a patient reported outcome (PRO), simple, valid, standardized health 
state measure. It consists of five questions that relates to five dimensions of health: 
mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each 
dimension/question can be scored on three levels of severity (1, no; 2, slight; 3, moderate; 
4, severe; 5, extreme problems). In addition, responders will be asked to rate their current 
health related quality of life (HRQoL) on a visual analogue scale (VAS) ranging from 0 
(bad) to 100 (very good). During the study the questionnaire will be provided in the local 
language of the patient. The EQ-5D-5L and VAS will be completed at Baseline and weeks 
12, 24,36, 48, 60 and 72 via a study App or online questionnaire. In case of technical 
issues with the ePRO device these questionnaires can be completed on a paper version 
as a backup. 
8.1.7. 
Cognition  
The neuropsychological status of patients will be evaluated using the Edinburgh Cognitive 
and Behavioral ALS Screen (ECAS). The ECAS is independent of motor disability and 
evaluates five cognitive domains: language functions, executive functions, letter fluency, 
memory and visuospatial functioning. The ECAS is designed for ALS patients and answers 
can be given verbally, or by a combination of writing or pointing. It is suitable for patients 
who are anarthric or patients who have no hand motor function. The total score is 136 
points and should take no longer than 15 minutes to administer. The ECAS will be 
completed by the investigator or designee at Baseline and weeks 24, 48, and 72. The total 
score of the questionnaire will be recorded in the eCRF.   
8.2. 
Safety Parameters 
Occurrence of AEs, changes on physical examination (including body weight), vital signs, 
ECG parameters and laboratory examinations (biochemistry, haematology and urinalysis) 
will be registered throughout the entire study duration. 
 


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All AEs will be actively collected at each visit, from spontaneous declarations of the patient 
as well as from oral inquiry and clinical examination. All concomitant medications and/or 
therapies should be documented in the patient file and reported in the electronic Case 
Report Form (eCRF). 
 
8.2.1. 
Physical and neurological examination 
Physical examinations will be performed by qualified personnel according to the Schedule 
of Events. Symptom directed physical exams will be performed as applicable. Physical 
examination includes the following assessments: general appearance, head, eyes, 
ears/nose/throat, neck, lymph nodes, skin, lungs, heart, abdomen, musculoskeletal, and 
neurologic evaluations. Breast, rectal, and genitourinary/pelvic exams should be 
performed when clinically indicated. Weight (kilograms) will be measured as part of all 
physical examinations. Height (centimeters) will be measured only at the screening visit. 
The BMI will be calculated.  
Neurological examination will be performed by qualified personnel according to the 
Schedule of Events to assess possible peripheral nerve dysfunction (= sensory or motor 
symptoms), diminished or absent reflexes (compared with baseline examination), sensory 
abnormalities (e.g. numbness or tingling) or weakness. In case a subject experiences 
clinical signs or symptoms at home, subjects will be asked to contact the clinic. 
All abnormal findings will be documented in the database. 
 
8.2.2. 
Laboratory Parameters 
The results of clinical laboratory tests conducted at the screening visit must be assessed 
by the investigator to determine each subje
ligibility for participation in the study. The 
results of all clinical laboratory tests conducted during the study must be assessed by the 
investigator to assess 
 safety. 
Any significant abnormalities is to be documented and followed up as AEs and should be 
fully investigated. Whenever possible, the etiology of the abnormal findings will be 
documented in the database. Laboratory results with significantly abnormal values should 
be investigated as such and checked for verification. Additional tests and other evaluations 
required to establish the significance or etiology of an abnormal result or to monitor the 
course of an AE should be obtained when clinically indicated. In particular, if a clinically 
significant abnormal result is observed that is not resolved by the final study visit, repeat 
tests will be performed if possible and resolution or stability of the abnormality will be 
recorded in the source documentation. 
Any significant laboratory abnormalities that are either serious or unexpected will be 
promptly reported to the sponsor
ical Monitor. Any additional relevant laboratory 
results obtained by the investigator during the course of this study will be reported to the 
sponsor or its representative. 
 


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8.2.3. 
ECG  
Twelve-lead ECGs will be performed according to the Schedule of Events. Subject should 
be resting supine/semi-supine for at least 5 minutes prior to all ECG measurements if 
possible. 
 
8.2.4. 
Vital Signs 
Vital signs, including blood pressure, heart rate, respiratory rate, pulse oximetry, and 
temperature, will be measured at study visits according to the Schedule of Events. Subject 
should be resting supine/semi-supine for at least 5 minutes prior to vital signs 
measurements.  
 
8.2.5. 
Nerve Conduction Study  
The NCS protocol evaluates the sensory nerve action potential (SNAP) amplitudes using 
standard ring-electrodes and predefined sites for both stimulus (antidromic) and recording 
sites, including standardized distances that also apply for the inter-electrode distances. 
Hence, routine signal averaging for the recorded SNAP s will be performed after 
supramaximal stimulation. These measures will eliminate any unwanted variation due to 
instrumentational differences. For these recordings, limb temperature should be at 310C, 
otherwise warming may be considered or alternatively accepted correction factor for 
decreased temperature could be done. Sensory latencies and velocities are less robust 
parameters that may also depend on filter settings between different machines and, 
therefore, will not be used. NCS criteria for neuropathy are decreased sural nerve SNAP 
amplitudes or decreased sural/radial nerve amplitude ratio (SRAR).  
 
NCS will include sensory recordings from sural nerves (unilateral) and sensory recordings 
from median, ulnar, radial nerves (unilateral) with standardized distances between 
recording and stimulation sites of 12cm. NCS data will be evaluated by neurophysiologists 
at the participating centres and also reviewed independently at the UMC Utrecht, taking 
into account reference values provided by participating sites, and using age adjusted 
reference values. Additional testing may be requested if required.  
Instructions on operational aspects of the NCS are described in a separate NCS manual. 
 
The main aim of NCS is to identify subclinical damage of sensory function before the 
potential development of a clinically significant neuropathy. The relevant expected clinical 
presentation of neuropathy is predominantly sensory and includes relative symmetric 
paraesthesia and/or numbness mainly in feet.   
 
The DSMB will assess the results of the NCS, simultaneously with the assessment on 
vitamin B6, clinical signs, ALSFRS-R questions related to leg functioning (8. walking and 
9. climbing stairs) for the first enrolled 60 patients (about 40 active and 20 placebo).  
The NCS will be conducted for the first enrolled 60 patients at  screening, and on weeks 4, 
12, and 24. Then according to the evaluation by the DSMB, one of the following options 
will be performed:  


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 If no neurological concerns are observed, the study will 
continue with one additional NCS at week 48 for the first 60 
patients. Then for the next enrolled patients, one NCS will be 
performed at screening and another one at week 48. 
Additional NCS(s) could be performed between screening    
and week 48 if any abnormality is detected by the 
neurological examination or any suggesting symptoms of 
neuropathy are reported by the patient.  
 If NCS show signs of neurological damage, intensive NCS 
monitoring will continue for all patients at screening and on 
weeks 4, 12, 24, 36, 48, 60, and 72.  
All NCS values will be recorded by the investigator in the eCRF at the corresponding time 
points. 
8.3. 
Pharmacokinetic Assessments  
Details of analyses methods of the pharmacokinetic, population PK, pharmacokinetic-
pharmacodynamic modelling and pharmacokinetic interaction between FAB122 and 
riluzole as well as the software packages used will be described in a separate PK analysis 
plan that will be finalized before the database closure and the formal treatment code 
breaking. 
The plasma concentration for FAB122 and riluzole will summarized over time. The primary 
pharmacokinetics parameters of interest derived of the plasma concentration of FAB12 
and riluzole are: Cmax, Tmax, t1/2, and AUC.  
Pharmacokinetic parameters may include, but not be limited to (see table 5): 


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Table 5: Pharmacokinetic parameters of FAB122 and riluzole  
 
Parameter 
Definition 
AUClast 
Area under the concentration-time curve from time 0 (time of drug 
administration) to the time of the last quantifiable concentration;
calculated using the linear trapezoidal rule 
Cmax 
Maximum plasma concentration  
Tmax 
Time of the maximum plasma concentration  
Clast 
Last quantifiable concentration 
Tlast 
Time of the last quantifiable concentration 
T1/2 
Time taken for Cmax to drop in half  
AUCinf 
Area under the concentration-time curve from time 0 to infinite 
The pre-dose concentration may be extrapolated to the 24-hour time point to estimate AUCtau, 
Vss/F and CL/F.  
 
8.3.1. 
Population and profiling PK Analysis 
FAB122 plasma concentration-time data will be subjected to a population PK analysis 
using nonlinear mixed-effects modelling. Blood sampling for FAB122 PK analysis will be 
done in ~90 subjects. Of those ~30 subjects will participate in a PK profiling sampling 
schedule at baseline, week 4 and week 48 and a population PK sampling schedule at 
baseline, ~60 subjects participate in the population PK sampling schedule at baseline, 
week 4 and week 48. Plasma concentrations of all these PK samples may be included in 
the population PK analysis. For this analysis, the data may be combined with results of 
other studies. The aim of the population PK analysis is to develop a compartmental model 
of the FAB122 concentration vs. time profiles, which will provide a good understanding of 
the inter-subject and intra-subject (if possible) variability in the exposure. Available subject 
characteristics (such as demographics, laboratory variables and co-medication) will be 
tested as potential covariates affecting PK parameters. 
 
It is estimated that about 90% of the patients included in this study will concomitantly 
receive riluzole treatment. Results from pharmacokinetic profiling and population PK 
analysis will therefore also be used to study the effect of riluzole on FAB122 
concentrations and vice versa.  Therefore, mean plasma PK parameters of subjects who 
received FAB122 and riluzole will be compared to those of subjects who received riluzole 
and placebo.  
 
In addition, blood sampling for the determination of riluzole concentrations will be done in 
the subjects included in FAB122 PK sampling in baseline and week 4 (~60 subjects). 
Mean plasma Ctrough and Cmax levels of subjects who received riluzole and FAB122 at 


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baseline visit and after 4 weeks of treatment with FAB122, as well as changes in these 
metrics between baseline and week 4 will be compared to those of subjects who received 
riluzole and placebo. If needed and feasible, modelling will be applied to support statistical 
analysis methods.  
 
8.3.2. 
Concentration-Response Relationship Analysis 
The data may be subjected to PK-PD modelling including retrospective assessment of 
dose- and exposure-response correlations. An additional advantage of this approach is 
that it allows the data to be included in further modelling and simulation analyses 
characterizing the effects of FAB122 on disease progression and enabling the 
development of a predictive model framework to support dose justification (including in 
special subpopulations) and aid in the optimization of the design of future clinical studies. 
In case PK-PD modelling will be performed, the details of the PK-PD modelling will be 
described in a separate PK analysis plan. 


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9. 
SAFETY REPORTING 
Adverse events will be recorded (using MEDRA version 24.0) beginning immediately after 
the ICF is signed. The investigator (and/or designee) must document all AEs reported by 
the subject from the signing of the ICF through completion of the final follow-up. Any 
subject who is withdrawn from the study due to an AE shall be followed until the outcome 
of the event is determined, and the investigator will document available follow-up 
information on the subjec
database. 
In this study, an external Data Safety Monitoring Board (DSMB) will be appointed to review 
all safety data generated during the study. For more details see section 13.2.1 
 
9.1. 
Definitions 
9.1.1. 
Adverse Event  
An AE is any unfavorable 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. An AE is any 
symptom, sign, illness, or experience that develops or worsens in severity during the 
course of the study. Adverse events reported after consent but before the first dose of 
study drug are still to be documented by the investigator but will be considered non-
treatment-emergent AEs.  
Intercurrent illnesses or injuries should be regarded as AEs. Abnormal results of laboratory 
tests or diagnostic procedures are considered to be AEs if the abnormality: 
 
Is associated with clinical signs or symptoms 
 
Is considered by the investigator to be of clinical significance 
 
Results in study withdrawal 
 
Fulfills any of the criteria for a SAE, as described in this section 
 
Requires intervention or further evaluation to determine the etiology of the 
abnormality and/or assess the risk to the subject 
 
Requires treatment 
Changes in ALS symptoms will not be documented as AEs unless they are extraordinary 
and/or unexpected. In the same way planned hospitalizations for procedures which are 
symptoms (i.e. PEG procedure; Mechanical ventilation set up) will not be considered as 
SAEs unless they are extraordinary and/or unexpected and/or of they meet other 
seriousness criteria. 


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A treatment-emergent adverse event (TEAE) is defined as an adverse event observed 
after the first dose of study drug. If a subject experiences an event both prior to and after 
starting study drug administration, the event will be considered a TEAE (of the treatment) 
only if it has worsened in severity (i.e., it is reported with a new start date) after study drug 
administration of the specific treatment, and prior to the start of another treatment, if any.  
9.1.2. 
Adverse Reaction  
All noxious and unintended responses to a medicinal product related to any dose should 
be considered an adverse drug reaction. 
 to a medicinal product means that a 
causal relationship between a medicinal product and an adverse event is at least a 
reasonable possibility (e.g., the relationship cannot be ruled out). 
9.1.3. 
Unexpected Adverse Reaction  
An Unexpected Adverse Reaction is defined as an adverse reaction, the nature or severity 
of which is not consistent with the applicable product information. For FAB122, the 
reference safety information is included in the Investi
hure. The reference 
safety information will be reviewed yearly, and the periodicity of the review will be 
harmonized with the reporting period of the Development Safety Update Report. 
 
9.1.4. 
Adverse Event of Special Interest 
AESI (serious or non-serious) is one of scientific and medical concern specific to the 
sponsor
roduct or program, for which ongoing monitoring and rapid communication by 
the investigator to the sponsor can be appropriate. Such an event might warrant further 
investigation in order to characterize and understand it. Depending on the nature of the 
event, rapid communication by the sponsor to other parties (e.g., regulators) might also be 
warranted.  
For this study, any significant abnormalities detected in the NCS or any AE which might 
suggest neuropathy (e.g., numbness) should be considered an AESI and must be 
communicated appropriately to the sponsor and DSMB.  
 
9.2. 
Severity Assessment  
The severity of each AE will be graded by the investigator according to the following 
criteria: 
 
Mild: awareness of sign or symptom, but easily tolerated 
 
Moderate: discomfort sufficient to cause interference with normal activities 
 
Severe: incapacitating, with inability to perform normal activities 
 


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9.3. 
Serious Adverse Event  
A Serious Adverse Event (SAE) is any untoward medical occurrence at any dose that: 
 
Results in death 
 
Is life threatening 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly/birth defect 
 
Is a medically important event that may jeopardize the subject or may require 
medical or surgical intervention to prevent one of the other outcomes listed 
above 
aten
in the definiti
fers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe. Death is an outcome of an 
event. The event that resulted in death should be recorded and reported on the SAE form 
and documented in the eCRF/study database. 
Any hospital admission with at least 1 overnight stay will be considered an inpatient 
hospitalization. An emergency room or urgent care visit without hospital admission will not 
be recorded as an SAE under this criterion, nor will hospitalization for a procedure 
scheduled or planned before signing of informed consent, or elective treatment of a 
preexisting condition that did not worsen from baseline. However, unexpected 
complications and/or prolongation of hospitalization that occur during elective surgery 
should be recorded as adverse events and assessed for seriousness. Admission to the 
hospital for social or situational reasons (ie, no place to stay, live too far away to come for 
hospital visits, respite care) will not be considered inpatient hospitalizations. 
 
9.4. 
Assessment of Causality 
The Investigator must determine the relationship between the administration of 
investigational product and the occurrence of an AE/SAE as Unrelated, Unlikely related, 
Possibly related or Probably related as defined below: 
Unrelated 
or
Unlikely related: 
Means a causal relationship of the adverse event to 
investigational product administration is unlikely or remote, or
other medications, therapeutic interventions, or underlying 
conditions provide a sufficient explanation for the observed
event. 
Event can be readily explained by other factors such as the 


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s underlying medical conditions, concomitant therapy, 
or accident; or there is no temporal relationship between study 
drug or procedure and the event.  
A reasonable possibility or clinical evidence that the study drug 
or procedure caused the event is lacking.  
Possibly 
or 
Probably 
related: 
Means 
there 
is 
a 
reasonable 
possibility 
that 
the 
administration of investigational product caused the adverse 
event. 
easonable possibili
ans there is evidence to 
suggest a causal relationship between the investigational
product and the adverse event. 
The AE follows a reasonable temporal sequence from
administration of the study drug or procedure and at least one 
of the following instances of clinical evidence: 
 
Follows a known or suspected 
response pattern to the study drug or
procedure.  
 
Is confirmed by improvement upon 
stopping the study drug, i.e., after 
single dose (dechallenge).  
There is a reasonable possibility that the study drug or 
procedure caused the event
i.e., there is evidence to suggest 
a causal relationship. In such case, the AE is considered an 
adverse reaction (AR). A suspected AR has a lesser degree of 
certainty about causality than an AR.  
 
Causality should be assessed and provided for every AE/SAE based on 
currently available information. Causality is to be reassessed and provided as 
additional information becomes available. 
 
9.5. 
Reporting Adverse Events 
All AEs (regardless of seriousness or relationship to study drug) including those from the 
time of signing of the ICF through to the follow-up/early withdrawal visit are to be recorded 
in the 
s source documents and on the corresponding page(s) in the database. 
Whenever possible, symptoms, signs, and laboratory abnormalities should be grouped as 
a single syndrome or diagnosis. The investigator should specify the date of onset, severity, 
action taken with respect to study drug, corrective treatment/therapy given, outcome and 
his/her opinion as to whether there is a reasonable possibility that the AE was caused by 
the study drug, according to the definitions noted above. All medications administered to 
treat an AE must be recorded in the subj
source documentation and documented in 
the database. 
 


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9.6. 
Reporting Serious Adverse Events 
Reporting of SAEs will be conducted in accordance with the appropriate regulatory 
guidelines. All SAEs that occur from the time of signing the ICF to the follow-up/early 
withdrawal visit must be reported, whether or not the event is considered associated with 
the study drug. SAEs must be reported, via eCRF, within 24 hours of site awareness. 
Safety reporting information and contact numbers will be provided to the clinical site. 
The investigator must complete the SAE Reporting Form in English and submit it via 
eCRF, 
with 
other 
relevant 
source 
documentation, 
to 
the 
medical 
monitor 
clinicalsafety@ferrer.com and the sponsor  Pharmacovigilance (PV) representative within 
24 hours of awareness of the event to: 
Miriam Abril (Head of PV team, Pharmalex)  
Tel: +34 976 20 44 00 / Fax: +34 976 20 44 02 
Email: clinical.trial@pharmalex.com 
The investigator must also provide with urgent priority (upon receipt of a request) other 
relevant documentation (e.g., copies of diagnostic test results, hospital discharge 
summary, and/or autopsy report) and send this information to the sponsor 
 medical 
monitor.  
All SAEs and medications administered in association with SAEs must be recorded in the 
study database. The investigator must also promptly notify the Independent Ethics 
Committee (IEC) of SAEs, including any follow-up information, in accordance with local 
institutional policy and applicable regulatory requirements. 
The responsible medical monitor at the Sponsor will evaluate causality and expectedness 
of SAEs and in case of a suspected unexpected serious adverse reaction (SUSAR), such 
information will be sent to the sponsor 
PV representative for review.  
 
9.6.1. 
Adverse Event Follow-up 
The investigator should take all appropriate measures to ensure the safety of the subjects, 
including referral to a specialist if indicated. The investigator should follow up on the 
outcome of any AE until the return to normal or stabilization of t
s condition. 
In case of an SAE, the subject must be followed up until clinical recovery is complete and 
laboratory results have returned to normal, or until the condition becomes chronic in 
nature, stabilizes (in the case of persistent impairment), or the patient dies. This implies 
that follow-up may continue after the subject discontinues from the study and that 
additional information may be requested. 
Any SAE brought to the attention of the investigator any time after cessation of study drug 
and considered by him/her to be caused by the study drug with a reasonable possibility, 
should be reported through the SAE reporting process. 


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Within 24 hours of receipt of follow-up information, the Investigator must update the SAE 
form and submit it by email or fax with other relevant source documentation to the 
sponsor
rmacovigilance (PV) representative. 
9.7. 
Expedited Reporting 
Competent authorities will be notified of any AE associated with the use of the study drug 
that is both serious and unexpected, in accordance with the appropriate local regulatory 
guidelines.  
The sponsor 
 PV representative will report all relevant information about SUSARs that 
are fatal or life-threatening as soon as possible to the applicable competent authorities in 
all the countries concerned, and to the Central Ethics Committee concerned (if applicable), 
in any case no later than 7 days after first knowledge by the Sponsor/designee of such a 
case,  followed by a period of maximum of 8 days to complete the initial preliminary report. 
All other SUSARs will be reported within a period of maximum 15 days after the 
sponsor/designee has first knowledge of the SAE. 
The Sponsor/designee will also report any additional expedited safety reports required in 
accordance with the timelines outlined in country-specific legislation. 
The Sponsor/designee will also inform all Investigators as required per local regulation. 
Events associated with placebo will usually not satisfy the criteria for a SUSAR and 
therefore for expedited reporting. 
 
9.8. 
Unblinding  
This study will be performed in a double-blind fashion. The randomization list will not be 
available to the investigator, study staff, subjects, sponsor, or monitor. The investigational 
drug and its matching placebo are indistinguishable and will be packaged in the same way. 
Treatment emergency codes should not be broken except in emergency situations i.e., in 
case of a medical emergency or in the case a SUSAR occurs, the investigator or the 
sponsor s Unblinding Manager, will break the 
s code, through interactive web 
response system (IWRS), and if possible, the sponsor should be contacted before the 
emergency code is opened.  
 
The investigator should only unblind the treatment allocation in the course of a clinical trial 
if this is relevant to the safety of the subject. 
 
As regards the sponsor, when an event may be a SUSAR the blind should be broken by 
the sponsor only for that specific subject. The blind should be maintained for persons 
responsible for the ongoing conduct of the study (such as the management, monitors, 
investigators) and those responsible for data analysis and interpretation of results at the 
conclusion of the study, such as biometrics personnel. Unblinded information should only 
be accessible to those who need to be involved in the safety reporting to national 
competent authorities, Ethics Committees and Data Safety Monitoring Boards (DSMB), or 
persons performing ongoing safety evaluations during the trial. 
 


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It should be noted that unblinding is not necessarily a reason for pat
ation 
and the patient could continue the study treatment and procedures after unblinding. 
Furthermore, pa
 not be considered a systematic reason for unblinding and 
will only be performed if deemed necessary or requested by the IEC and/or CA.  
 
 
The Unblinding Manager contact details are: 
Miriam Abril (Head of PV department, Pharmalex)  
Tel:0034976204400 
Email: clinical.trial@pharmalex.com 
 
9.9. 
Pregnancy  
If a patient becomes pregnant during the study or within the safety follow-up period defined 
in the protocol, the Investigator is to stop dosing with study drug(s) immediately and the 
patient should be withdrawn from the study. Early termination procedures should be 
implemented at that time. 
A pregnancy as such is not an AE, however, it must be reported to the Sponsor within 24 
hours of knowledge of the event completing a Pregnancy Reporting Form. 
Female patients will be instructed to notify the investigator immediately if they become 
pregnant during the study. Male patients will be instructed to notify the investigator 
immediately if their partner becomes pregnant. Pregnant patients will be withdrawn from 
further study treatment. The patients will also be instructed to report pregnancies 
discovered after the last visit, if they believe that conception occurred during their 
participation in the study.  
The pregnant patient or partner will be followed until the end of the pregnancy. Any 
complication during the pregnancy should preferably be reported as an AE. The outcome 
of the pregnancy must be reported on the Pregnancy Reporting Form. Any spontaneous 
abortion, stillbirth, birth defect/congenital anomaly, death, or other serious infant condition 
must be reported and followed up as an SAE. If the pregnancy outcome meets 
seriousness criteria the both the SAE form and pregnancy form should be forwarded. 


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10. 
HEALTH ECONOMICS  
 
ALS is a devastating neurological disease for which there is no cure. The disease results 
in a progressive impairment in activities of daily living, including walking, eating and 
speaking. As a result, there is a significant negative impact on the quality of life of both 
patients and their families with associated considerable economic burden.  
Expenses associated with the disease can be divided into direct and indirect costs. Direct 
costs are those expenses requiring payment, whether by the patient, government or a 
third-party payer (i.e., health insurance and non-profit-organizations), such as those 
associated with formal health care, medications, equipment, home or vehicle adaptations, 
medical devices, mobility aids and services. Direct costs can be further divided into 
healthcare costs and non-healthcare costs. Indirect costs represent opportunity loss, most 
notably lost income due to a patient
illness related absence from work or the voluntary 
caregiver duties taken on by family or friends. Both direct and indirect costs can 
overwhelm the financial resources of patients and their families and should be considered 
when evaluating the overall economic burden of ALS. 
 
In this study, an exploratory cost-utility analysis for treatment with FAB122 will be 
conducted using the following data: 
 
Cost questionnaire: Data provided by a specific questionnaire 
for the direct and indirect costs associated with the disease (see 
annex 5). The consented patients will complete the questionnaire at 
baseline and every 12 weeks up to the end of the study.   
 
eCRF: Some data will be gathered form the 
 dataset 
such as hospitalizations, concomitant medications, and occurrence 
of AEs.  
The following cost parameters will be considered for the cost-utility analysis among study 
groups:  
1. Number of visits classified per specialist and type of visit 
(scheduled vs not scheduled). 
2. Number of hospitalizations related to ALS classified per unit 
of stay and length of stay. 
3. Medication and administration cost (inpatient vs outpatient). 
4. Specialized equipment / Devices cost (i.e. mechanical 
ventilation-invasive or not, artificial nutrition  percutaneous 
endoscopic gastrostomy). 
5. Number of new orthopaedic devices (i.e. wheelchair). 
6. Paramedical 
treatment 
visits 
(i.e. 
physical 
therapy, 
rehabilitation, occupational therapist, speech and language 
therapist, or otherwise specified by the patient). 
7. Formal care (i.e. health professional) and informal care (i.e. 
familiar/friend). 
8. Employment situation.  
9. Occurrence of AEs in each group.   
 


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An ad-hoc cost questionnaire will be completed at Baseline and weeks 12, 24,36, 48, 60 
and 72 via a study App or online questionnaire. 
 
After the end of the study, analysis of each category will be done, then costs will be 
calculated by category and for all categories per patient. Costs would be calculated 
according to local tariffs and according to guidelines for cost analysis in healthcare 
research. All costs will be presented in euros. 
 
 


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11. STATISTICS 
 
11.1. 
Statistical Analysis Plan (SAP) 
The statistical analysis will be carried out in accordance with the principles specified in the 
International Conference on Harmonization (ICH) Topic E9. A detailed Statistical Analysis 
Plan (SAP) will be made available before the un-blinding of the data base.  
The plan for the pharmacokinetic analysis will be fully detailed in the pharmacokinetic 
analysis Plan (PAP) that will be finalized before data base closure. 
All statistical analyses will be performed using SAS Version 9.4 or higher (SAS Institute, 
Cary, NC 27513). 
 
11.2. 
Sample Size Determination  
The sample size estimation is based on the primary endpoint: the change from baseline in 
ALSFRS-R score after 48 weeks. A difference of 3.0 points between FAB122 treatment 
arm and placebo is assumed with a (pooled) standard deviation of 7.5 and an allocation 
ratio of 2:1 (FAB122:Placebo). With these assumptions, a total sample size of 300 (200 
patients on FAB122 and 100 on placebo) is needed to achieve 90% power to detect the 
difference of 3.0 points between the two treatment groups at a 5% (2-sided) level of 
significance.  
The standard deviation of 7.5 is based on recent study results with edaravone using a 
similar trial population as applied in this trial, where standard deviations varied between 
3.4 and 6.9 (The Writing Group on behalf of the Edaravone (MCI-186) ALS 19 Study 
Group. 2017 b, 2017;). The variability in this study can be expected to be somewhat higher 
due to the change of formulation and due to the fact that in this study patient can use 
riluzole as background therapy.  
The hypothesis in this study includes detection of a difference of 3 points in ALSFRS-R at 
week 48 between the two treatment arms. The patients in the placebo group in ALS 
studies typically deteriorate by 1 point per month, so 12 points in 12 months. A difference 
of 3 points therefore corresponds to a 25% difference in deterioration, which is considered 
clinically significant. 
 
11.3. 
Description of Statistical Methods 
11.3.1. 
Analysis Populations  
 
Intent-to-treat (ITT) Analysis Set: The ITT analysis set will consist of all 
randomized subjects. 


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Modified Intent-to-treat (mITT) Analysis Set: The mITT analysis set will consist 
of randomized subjects who receive at least 1 dose of investigational product 
(IP) regardless of any protocol deviation. The treatment arm will be the arm to 
which they were randomized, regardless of what treatment they received. 
 
Safety Analysis Set: The safety analysis set will consist of randomized subjects 
and who receive at least 1 dose of IP. Subjects will be analysed according to 
treatment received. This population will be used for baseline characteristics and 
for safety data summaries 
 
Per-protocol (PP) Analysis Set: The PP analysis set will consist of all mITT 
subjects who do not have major protocol deviations that may affect the primary 
efficacy endpoint. These deviations will be determined before the study 
database will be closed.  
 
The PK Population will consist of all subjects who received study drug and 
provided evaluable PK data.  
Subjects who prematurely discontinue from the study will be included in the safety 
population but may be excluded from the PK analysis population unless sufficient data is 
provided for PK evaluation. Subjects who are included in the PK population but have 
missing data for a particular endpoint will not be included in the analysis for that endpoint. 
Unused data, measurements from excluded subjects, unscheduled collections, or extra 
measurements, will not be included in the summaries, but will be presented in the subject 
listings. 
The primary analysis will be performed on the modified intent-to-treat population (mITTs), 
i.e. all randomized patients who had at least one treatment intake. The analysis of the 
primary endpoint will be also assessed with the PP and ITT populations as per sensitivity 
analysis. 
 
11.3.2. 
Demographics, baseline characteristics 
Demographics and medical history will be collected during Screening and summary of data 
will include date subject signed the informed consent. The subject
 height, weight, 
and baseline characteristics will be summarized by treatment using descriptive statistics, 
while gender, race and other categorical variables will be provided using frequency 
tabulations. Medical history data will be listed. Medical history data will include any prior 
reaction to drugs, use of alcohol and tobacco, history and treatment (if any) of 
cardiovascular, pulmonary, gastrointestinal, hepatic, renal, immunologic, neurologic, or 
psychiatric diseases, and confirmation of relevant inclusion criteria. 
 
11.3.3. 
Subject Disposition  
Subject disposition (analysis population allocation, entered, discontinued, along with 
primary reason for discontinuation) will be summarized using frequency and percent for 


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both treatment and follow-up phase. A summary of subjects screened and enrolled will be 
provided.  
A subject is considered to complete the study if he/she completed the 72 week period OR 
if she/he completed at least 48 week at study completion (i.e. after the last subjects have 
completed the study up to at least 48 week). Withdrawal from treatment or protocol 
deviations will not necessarily preclude from recording the respective follow-up 
information. Efforts will be made to follow all subjects up to 72 or 48 weeks after start of 
treatment (or to study end if that occurs earlier) and collect data as planned. 
 
11.3.4. 
Efficacy Analysis 
11.3.4.1. 
 Hierarchical multiple testing 
A hierarchical multiple testing procedure will be used to evaluate superiority of the primary 
endpoint, followed by the evaluation of superiority of the key secondary endpoints. A fixed 
sequence stepwise multiple testing procedure at the 0.05 level will be performed in the 
following pre-specified hierarchical order: 
I. Primary endpoint: change from baseline ALSFRS-R score after 48 weeks. 
II. Key secondary endpoint: CAFS at 48 weeks 
III. Key secondary endpoint: Survival time (death, tracheostomy or initiation of non-
invasive ventilation for more than 20 hours a day for more than 10 consecutive days) over 
72 weeks 
Each step will be considered confirmatory if all previous steps were successful (i.e. if 
superiority was achieved). If any of the previous steps were unsuccessful, the subsequent 
steps are regarded as exploratory. 
11.3.4.2. 
Primary Efficacy Endpoint  
The primary endpoint is defined as the change from baseline in ALSFRS-R score after 48 
weeks (primary time point). 
For the primary analyses placebo (reference) multiple imputation will applied to impute 
missing data for any subjects (i.e. from both treatment arms) who discontinue treatment 
early, irrespective the reason for drop-out, and for which no data was collected after 
treatment discontinuation.  A total of 20 imputed data sets will be created. 
Linear mixed modelling for repeated measures will be applied on each of the imputed data 
set to estimate the average (lsmeans) treatment effects and the treatment difference 
(estimand) of the change from baseline of ALSFRS-S score at week 48. 
The model will include factors for treatment, time, treatment-by-time interaction, and 
concomitant use of riluzole (yes/no) as fixed effects and baseline ALSFRS-R score and 
slope of disease progression (based on change in ALSFRS-R score) as (random) 
covariates.  
The results of the 20 imputed data sets will be combined to obtain the final estimate of the 
treatment difference with 95% confidence interval an p-value. 
 


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The primary analysis will be performed on the modified intent-to-treat population (mITTs), 
i.e. all randomized patients who had at least one treatment intake 
 
11.3.4.3. 
Secondary Efficacy Endpoints  
Key secondary endpoints 
 
Combined assessment of function and survival (CAFS) at 48 and 72 weeks  
 
Survival time, i.e. time to death, tracheostomy or initiation of non-invasive ventilation 
for more than 20 hours a day for more than 10 consecutive days, over 72 weeks  
 
The CAFS will be used as key secondary endpoint as it combines information on survival 
and ALSFRS-R scores. For this endpoint, ea
ome will be ranked: the worst 
patient outcomes will receive the lowest rank numbers such that a higher CAFS score 
indicates a better outcome. The deceased cases will receive the lowest rank numbers 
followed by the level of decreases in ALSFRS-R scores. Descriptive statistics for this 
endpoint will be made but are difficult to interpret as mean values depend on the size of 
the study. In this study, with 300 patients the CAFS scores range from 1 to 300 with a total 
sum of 28,920 and an overall mean value of 120.5. The difference between treatments will 
be assessed using an ANCOVA model with the same covariates as the primary efficacy 
analysis. A rank-ANOVA will be used as a sensitivity analysis. Subsequent component 
analyses of function and survival will be used to determine which parameter(s) drive the 
overall effect on the CAFS results. The direction and magnitude of the function and 
survival components of the CAFS will inform the interpretation of the results. 
 
e. time to death, tracheostomy or initiation of non-invasive ventilation for more 
than 20 hours a day for more than 10 consecutive days, over 72 weeks Descriptive 
statistics (median and 25% and 75% quartiles with 95% confidence intervals) and Kaplan-
Meier curves will be provided. The difference between oral FAB122 and placebo will be 
assessed using restricted mean survival time (RMST) analysis up to week 48 (and week 
72), controlling for the stratification variables. In addition, also a Cox regression model and 
a stratified log-rank test will also be applied as sensitivity analysis, including factors for 
treatment and stratification variables. 
 
Other secondary endpoints 
The following exploratory secondary endpoints will also be summarized, as applicable: 
Continuous endpoints will be summarized by descriptive statistics (mean, median, 
standard deviation, minimum and maximum), but can also be summarized with frequency 
count and percentage for appropriated categories. These will be defined in the SAP. 
Binary or categorical endpoints will be summarized with frequency counts and 
percentages. Time to event endpoints will be summarized by median values with 95% 
confidence intervals. The statistical method that will be applied for each endpoint will be 
detailed in the SAP.   
 
Change from baseline in ALSFRS-R score after 24 and 72* 
weeks; 
 
The slope of the decrease in ALSFRS-R score over time at 
24, 48 and 72* weeks; 


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Change from baseline in ALSFRS-R score on Bulbar function 
(question 1-3 of the ALSFRS-R) after 24, 48 and 72* weeks; 
 
Change from baseline in ALSFRS-R score on Fine motor 
function (question 4-6 of the ALSFRS-R) after 24, 48 and 72* 
weeks; 
 
Change from baseline in ALSFRS-R score on Gross motor 
function (question 7-9 of the ALSFRS-R) after 24, 48 and 72* 
weeks; 
 
Change from baseline in ALSFRS-R score on Respiratory 
function (question 10-12 of the ALSFRS-R) after 24, 48 and 
72* weeks; 
 
Time to a 3, 6, 9 and 12 points change or death from baseline 
in ALSFRS-R score over 72* weeks;  
 
Proportion of subjects with change from baseline in ALSFRS-
R score at 24, 48 and 72* weeks in categories: categories will 
include change 
between <0 and 
-1, change 
between <-
-2 etc.; 
 
Time to change in clinical staging or death (
staging 
system and MiToS) over 72* weeks; 
 
Overall survival: Proportion of subjects alive (survival rate) 
after 24, 48 and 72* weeks; 
 
Proportion of subjects alive and no tracheostomy, or no 
initiation of non-invasive ventilation for more than 20 hours a 
day for more than 10 consecutive days after 24, 48 and 72* 
weeks; 
 
Change from baseline in slow vital capacity (SVC, liters) at 
24, 48 and 72* weeks;  
 
Change from baseline in the overall mega score for the hand-
held dynamometer (HHD) at 24, 48 and 72* weeks.  
QoL 
 
Change from baseline in the total score on the ALS 
Assessment Questionnaire-40-Item (ALSAQ-40) Form at 24, 
48 and 72* weeks; 
 
Change from baseline in EuroQoL  5 Dimensions-5 Levels 
(EQ-5D-5L) questionnaire score 24, 48 and 72* weeks. 
 
Change from baseline in Health related QoL Visual Analogue 
Scale (VAS) score at 24, 48 and 72* weeks. 
Cognition 
 
Proportion of subje
ALS Specific, ALS Non-Specific, and ECAS (Edinburgh 
Cognitive and behavioural ALS Screen) total score;  
 
Change form baseline for ALS specific and ALS non specific, 
and ECAS total score at 24, 48 and 72* weeks. 
 
Time to 
ALS Non-Specific, and ECAS total score. 
 


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*All secondary endpoints at 72 weeks will be analyzed for the subgroup of patients that 
reach 72 weeks (or IE). 
 
11.3.4.4. 
Additional analysis 
As an additional analysis, the joint assessment of change in functional decline and overall 
mortality using a joint modelling (i.e. shared-parameter) framework over 72 weeks will be 
determined. The statistical model will combine ALSFRS-R score and survival, using a 
linear mixed model and a Cox model as sub models combined into a non-linear mixed 
model using the SAS procedure PROC NLMIXED.  
11.3.5. 
PK Analysis  
Refer to the PAP for full analysis details. Differences between scheduled and actual PK 
sampling times will be listed for all subjects. All statistical summaries and displays will be 
based on scheduled sampling times unless there are significant deviations of actual 
sampling times from scheduled sampling times.  
Concentration-time data and PK parameters will be summarized by treatment group with 
summary statistics at each scheduled time point, where applicable. Summary statistics will 
include: Number (N), mean, standard deviation (SD), coefficient of variation (%CV), 
median, minimum (min), maximum (max). In addition, geometric mean and CV% 
geometric mean will be presented for Cmax and AUClast.  
Each s
s exposure to study drug will be summarized using descriptive statistics, as 
described in detail in the PAP.  
 
11.3.6. 
Safety Analysis 
Safety evaluations will be based on the incidence, severity, and type of AEs and clinically 
significant changes in the sub
physical examination findings, vital signs, and clinical 
laboratory results. Safety variables will be tabulated and presented for all subjects in the 
Safety Population. Data will be summarized by treatment and time. Exposure to study drug 
and reasons for discontinuation of study drug will be tabulated.  
11.3.6.1. 
Physical Examination  
All abnormalities reported by the physical examinations will be listed and tabulated by 
treatment arm. Weight (kilograms), Height, and BMI (calculated) will be summarized by 
treatment and time.  


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11.3.6.2. 
Adverse Events 
All treatment emergent AEs (TEAE) will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA version 23.0) coding dictionary. And all preferred terms 
(PT) will be tabulated by System organ Class (SOC) and additional tabulations will be 
made by severity and drug relatedness. A separate table (or listing will be created for 
serious TEAEs (SAE). 
 
11.3.6.3. 
Concomitant Medication 
All concomitant medications will be summarized by medication class or ATC classification. 
  
11.3.6.4. 
Laboratory Parameters 
Clinical laboratory tests (including re-check values if present) will be listed chronologically. 
 or below the investigator reference range (when 
present), will flag out-of-range results. At each time point, absolute values and change 
from baseline of the hematology and chemistry variables will be summarized by treatment 
and time with n, mean, SD, SEM, median, Min, and Max values. The categorical data of 
the urinalysis will be summarized by treatment and time in frequency tables by variable. 
 
11.3.6.5. 
ECG 
From the 12-lead ECG data, HR, PR, QRS, QT, and QTcF will be reported for each time-
point and summarized using descriptive statistics. Mean (SD) temporal profiles for 12-lead 
ECG (QT, QTcF) will be presented graphically. The frequency (number) of clinically 
significant findings may be reported and summarized. 
 
11.3.6.6. 
Vital Signs 
Vital signs, including blood pressure, pulse rate, respiratory rate, pulse oximetry and 
temperature will be summarized at each time point for each group and treatment, using 
descriptive statistics and will be presented graphically.  
 
11.4. 
Study Estimand and Handling of Missing Data 
To be noted that in this study all efforts will be made to ensure collection of data up to 
week 48 for all randomized subjects and at least for 100 subjects up to week 72 regardless 
of treatment withdrawal or protocol deviations.  
As per the ICH E9(R1) (draft addendum on estimands and sensitivity analysis in clinical 
trials), the plan for the assessment of the Primary endpoint (PEP) is described here after 
using the 4 attributes of the estimand: 


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1. Population: ALS patients fulfilling the selection criteria, as described 
in section 5 of this protocol 
2. Primary endpoint (PEP): Change from baseline in Amyotrophic 
Lateral Sclerosis Functional Rating Scale  Revised (ALSFRS-R) 
score after 48 weeks (see sections 3.2.1 and 11.3.4.1)  
3. Intercurrent events (IE): The assumptions and expectations on the 
relevant intercurrent for this study have been based on the 
publication of a similar trial (Cudkowicz et al., 2013)  
4. Accordingly, the following situations have been identified: 
a. No treatment initiation with the IMP: exclusion from the main 
analysis with the mFAS population. 
b. Treatment discontinuation because of adverse events: 
expected rates 
 (control arm) - 7% (experimental arm).  
c. Treatment discontinuation because of lack of efficacy: 
expected rates 
 (control arm) 10% (experimental arm). 
d. Other treatment related reasons (i.e. due to efficacy or safety 
issues). To this category will apply other treatment related 
reasons that those specif
a priori, 
no potential scenarios are foreseen at the moment of the 
planning.  
e. Rescue medication. No clear prevalence rates can be 
ascertained, but differential higher rates are expected in 
placebo. This situation is likely to be closely related to IE #c. 
f. Non treatment-related reasons, others than specified in this 
list of IE: very low expected rates (i.e. 
). This will also 
situations like patients moving (not because bad prognosis) 
to another location or death for completely treatment-
unrelated reasons. 
g. Related death (or death with unknown reasons): it is 
expected that the rate of death at 52 weeks will be lower 
than the observed in that trial (<17%). A non-substantial but 
lower rate is expected in the experimental arm. 
The primary strategy for handling the IE will consist of the 
strategy applied for all these intercurrent events, i.e., the efficacy observed 
assessment will be used regardless of the intercurrent event. Therefore, overall 
the amount of missing data generated will be a very small. For these cases a 
placebo (copy from reference) multiple imputation will applied. A total of 20 
imputed data sets will be created. 
However, it is noted that the 
strategy will not be applicable 
for terminal intercurrent events such as death (IE #g) or when there are real lost 
to follow-up cases after doing all efforts to retrieve the data (some cases in IE 
#f). For cases with missing data in IE #f, the same general approach as 
described above will be implemented. For related death (IE #g) it is proposed to 
 a conservative scenario using a 95th worst 
percentile combined with multiple to avoid variance artefactual shrinking.  


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h. Population-level summary: the change from baseline in 
ALSFRS-R score after 48 weeks (primary time point), using 
a linear mixed modelling for repeated measures. The model 
will include factors for treatment, time, treatment-by-time 
interaction, and concomitant use of riluzole (yes/no) as fixed 
effects and baseline ALSFRS-R score and slope of disease 
progression (based on change in ALSFRS-R score) as 
(random) covariates (see section 11.3.4.1)).  
 
To evaluate the impact of missing data and of the handling methods, a number of 
sensitivity analyses will be performed for the primary endpoint:  
 
As treatment multiple imputation: For any subject with missing 
values, the estimates for the missing assessments will be based on the 
actual treatment group of that subject. One hundred imputations will be 
performed. 
 Tipping-point analysis: The tipping point is defined as the difference in 
the change from baseline in ALSFRS-R score at week 48 between 
FAB122 and placebo at which the study conclusion (i.e. the statistical 
significance) changes. To find this tipping point a systematic shift will be 
applied to the (as-treated) imputed values (i.e. a MNAR adjustments in 
the multiple imputation process) in the FAB122 treatment arm. These 
shifts will cover a large enough range, in steps of 0.2 to find the value 
for which the analyses shows a change of in significance of the primary 
hypothesis test, the tipping point. For each shift the primary analysis 
method will be repeated on the 20 multiple imputed data sets. In case 
such a tipping point has an unrealistic value, this will increase the 
confidence of the primary analysis. 
 
Hybrid approach: With the hybrid approach the missing weeks for 
subjects who discontinued due to AE or lack of efficacy will be imputed 
using placebo-based pattern imputation under the MNAR assumption. . 
All other discontinuation/missing will be imputed using multiple 
imputation by treatment group using a multivariate step-wise approach 
using a fully conditional specification (FCS) regression method (Rubin, 
1987). Missing baseline values if any, will be imputed using age and 
time since diagnose. Subsequent visits will be imputed using data of all 
previous weeks in a stepwise fashion. One hundred imputations will be 
performed. 
 
Completer analysis: This analysis includes only subjects who have 
completed the study up to week 48. 
 
Per Protocol and ITT Analysis: This analysis will include subjects 
from the PP and the ITT analysis sets. 
 
11.5. 
Health Economics Analysis 
Descriptive statistical methods will be used to evaluate health economics parameters.  A 
more detailed approach will be described in the SAP. 


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12. 
DATA MANAGEMENT 
12.1. 
Case Report Form 
The investigator or designee will record all data collected in the eCRF provided for that 
purpose. The site will be suitably trained on the use of the eCRF and appropriate site 
personnel will be provided electronic signatures. 
Completed eCRFs will be submitted according to the instructions of the CRO and reviewed 
by the CRO to determine their acceptability. If necessary, data correction requests will be 
generated for resolution by the study site. The investigator or designee will make 
necessary eCRF corrections. 
All site entries will be made in a secured web site and the Principal Investigator (PI) will 
review the record for completeness. Upon completion of the review, including review of 
any corrections, the PI will sign electronically in the signature page of the eCRF. 
 
12.2. 
Source Data 
Patient confidentiality is strictly held in trust by the participating investigators, research 
staff, and the sponsoring institution and their agents. This confidentiality is extended to 
cover testing of biological samples and genetic tests in addition to the clinical information 
relating to patients. Authorized representatives of the sponsoring institution may inspect all 
documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic or hospital) and pharmacy records for the patients 
in this study. The clinical study site will permit access to such records. Any data, 
specimens, forms, reports, and other records that leave the site will be identified only by a 
patient identification number to maintain confidentiality. 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented and the study data to be subsequently verified. These 
documents include Investigato
y Files and original patient clinical source 
documents g
data. 
The investigator will ensure the site master files are maintained, including the study 
protocol and its amendments, IRB/IEC and regulatory approvals with associated 
correspondence, informed consents, study drug records, staff curriculum vitae, all 
correspondence, and other appropriate documents. 
Patient clinical source documents may include, but are not limited to, patient hospital/clinic 
records, physicia
notes, appointment books, laboratory reports, ECGs, 
radiographs, pathology and special assessment reports, and consultant letters. The 
investigator must assure that all original source documents are available to support 
monitoring activities. 


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12.2.1. 
Remote Source Data Verification 
Remote source data verification (SDV) may be applied during the public health crisis 
related to COVID-19, following the recommendation on Guidance on the Management of 
clinical trials during the Covid-19 Pandemic . Remote SDV will focus on the quality control 
of critical data such as primary efficacy data and important safety data. Important 
secondary efficacy data may be monitored simultaneously if these are captured on the 
same documents. The data to be checked via remote SDV will be documented in the 
monitoring plan. 
When the situation allows and the COVID-19 outbreak has passed, full (re-)monitoring will 
be performed on-site.  
Remote SDV will be performed through:  
 Sharing pseudonymised copies of trial related source documents with the monitor; 
 Video review of medical records with clinical site team support, without sending any copy 
to the monitor and without the monitor recording images during the review; 
 Direct, suitably controlled remote access to the subjects  electronic medical records. 
During remote SDV adequate data protection will be ensured, including data security and 
protection of personal data even if pseudonymised. The 
institution and the sponsor will be jointly responsible as controllers for ensuring information 
is safeguarded. The following controls will be implemented:   
 Site staff will inform each subject and ensure that they do not object to the remote review 
of their records for trial purposes. This process will be documented in 
records.  
 Remote SDV of subject
location within the European Union (EU)/European Economic Area (EEA). In case the data 
are processed outside the European Union (EU)/European Economic Area (EEA), it will be 
contractually ensured that a level of data protection will be applied that is essentially 
equivalent to EU data protection legislation. 
 Performance of remote SDV will only occur in locations that prevent viewing by any 
unauthorised person, through a secure internet connection and on a computer 
appropriately protected against unauthorised access to the data.  
 Monitors will sign a written confidentiality agreement committing to securely destroy any 
copy of redacted documents, whether paper or electronic, as soon as they have been 
used for SDV and committing not to make any copy (or recording in the case of video 
access) of any non-pseudonymised document. 


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If the agreed remote SDV process involves redaction by the site staff (pseudonymisation) 
of source records: 
- 
The monitor 
records required for SDV; 
- 
Site staff will create copies of the requeste
rds, redact the copies 
(i.e., pseudonymise and mask any unnecessary private information unrelated to the 
trial), identify them with the subject identification code, have a second person 
perform and document a quality control to ensure that all identifying information 
has been redacted and is no longer readable, and make the pseudonymised 
copies available to the monitor using a secure mechanism. The redacted copies 
will be kept in the investigator's site master file with records of their communication 
to the monitor; 
- 
The monitor will access the records securely, complete the monitoring task, 
securely destroy any copy made locally. 
- 
Once on-site monitoring visits are again feasible, the monitor will verify that the 
provided pseudonymised (coded) data are indeed data related to the subject with 
the provided code. 
If the agreed remote SDV process involves a video review of records: 
- 
It will be assured that the quality of the video adequately enables reading; 
- 
No videoconferencing solutions will be used where data may be captured on third 
country servers;  
- 
The transmission of the data will be adequately protected against unauthorised 
third party access. 
If the agreed remote SDV process involves the site providing the monitor remote access to 
the site electronic medical record (EMR) system: 
- 
The monitor will be provided with a secure, read-only access to the EMR system, 
including all modules relevant for review. This access will be restricted to the 
records of only those patients who participate in the trial and who did not object 
against remote access to their medical records. Access rights will be revoked once 
remote SDV tasks have been completed; 
- 
A list of the monitors to whom remote access has been granted will be maintained; 
- 
The EMR system will have an audit trail and be able to log information on who 
accessed data and when; 
- 
Remote access to the EMR will only be possible using a two-factor authentication. 


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Measures will be taken to prohibit making local copies of subjects' health records. Any 
automatically created temporary files on the monit
en reviewing subject 
data, will be securely deleted immediately after each SDV session. 
12.3. 
Data Processing 
Julius Clinical will be responsible for data management. A Data Management Plan (DMP) 
will be prepared in order to define all activities in the data collection, validation and 
cleaning process. The detailed DMP will be based on the protocol, work scope, contract, 
analysis plans, data-flows, database, data cleaning procedures, other supporting 
documents, and data management standards and practices. 
Programmed data validations will be run to check for database completeness and 
consistency, and queries will be generated upon data entry or via review by a Clinical Data 
Manager after entry. The sites will respond to the data queries in a timely manner. 
At the end of the study, database will be locked and an expert Statistician will check the 
database and extract all data for statistical analyses. 
 
12.4. 
Central Data Monitoring  
Central monitoring of data will be conducted in order to review data for completeness, 
systemic and/or significant errors, query resolution and protocol deviations, to identify 
outliers and review for plausibility and completeness, to analyse site characteristics and 
performance metrics and to identify high-risk sites for targeted on-site monitoring.  
 
 


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13. 
QUALITY ASSURANCE PROCEDURES 
The CRO and the Sponsor has implemented a quality assurance system to ensure that the 
study is performed, and the data are generated, documented (recorded), and reported in 
compliance with GCP as defined in ICH E6 (R2) guidelines and the applicable regulatory 
requirement(s). 
The Sponsor and the CRO SOPs have been created to ensure that clinical studies are 
conducted in compliance with regulatory requirements and GCP. Quality control will be 
applied to each stage of data handling to ensure that data are accurate, reliable and 
processed correctly. 
Authorised representatives of CRO, the Sponsor and/or a Competent Authority and/or the 
EC may visit the centre to perform audits/inspections, including source data verification. 
 
13.1. 
Monitoring  
The monitor will visit the study site on a regular basis to ensure that the study is conducted 
and documented in accordance with this protocol, applicable SOPs, ICH GCP guidelines, 
regulatory requirements and any study specific document. 
Monitoring visits will be conducted to confirm, but not limited to, that: 
 
The investigational team is adhering to this study protocol 
 
Informed consent has been obtained for all participants 
 
AEs have been collected and reported 
 
Data are being accurately recorded in the CRFs 
 
Investigational products have been stored correctly and that drug accountability 
has been performed 
 
Facilities are and remain acceptable 
 
The Investigator and the site receive sufficient information and support 
Moreover, during monitoring visits the data recorded in the CRFs, source documents and 
other study-related records will be compared against each other in order to ensure 
accurate data that reflects the actual existence of the patient in the study i.e. source data 
verification. 
When a protocol deviation is detected, the investigator will contact the sponsor to discuss 
the measures to be adopted, and if required, the expedited notification to the IEC and CAs.  
 
 


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13.2. 
Study committees 
13.2.1. 
Data Safety Monitoring Committee 
An independent data safety monitoring board (DSMB) will oversee the safety aspects of 
this study. The DSMB will include a neurologist with expertise in ALS, neurophysiologist 
with expertise in ALS, and a biostatistician. The DSMB will periodically examine the safety 
data emerging from the study and provide its recommendations to the sponsor who will 
then pass these to IEC and CA, if applicable. The roles and responsibilities of the DSMB, 
their operational procedures, and method of communication with the sponsor will be 
described in a separate DSMB charter. Members of DSMB will not be investigators in the 
study nor will they have any conflict of interest with the 
 investigators. 
 
The study may be prematurely suspended or terminated if, in the opinion of the DSMB, 
there is reasonable cause. Written notification, documenting the reason for study 
suspension or termination, will be provided by the suspending or terminating party. The 
pertinent regulatory authorities will be informed according to the national regulations. 
 
Circumstances that may warrant termination include: 
 Determination of unexpected, significant, or unacceptable risk 
to patients. 
 Insufficient adherence to protocol requirement 
 Data that are not sufficiently complete and/or evaluable. 
 Plans to modify, suspend, or discontinue the development of 
the FAB122. 
If the study is prematurely terminated or suspended, the CRO will promptly inform the site-
specific PIs, their institutions, IEC, and the regulatory authority of the termination or 
suspension and the reason(s) for the termination or suspension.  
 
The schedule of the DSMB meetings and the safety aspects which will be analised will be 
detailed in the DSMB charter.  
 
 
 
 
 


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14. 
ETHICS AND REGULATORY CONSIDERATIONS  
14.1. 
Approvals  
This protocol and any amendments will be submitted to and approved in writing by a 
properly constituted EC and by the Competent Authorities, in accordance with the 
International Conference on Harmonization (ICH) guidelines and local legal requirements, 
for formal approval of the study. 
14.2. 
Ethical Conduct of the Study 
The study will be conducted in compliance with the protocol, regulatory requirements, data 
protection laws, good clinical practice (GCP) and the ethical principles of the Declaration of 
Helsinki as adopted by the World Medical Assembly, 1964 (and subsequent revisions). 
Before the first subject is enrolled in the study, all ethical, regulatory, and legal 
requirements must be met. 
An investigator participating in this study is required to maintain complete and accurate 
study documentation in compliance with current GCP standards and all applicable local 
regulations related to the conduct of a clinical study 
14.3. 
Participant Information and Confidentiality  
All subjects will receive written and verbal information regarding the study prior to any 
study related procedures. This information will emphasise that participation in the study is 
voluntary and that the subject may withdraw from the study at any time and for any reason. 
All subjects will be given the opportunity to ask questions about the study and will be given 
sufficient time to decide whether to participate in the study. 
Before any study-related procedures, the informed consent will be signed and dated by the 
subject (or their legally acceptable representative and/or witness, as applicable) and by the 
Investigator who gave each subject the verbal and written information. 
The consent includes information that data will be recorded, collected processed and may 
be transferred (to EU and non-EU countries). The data will not identify any persons taking 
part in the study, in accordance with the applicable legislation. 
A copy of the subject information including the signed consent form must be provided to 
the subject. 


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15. 
FUNDING AND INSURANCE  
Each subject is insured against study-related injuries in accordance with applicable laws 
and regulations and the ICH E6 (R2) GCP guideline. 
According to the ICH Good Clinical Practice guidelines, the sponsor has contracted an 
insurance policy which covers the liabilities of the sponsor/principal investigator, the 
research staff and the sites where the clinical trial is conducted, in the event of any 
damage or injury to the health of the patient resulting from this research, conducted strictly 
in accordance with both the scientific protocol and applicable law and professional 
standards, during the conduct of the study and for one year following termination of the 
study treatment, unless otherwise proven.  
 
Ferrer Internacional, S.A.is the sponsor of the study and is funding the study 
 


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16. 
PUBLICATION POLICY  
All publications and presentations must be based upon the clinical study protocol and 
report.  
All information supplied by the sponsor in connection with this study will remain the sole 
property of the sponsor and is to be considered confidential information. No confidential 
information will be disclosed to others without obtaining prior written consent from the 
sponsor and will not be used except in the performance of this study. 
The Sponsor will be the owner of all CRFs, data analysis and reports derived from this 
study. All the information obtained as a result of the study will be considered confidential 
until its analysis and review by the Sponsor and Researchers has been completed. 
The Sponsor undertakes to make the results of the study public. The Sponsor may choose 
to publish or present data from this study.  
The researchers will agree that the first publication on the results should be a joint 
publication that includes all the centers participating in the study. However, if a joint 
manuscript has not been submitted for publication before 12 months after the end of the 
study in all participating centers, the investigator is free to publish separately, subject to 
the other requirements listed in this section. 
If an Investigator wishes to publish results from this clinical study, written permission to 
publish must be obtained from the sponsor in advance. As some of the information 
regarding the investigational product and development activities at the sponsor may be of 
a strictly confidential nature, the sponsor must first review any publication manuscript prior 
to their submission to journals, meetings or conferences. The researcher will provide 
manuscripts, abstracts or the full text of any other planned disclosure (poster presentation, 
guest speaker reading or guest speaker written presentation, etc.) to the Sponsor at least 
30 days before they are submitted for publication or disclosed by another way. If any overt 
action is required to protect intellectual property rights, the investigator will delay the 
disclosure for a period not exceeding 60 additional days. The investigator will remove, 
upon request, any previously undisclosed confidential information (other than the study 
results itself) prior to disclosure. 
If an Investigator is offered first authorship, he/she will be asked to comment and approve 
the publication. The sponsor has the right to use the results for registration and internal 
presentation and for promotion. 
For all publications related to the study, the institution will comply with all recognized 
ethical standards related to the publications and their authorship, including Section II - 
«Ethical Considerations in the Conduct and Reporting of Research » of the Uniform 
Requirements 
for 
Manuscripts 
Submitted 
to 
Biomedical 
Journals, 
http://www.icmje.org/index. html # authorship, established by the International Committee 
of Medical Journal Editors. 
 


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17. 
ARCHIVING  
Clinical Study Documentation including but not limited to all study related correspondence, 
patient's notes, consent forms, Data Protection Consent Forms, drug accountability 
documentation, need to be retained by the Investigator at each site for the period of time 
according to applicable regulatory requirements. Clinical Study Documentation is to be 
retained in a secure place and treated as confidential material. 
Clinical Study Documentation has to be retained according to International Conference on 
Harmonization (ICH) guidelines. 
 Investigator shall inform the Sponsor about the allocation of the Clinical Study 
Documentation and in case of having any problem with regard to retention of the Clinical 
Study Documentation. The Documentation may not be destructed by the Investigator until 
receipt of the Spons
s approval in writing. 
All data will be stored in a purpose-built data base for the study.  
 


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19. 
ANNEXES  
Annex 1, El Escorial Criteria 
 
Categories of clinical diagnostic certainty on clinical criteria alone  
Definite ALS 
UMN signs and LMN signs in 3 body regions  
Probable ALS  
UMN signs and LMN signs in 2 regions with at least some UMN signs rostral to LMN 
signs  
Probable ALS  Laboratory supported  
UMN signs in 1 or more regions and LMN signs defined by EMG in at least 2 regions  
Possible ALS  
UMN signs and LMN signs in 1 region (together), or  
UMN signs in 2 or more regions  
UMN and LMN signs in 2 regions with no UMN signs rostral to LMN signs  
 
UMN signs: clonus, Babinski sign, absent abdominal skin reflexes, hypertonia, loss of 
dexterity.  
LMN signs: atrophy, weakness. If only fasciculation: search with EMG for active 
denervation.  
Regions reflect neuronal pools: bulbar, cervical, thoracic and lumbosacral.  
 
Principles (from the Airlie House criteria) 
The diagnosis of amyotrophic lateral sclerosis [ALS] requires 
the presence of 
 
evidence 
of 
lower 
motor 
neuron 
(LMN) 
degeneration 
by 
clinical, 
electrophysiological or neuropathological examination 
 
evidence of upper motor neuron (UMN) degeneration by clinical examination; 
and 
 
progressive spread of symptoms or signs within a region or to other regions, 
as determined by history, physical examination, or electrophysiological tests 
the absence of 
 
electrophysiological or pathological evidence of other disease processes that 
might explain the signs of LMN and/or UMN degeneration, and 
 
neuroimaging evidence of other disease processes that might explain the 
observed clinical and electrophysiological signs 


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Diagnostic categories 
Clinically definite ALS is defined by clinical or electrophysiological evidence by the 
presence of LMN as well as UMN signs in the bulbar region and at least two spinal regions 
or the presence of LMN and UMN signs in three spinal regions 
Clinically probable ALS is defined on clinical or electrophysiological evidence by LMN and 
UMN signs in at least two regions with some UMN signs necessarily rostral to (above) the 
LMN signs 
Clinically possible ALS is defined when clinical or electrophysiological signs of UMN and 
LMN dysfunction are found in only one region; or UMN signs are found alone in two or 
more regions; or LMN signs are found rostral to UMN signs. Neuroimaging and clinical 
laboratory studies will have been performed and other diagnoses must have been
excluded. 
 


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Annex 2, ALS Functional Rating Scale  revised (ALSFRS-R) 
Bulbar function 
Gross Motor Function 
1. Speech  
4 Normal speech processes  
3 Detectable speech disturbance  
2 Intelligible with repeating  
1Speech combined with non-vocal communication  
0 Loss of useful speech  
7. Turning in bed and adjusting bed clothes 
4 Normal function 
3 Somewhat slow and clumsy, but no help needed  
2 Can turn alone or adjust sheets, but with great 
difficulty  
1 Can initiate, but not turn or adjust sheets alone  
0 Helpless  
2. Salivation  
8. Walking  
4 Normal  
4 Normal  
3 Early ambulation difficulties  
2 Walks with assistance  
1 Non-ambulatory functional movement only  
0 No purposeful leg movement  
3 Slight but definite excess of saliva in mouth; may have 
night time drooling  
2 Moderately excessive saliva; may have minimal 
drooling  
1 Marked excess of saliva with some drooling  
0 Marked drooling  
3. Swallowing 
9. Climbing stairs 
4 Normal eating habits  
4 Normal  
3 Early eating problems-occasional choking  
3 Slow  
2 Dietary consistency changes  
2 Mild unsteadiness or fatigue  
1 Needs supplemental tube feeding  
1 Needs assistance  
0 NPO  
0 Cannot do  
Fine Motor Function  
Respiratory Function  
4. Handwriting  
10. Dyspnea  
4 Normal  
3 Slow or sloppy; all words are legible  
2 Not all words are legible  
1 No words are legible, but can still grip a pen 
0 Unable to grip pen  
4 None  
3 Occurs when walking  
2 Occurs with one or more of the following: eating, 
bathing, dressing   
1 Occurs at rest:difficulty breathing when either sitting or 
lying 
0 Significant difficulty, considering using mechanical 
respiratory support  
5a. Cutting Food and handling utensils (without 
gastrostomy) 
11. Orthopnea  
4 Normal  
3 Somewhat slow and clumsy, but no help needed  
2 Can cut most foods (>50%), although slow and 
clumsy; some help needed  
1 Food must be cut by someone, but can still feed 
slowly  
0 Needs to be fed  
4 None  
3 Some difficulty sleeping at night due to shortness of
breath, 
does not routinely use more than two pillows  
2 Needs extra pillow in order to sleep (more than two)  
1 Can only sleep sitting up 
0 Unable to sleep without mechanical assistance  
5b. Cutting Food and handling utensils (with 
gastrostomy) 
12. Respiratory insufficiency 
4 Normal 
3 Clumsy but able to perform all manipulations 
independently 
2 Some help needed with closures and fasteners 
1 Provides minimal assistance to caregiver 
0 Unable to perform any aspect of task 
4 None
3 Intermittent use of BiPAP 
2 Continuous use of BiPAP 
1 Continuous use of BiPAP during day and night 
0 Invasive mechanical ventilation by intubation or 
tracheostomy 
6. Dressing and hygiene 
 
 
4 Normal function 
 
3 Independent; cancomplete self-care with effort or 
decreased efficiency 
 


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2 Intermittent assistance or substitute methods 
 
1 Needs attendant for self-care 
 
0 Total dependence 
 
 
Annex 3, Treatment options for ALS 
Treatment 
Administration 
Indication 
Riluzole 
50 mg BID 
ALS 
Multidisciplinary care 
Every three monthly visits 
All symptoms of ALS 
Non-invasive ventilation 
Night time and during symptoms as needed  
Respiratory insufficiency 
Gastrostomy 
Daily calorie supplements 
Dyshagia and malnutrition
Dextromethorphan/quinidine 
20 mg/10 mg BID 
Pseudobulbar affect 
Amitriptyline 
12.5 - 125 mg OD 
  
SSRI antidepressants 
10 - 100 mg OD 
  
Mirtazapine 
15 - 30 mg OD 
Anxiety 
Buspirone 
10 mg TID 
  
Diazepam 
2 - 10 mg TID 
  
Lorazepam 
0.5  -2 mg TID 
  
Diazepam 
2 - 10 mg tid 
  
Phenytoin 
100 - 300 mg OD 
Cramps 
Vitamin E 
400 IU TID 
  
Mirtazapine 
15 - 30 mg OD 
  
SSRI antidepressants 
20 - 100 mg OD 
Depression 
Tricyclic antidepressants 
12.5 - 150 mg OD 
  
Venlafaxine 
37.5 - 75 mg OD 
  
Amantadine 
100 mg BID 
  
Buproprion SR 
150 - 450 mg OD 
  
Fluoxetine 
20 - 80 mg OD 
Fatigue 
Pemoline 
18.75 - 93.75 mg OD 
  
Pyridostigmine 
60 mg TID 
  
Venlafaxine 
75 - 225 mg OD 
  
Amitriptyline 
12,5-125 mg qhs 
  
Atropine sulphate 
0.4 mg q4-6h 1-2 / Ophthalmic drops SL q4-6h 
  
Diphenhydramine 
25  -50 mg TID 
Sialorrhea 
Hyoscyamine sulphate 
0.125 - 0.25 mg q4h 
  
Scopolamine 
transdermal 
patch 
0.5 mg q72h 
  
Baclofen 
10 - 60 mg TID 
  
Benzodiazepines 
2  -10 mg TID 
Spasticity 
Dantrolene 
25 - 100 mg TID 
  
Tizanidine 
2  -8 mg TID 
  
 
 


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Protocol Version 4.0 
 
 
24/05/2023 
 
 
 
Confidential  
 
                                      Page 113 of 127 
 
 
Annex 4, COVID-19 impact mitigation Plan  
The details of potential COVID-19 impact on the 
rocedures and activities will be provided in 
the Risk Management Plan of the study and other applicable study plans (i.e: monitoring plan).  
Screening and Baseline assessment will always be done in clinic by the study physician and nurse. 
Every effort should be made to perform these visits, depending on local regulations. The 
contingency would only be applicable for the randomized/ongoing subjects. 
 
In case of sanitary restrictions, the following assessment might be performed at patie
s home by 
the site study team personnel or by a validated Home Nursing services provider, provided by the 
sponsor. 
 
COVID-19 
situation 
 
Assessment 
to be 
performed 
by nurse at
patien
home
V2 
D28
W4 
±3D
V3 
D84 
W12
±3D 
V4 
D182
W24 
±7D 
V5 
D252
W36 
7D 
V6 
D336 
W48 
7D 
V7 
D420 
W60 
7D 
V8 
D504
W72 
OR 
EoT 
Weight 
YES
 
 
X 
 
X 
 
X 
Height 
YES 
 
 
 
 
 
 
 
Vital Signs  
YES
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
YES 
(optional) 
 
 
X 
 
X 
 
X 
(S)AE 
monitoring 
YES 
X 
X 
X 
X 
X 
X 
X 
Laboratory  
procedures 
 
 
 
 
 
 
 
 
Chemistry/ 
Haematology 
YES 
X 
X 
X 
X 
X 
X 
X 
Vitamin B6 
monitoring 
YES 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
YES 
X 
X 
X 
X 
X 
X 
X 
-hCG 
YES
 
 
 
 
 
 
 
Urine 
Pregnancy Test 
YES 
 
X 
X 
X 
X 
X 
X 
ALS evaluation 
procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SVC  
YES 
(reduced) 
 
 
X 
 
X 
 
X 
ALSAQ-40  
YES 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
EQ-5D-5L  
YES 
 
X 
X 
X 
X 
X 
X 
 
 
 
 


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Protocol Version 4.0 
 
 
24/05/2023 
 
 
 
Confidential  
 
                                      Page 114 of 127 
 
 
The following assessments will be done by phone by the site study team personnel: 
 
COVID-19 
situation 
 
 
V2 
D28
W4 
±3D
V3 
D84 
W12
±3D 
V4 
D182
W24 
±7D 
V5 
D252 
W36 
7D 
V6 
D336 
W48 
7D 
V7 
D420 
W60 
7D 
V8 
D504
W72 
OR 
EoT 
ALS evaluation 
procedures 
 
 
 
 
 
 
 
 
ALSFRS-R  
YES 
X 
X 
X 
X 
X 
X 
X 
ECAS   
YES  
 
 
X 
 
X 
 
X 
 
For safety reasons, every effort should be made in order to perform NCS assessment in 
clinic, depending on local regulations. The sponsor will provide all the necessary measures, 
according to local regulations, to facilitate the performance of this testing. 
 
 


Ferrer Internacional, S.A. 
 
FAB122-CT-2001 
 
 
Protocol Version 4.0 
 
 
24/05/2023 
 
 
 
Confidential  
 
                                      Page 115 of 127 
 
Annex 5: Cost Questionnaire  
 
Disclaimer (original English version): The following cost questionnaire is the original version which 
was included in the clinical trial protocol for FAB-122. The sections included in the questionnaire are 
the following: 
- 
Clinical visits & hospitalisations 
- 
Paramedical treatment visits 
- 
Specialized equipment & devices 
- 
Formal care 
- 
Informal care 
 
Disclaimer (translated versions from English): The following cost questionnaire is a straightforward 
translation of the original English version. The authors want to note that the translational process 
did not use forward and backward translation techniques as this was not the main goal of the 
protocol and beyond the scope of the study. The English version should therefore be taken as a 
useful starting point for a more in-depth adaptation. This should also take then into count the 
peculiarities of the service provision in the country in which the questionnaire is to be used. 
 
Presentation 
 
We would like to find out what extra money you and your family had to spend due to your disease. 
Your answers are important because they will give professionals who make decisions about patient 
treatment within the National Health Service an idea of how much it costs you to use health 
services. 
We hope you will be able to find the time to complete this questionnaire. It would be very helpful if 
you could reply every 12 weeks. If you have difficulty with answering any of the questions, please 
give the best answer you can. 
The information that you provide will be completely confidential. Your answers will be combined with 
the answers of other patients involved in the study and reported in such a way that it will not identify 
you or influence your pattern of treatment. 
 
If you would like any further information about this study, please contact (name) at (location) on 
(telephone number). (Investigator`s contact details)  
 
 
 
 


Ferrer Internacional, S.A. 
 
FAB122-CT-2001 
 
 
Protocol Version 4.0 
 
 
24/05/2023 
 
 
 
Confidential  
 
                                      Page 116 of 127 
 
 
Instructions for filling out the cost diary  
 
Please fill out this diary before visits 1, 3, 4, 5, 6, 7 and 8 (every 12 weeks). 
While filling out, please keep in mind that for this study, only expenditures and benefits related to 
your disease (ALS, motor neurone disease) are of importance. Should you, for example, have 
visited a doctor due influenza and would have been prescribed medication, please do not enter this 
into the cost book.  
Please go over the following pages step-by-step, unhurriedly. Even if our cost diary may seem bulky 
to you on a first glance, you will not need much time for answering the questions. It is very unlikely, 
that you will be able to answer all questions.  
Please, answer each question. If No  applies, you may directly move on to the next question. If 
 please also fill out the associated table.  
There you may put several statements one below the other, e.g. if you took several types of drugs.  
Sometimes you will be asked for multiple statements about an issue. For example, if you accepted 
help from relatives, please enter the accrued time. Should there have also been expenses, please 
enter that into the table as well.  
Example:  
Help 
(Kind of help) 
Overall expenditure of time and costs per week 
Help from relatives, friends or 
acquaintances 
Hours:  
     
4 
 
20 
 
In this way, please go through every question, one after the other. Keep in mind, that sometimes 
instead of number of contacts or costs, you will be asked for different statements.  
You will find several answers to questions which may arise while filling out the cost diary.  
Once you complete the diary, data will be sent to the study database for further analysis. 
We assure you, that we will handle your data confidentially.  
 
 
 
 
 
 
 
 


Ferrer Internacional, S.A. 
 
FAB122-CT-2001 
 
 
Protocol Version 4.0 
 
 
24/05/2023 
 
 
 
Confidential  
 
                                      Page 117 of 127 
 
Please note:  
e related to your disease (ALS, motor neurone disease).  
Please answer every question. If you are not sure or cannot remember the exact details, please 
give the best answer you can. If you have a problem in answering any question, please write that 
problem beside the question. 
Please note that the following questions apply to the period of the last 12 weeks. 
12 weeks ago 
8 weeks ago 
Last 4 weeks 
Day 1. 
Day 1. 
Day 1. 
Day 2. 
Day 2. 
Day 2. 
Day 3. 
Day 3. 
Day 3. 
 
 
 
Day 29. 
Day 29. 
Day 29. 
Day 30. 
Day 30. 
Day 30. 
Day 31. 
Day 31. 
Day 31. 
 
Your participation by periodically responding to this Questionnaire will be of invaluable help to better 
understand the reality of patients affected by ALS and thus help making better decisions regarding 
your treatment and care. 
 
We deeply appreciate your collaboration and support. 
 
Sincerely, 
ADORE Trial Group 
 
 
 
 
 
 
 
 
 
 
 
 
 


Ferrer Internacional, S.A. 
 
FAB122-CT-2001 
 
 
Protocol Version 4.0 
 
 
24/05/2023 
 
 
 
Confidential  
 
                                      Page 118 of 127 
 
Quarterly questionnaire (From ____.____.____ to ____.____.____) (DD-MM-YYYY) 
 
CLINICAL VISITS & HOSPITALISATIONS 
1. During the last 12 weeks, due to your disease, have you 
had to see a doctor (e.g. general practitioner, neurologist, 
etc)? (also telephone calls, apart from the ones for the 
clinical study) or to make an appointment for a home visit? 
 
 
 
 
 
 
 
 
If you have checked 
the subsequent table 
A. If you have 
lease 
move on to question 
number 2. 
1 
2 
 
Table A
 
 
GP and specialist 
visits (specialization) 
Number of 
contacts during the last 12 
weeks 
What was done? 
How often? 
General practitioner 
 
_____________________ 
 
 Blood test 
 Prescription filled 
 Telephone call 
 Computer 
tomography 
 Magnetic 
resonance imaging 
 _______________ 
 
_________
_________
_________
_________ 
Nurse 
_____________________ 
 
 Blood test 
 Prescription filled 
 Telephone call 
 Computer 
tomography 
 Magnetic 
resonance imaging 
 _______________ 
 
_________
_________
_________
_________ 
Neurologist 
_____________________ 
 
 Blood test 
 Prescription filled 
 Telephone call 
 Computer 
tomography 
 Magnetic 
resonance imaging 
 _______________ 
 
_________
_________
_________
_________ 
Psychologist  
_____________________ 
 
 Counselling 
 Prescription filled 
 Telephone call 
_________
_________
_________


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Protocol Version 4.0 
 
 
24/05/2023 
 
 
 
Confidential  
 
                                      Page 119 of 127 
 Computer 
tomography 
 Magnetic 
resonance imaging 
 _______________ 
 
_________ 
Ambulatory care 
in hospital 
_____________________ 
 
 Blood test 
 Prescription filled 
 Telephone call 
 Computer 
tomography 
 Magnetic 
resonance imaging 
 _______________ 
 
_________
_________
_________
_________ 
Emergency 
department 
_____________________ 
 
 Blood test 
 Prescription filled 
 Telephone call 
 Computer 
tomography 
 Magnetic 
resonance imaging 
 _______________ 
 
_________
_________
_________
_________ 
Other (please specify) 
__________________ 
_____________________ 
 
 Blood test 
 Prescription filled 
 Telephone call 
 Computer 
tomography 
 Magnetic 
resonance imaging 
 _______________ 
 
_________
_________
_________
_________ 
Other (please specify) 
__________________ 
_____________________ 
 
 Blood test 
 Prescription filled 
 Telephone call 
 Computer 
tomography 
 Magnetic 
resonance imaging 
 _______________ 
 
_________
_________
_________
_________ 
 
2. During the last 12 weeks, due to your disease, were you in 
hospital or a rehabilitation clinic? 
 
 
 
If you have checked 
 please complete 
the subsequent table 
B. If you have 
move on to question 
1 
2 
 


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FAB122-CT-2001 
 
 
Protocol Version 4.0 
 
 
24/05/2023 
 
 
 
Confidential  
 
                                      Page 120 of 127 
number 3. 
 
Table B. Please enter the number of activities.  
 
Hospital/ 
Rehabilitation spells 
Date from  until 
(DD-MM-YY) 
Date from  until 
(DD-MM-YY) 
Date from  until 
(DD-MM-YY) 
Hospital spells 
From ___.___.___ 
Until ___.___.___ 
 
From ___.___.___ 
Until ___.___.___ 
From ___.___.___ 
Until ___.___.___ 
Centre (& Town) 
 
 
 
 
Reason for 
admittance 
 Surgery 
 Other 
________________
_ 
 
 Surgery 
 Other 
________________
_ 
 
 Surgery 
 Other 
________________
_ 
 
Unit of hospital stay 
(e.g. neurology, 
intensive care unit) 
 
 
 
 
Procedure (e.g. 
percutaneous 
endoscopic 
gastrostomy) 
 
 
 
 
Rehabilitation stays 
From ___.___.___ 
Until ___.___.___ 
 
From ___.___.___ 
Until ___.___.___ 
From ___.___.___ 
Until ___.___.___ 
 
 
PARAMEDICAL TREATMENT VISITS 
3. During the last 12 weeks, due to your disease, have you 
regularly been active for prevention or relief of your disease, 
e.g. by going to rehabilitation groups, alternative practitioner 
or going to physical therapy? 
If so, which type of treatments did you make use of? (e.g. 
exercise therapy). 
 
 
 
If you have checked 
 
the subsequent table 
C. If you have 
move on to question 
number 4. 
1 
2 
 
Table C. Please enter the number of activities.  
 
Activities 
Treatments  
(please give a short description) 
Number of 
treatments 
Cost of all 
 
Physical therapy 
 
1. __________________________
 
2. __________________________
 
__________
_________ 
Rehabilitation 
1. __________________________
__________
_________ 


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FAB122-CT-2001 
 
 
Protocol Version 4.0 
 
 
24/05/2023 
 
 
 
Confidential  
 
                                      Page 121 of 127 
Occupational therapist 
 
2. __________________________
 
Speech and language 
therapist 
1. __________________________
 
2. __________________________
 
__________
_________ 
Gym 
 
1. __________________________
 
2. __________________________
 
__________
_________ 
Alternative practitioner 
1. __________________________
 
2. __________________________
 
__________
_________ 
Social worker 
1. __________________________
 
2. __________________________
 
__________
_________ 
Homeopath/ 
Naturopath 
1. __________________________
 
2. __________________________
 
__________
_________ 
Acupuncturist 
 
1. __________________________
 
2. __________________________
 
__________
_________ 
Other (please specify) 
__________________ 
1. __________________________
 
2. __________________________
 
__________
_________ 
 
4. During the last 12 weeks, did you attend events/courses, 
which were directly related to your disease or your emotional 
situation e.g., information evenings, adult 
evening classes or similar? 
 
 
 
If you have checked 
the subsequent table 
D. If you have 
ease 
move on to question 
number 5. 
 
1 
2 
 
Table D. Please enter the number of activities.  
 
Event/Course 
Cost/period (DD-MM-YY) 
 
______
 
From ___.___.___ 
Until ___.___.___ 
 
 
______
 


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Confidential  
 
                                      Page 122 of 127 
From ___.___.___ 
Until ___.___.___ 
 
 
_____
 
From ___.___.___ 
Until ___.___.___ 
 
 
_____
 
From ___.___.___ 
Until ___.___.___ 
 
 
 
SPECIALIZED EQUIPMENT & DEVICES 
5. During the last 12 weeks, did you, e.g. in connection with 
your disease buy yourself medical aids, e.g. wheelchair? Did 
you even have done modification measures (e.g. build in a 
stairlift)? Or did you have further expenditures?  
 
 
 
If you have checked 
the subsequent table 
E. If you have 
move on to question 
number 6. 
 
1 
2 
 
Table E. Please enter the names and description.  
If you used any equipment but did not pay for it please specify who arranged this for you (e.g. 
hospital, social services, voluntary sector etc.) 
P
. 
If you had any adaptations done to your home but did not pay for it please specify who 
provided this for you 
 
 
Medical Aids 
(examples) 
Dida you have to 
pay anything? 
Provided by 
 
 Wheelchair 
Special bedding 
Special mattresses 
 Dehumidifier 
Medical lift 
 Other 
____________________________
_ 
 Other 
____________________________
_ 
 
 
 
 
 
 
 
 
 
 
__________
__________
__________
__________
__________
__________
__________ 
 
__________ 
__________
__________
__________
__________
__________ 
__________
__________ 
 
__________ 
 Books 
 Videos 
 Other 
____________________________
_ 
 
 
 
 
__________
__________
__________ 
__________
__________
__________ 


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FAB122-CT-2001 
 
 
Protocol Version 4.0 
 
 
24/05/2023 
 
 
 
Confidential  
 
                                      Page 123 of 127 
 Private medical care 
 
 
N/A 
__________ 
 Stairlift 
 Ramp 
 Changes to the bathroom/shower 
 Car modifications 
 Other home modifications 
____________________________
_ 
 
 Other car modifications 
____________________________
_ 
 
 Other modifications 
____________________________
_ 
 
 Change residence (own) 
 Change residence (new house) 
 Change residence (relat
house) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
__________
__________
__________
__________ 
 
__________ 
 
 
__________ 
 
 
N/A 
 
N/A 
N/A 
 
N/A 
 
__________
__________
__________
__________ 
 
__________ 
 
 
__________ 
 
 
N/A 
 
N/A 
__________ 
 
N/A 
 
 
 
6. In the following table you may enter all expenses, which you had due to your disease, which 
have not been accounted for so far. 
 
 
Further expenses, which have not 
been accounted for so far (name) 
 
___________________________________
_ 
 
___________________________________
_ 
___________________________________
_ 
 
___________________________________
_ 
___________________________________
_ 
 
___________________________________
_ 
___________________________________
_ 
 
___________________________________
_ 
 
 
FORMAL CARE 
7. During the last 12 weeks, due to your disease, did you 
have to hire professional services for homecare?  
 
 
 
 
If you have checked 
ete 
the subsequent table 
F. If you have 
1 
2 


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FAB122-CT-2001 
 
 
Protocol Version 4.0 
 
 
24/05/2023 
 
 
 
Confidential  
 
                                      Page 124 of 127 
move on to question 
number 8. 
 
Table F. Please enter the names and description. 
 
Kind of service 
Number of days per 
week 
Number of hours per 
day 
Wage per hour 
Day homecare 
 
 
 
Night homecare 
 
 
 
Full time homecare 
 
 
 
Housekeeping 
 
 
 
 
 
INFORMAL CARE 
8. During the last 12 weeks, due to your disease, did you 
have to accept help from relatives, friends or from 
professional services for work, which you usually carry out by 
yourself? For example; for housekeeping or for shopping. 
 
 
 
 
If you have checked 
the subsequent table 
G. If you have 
move on to question 
number 9. 
 
1 
2 
Table G. Please insert here the average time in hours of help and the average cost of help per 
week. In case you do not know the cost please insert a question mark. 
 
Kind of help 
Average duration 
per week 
Average cost per 
week 
Help from relatives, 
friends or acquaintances 
___________ h 
 
Home help 
 
___________ h 
 
Professional aids (e.g. 
Red cross) 
___________ h 
 
 
 
___________ h 
 
 
 
___________ h 
 
 
 
___________ h 
 
 
 
EMPLOYMENT SITUATION 
 
9. Are you currently employed? 
 
 
 
1 
2 
 


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                                      Page 125 of 127 
If you have checked 
move on 
to question number 10. 
If you have 
move on to question 
number 13. 
 
10. If you returned to work in the last 12 weeks, is it the same 
employment that you had before your illness? 
 
 
 
1 
2 
 
11. During the last 12 weeks, have you been on sick leave 
due to your disease (at home or in hospital)? 
 
 
 
If you have checked 
the subsequent table 
H. If you have 
please 
move to question 
number 12. 
 
1 
2 
 
Table H. Please complete the information.  
 
Time you were on 
sick leave 
Date from  until 
(DD-MM-YY) 
Date from  until 
(DD-MM-YY) 
Date from  until 
(DD-MM-YY) 
Medically certified 
absence from work 
From ___.___.___ 
Until ___.___.___ 
 
From ___.___.___ 
Until ___.___.___ 
From ___.___.___ 
Until ___.___.___ 
Reduced hours of 
work for gradual 
reintegration 
From ___.___.___ 
Until ___.___.___ 
From ___.___.___ 
Until ___.___.___ 
From ___.___.___ 
Until ___.___.___ 
 
 
12. During the last 12 weeks, have you seen a doctor or 
therapist during your working hours? 
 
 
 
If you have checked 
the subsequent table I. 
If you have 
 
move on to question 
number 14. 
 
1 
2 
 
Table I. Please complete the information. 
 
Number of working hours, which 
Overall loss of working time 


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FAB122-CT-2001 
 
 
Protocol Version 4.0 
 
 
24/05/2023 
 
 
 
Confidential  
 
                                      Page 126 of 127 
you spent to see a doctor or therapist 
General practitioner 
 
____________________ h 
 
Nurse 
 
____________________ h 
Neurologist 
 
____________________ h 
Psychologist  
 
____________________ h 
Ambulatory care 
in hospital 
____________________ h 
Emergency department 
 
____________________ h 
Other (please specify) 
__________________ 
 
____________________ h 
Other (please specify) 
__________________ 
 
____________________ h 
 
 
13. Which category describes best your status? 
Retired
 
Retired on medical 
grounds
 
Unemployed
 
Student
 
 
1 
 
2 
3 
4 
 
14. During last 12 weeks have you suffered from income loss 
due to your illness? 
 
 
 
1 
2 
 
15. Do you have any health-related insurance policy/plan? 
 
 
 
 
If you have checked 
question 16. If you 
you 
have finished the 
questionnaire. 
 
1 
2 
16. Is your health-related insurance policy/plan public or 
private? 
Public
 
Private
 
 
1 
2 
 
17. Please tell us what it covers by ticking one or more of the 
Health care costs (i.e. 
1 


Ferrer Internacional, S.A. 
 
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Protocol Version 4.0 
 
 
24/05/2023 
 
 
 
Confidential  
 
                                      Page 127 of 127 
following options: 
medical, visits) 
Medication 
Income protection 
Any other (please 
specify) 
____________ 
__________________ 
 
 
2 
3 
 
4 
 
 
 
Frequently asked questions  
I have had the flu and have therefore visited my doctor, who certified me unfit for work. Do I have to enter the 
drugs, the doctor visit, the time of sick leave and the time in which I was not able to carry out my housework?  
No, please only enter things, which are directly related to your  disease. We do not want to include all 
treatments and expenses, you had due to other diseases.  
I cannot remember the exact information on the package of my drug. What should I enter?  
Please try to answer as exactly as possible. If you do not have the package of the drug for copying the name 
from it anymore, please enter the type of drug, e.g. beta blocker.  
I have not received the bill for my alternative practitioner visit yet. What should I do now?  
Please enter a question mark. Unless, from experience, you are quite sure how much the bill will be. In that 
case, please enter your estimate.  
Due to my ALS disease, I have had expenses, which I do not know where to put, because none of the tables 
seems to really apply to them. Where should I enter these expenses?  
Please enter all expenses, treatments and applications which you cannot clearly assign to any question, into 
the questionnaire. Please do not leave out anything that is related to your  disease. 

SAP_001.pdf: 
Ferrer Internacional, S.A.
Protocol ID: FAB 122-CT-2001
Clinical Study Reference: ADORE 
 
07 December 2023 
 
TMP-516A Statistical Analysis Plan Template
Version 2.0, Document Number:  iDD-000074  
Page 1 of  42 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
(Short) study title:  
ADORE (ALS Daily ORal Edaravone) study
Name of the sponsor:  
Ferrer Internacional, S.A. 
Protocol identification:
FAB 122-CT-2001
Version and date of SAP:
Updated final 4.0, 07 December 2023
Confidentiality statement
This Ferrer document is confidential. The information within this document may not be reproduced or otherwise 
disseminated without approval of Ferrer Internacional, S.A. 


Ferrer Internacional, S.A.
Protocol ID: FAB 122-CT-2001
Clinical Study Reference: ADORE 
 
07 December 2023 
 
TMP-516A Statistical Analysis Plan Template
Version 2.0, Document Number:  iDD-000074  
Page 2 of  42 
 
 
VERSION HISTORY
 
Version
Date
History list 
0.1 
15 Nov 2021 
Draft version for sponsor review. 
0.2 
22 Feb 2022
2nd draft version for review 
0.3 
13 May 2022
Pre-final version 
0.4 
09 Dec 2022 
Updated pre-final version
1.0
19 Dec 2022
Final, including changes in updated protocol version
1.1
01 Jun 2023
Updated version for review. Due to update protocol, 
updated CRF, additional derivations, and additional 
analyses.
2.0 
22 Jun 2023
Final for signature 
2.1 
11 Sept 2023 
Updated version for review. Use of new SAP template. 
Derivations added for NCS, added handling of mis-
randomized patients not being treated (for ITT), removal 
of CTC-AE summaries, adding mapping of unscheduled 
visits. 
3.0 
14 Sept 2023 
Final for signature 
4.0 
07 Dec 2023 
Final for signature, changes for primary endpoint analysis
and some additional clarification for the PP/ITT sensitivity 
analysis.
 


Ferrer Internacional, S.A.
Protocol ID: FAB 122-CT-2001
Clinical Study Reference: ADORE
07 December 2023
TMP-516A Statistical Analysis Plan Template
Version 2.0, Document Number: iDD-000074                                                                                  Page 3 of  42
APPROVAL PAGE
I hereby declare that I have read and reviewed this document. To the best of my knowledge, the 
content accurately states the intended analyses and output to be provided. This document is 
intended for an agreement on analysis and reporting details between the sponsor and Author! et 
al B.V.
Lead Statistician:
Name, title, company:  C. Baljé-Volkers, MSc, Certara
______________________
Signature
______________
Date
Sponsor contact:
Name, title, company:  Núria Albareda López, BSc, Ferrer Internacional
______________________
Signature
______________
Date
C. Baljé-Volkers, MSc, Certara
Núria Albareda López, BSc, Ferrer Internacional


Ferrer Internacional, S.A.
Protocol ID: FAB 122-CT-2001
Clinical Study Reference: ADORE 
 
07 December 2023 
 
TMP-516A Statistical Analysis Plan Template
Version 2.0, Document Number:  iDD-000074  
Page 4 of  42 
 
 
TABLE OF CONTENTS
Version history................................................................................................................................ 2
Approval page................................................................................................................................. 3
Table of contents............................................................................................................................. 4
List of abbreviations ....................................................................................................................... 6
1
General .................................................................................................................................. 9
2
Study Information .................................................................................................................. 9
2.1
Study Objective(s) ..................................................................................................... 9
2.2
Design of the Study ................................................................................................... 9
2.3 
Study medication ..................................................................................................... 10
2.4 
Sample size .............................................................................................................. 10
2.5 
Study assessments.................................................................................................... 11
3
Subjects for Analysis........................................................................................................... 13
3.1
Analysis populations................................................................................................ 13
3.1.1
Intent-to-treat (ITT) Analysis Set..................................................................... 13
3.1.2
Modified Intent-to-treat (mITT) Analysis Set .................................................. 13
3.1.3
Per protocol (PP) Analysis Set ......................................................................... 13
3.1.4
Safety (SAF) population ................................................................................... 13
3.1.5
Pharmacokinetics (PK) population ................................................................... 13
3.2 
Protocol deviations .................................................................................................. 13
3.3 
Blind Data Review Meeting .................................................................................... 13
4
Study endpoints ................................................................................................................... 14
4.1 
Hierarchical multiple testing ................................................................................... 14
4.2
Primary endpoint ..................................................................................................... 14
4.3 
Secondary endpoint(s) ............................................................................................. 14
4.4 
Exploratory endpoint(s) ........................................................................................... 15
4.5 
Safety endpoint(s).................................................................................................... 16
5
Statistical Analysis .............................................................................................................. 16
5.1 
General considerations ............................................................................................ 16
5.2 
Missing or excluded data or intercurrent events ...................................................... 17
5.3 
Mapping of unscheduled or early termination visits ............................................... 20
5.4 
Interim analysis........................................................................................................ 20
5.5 
Baseline characteristics ............................................................................................ 21
5.5.1
Inclusion/exclusion criteria............................................................................... 21
5.5.2
Demographics................................................................................................... 21


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5.5.3
Baseline characteristics..................................................................................... 21
5.5.4
Disposition ........................................................................................................ 21
5.5.5
Medical history................................................................................................. 21
5.5.6
ALS history ...................................................................................................... 22
5.5.7
Other screening data......................................................................................... 22
5.6 
Statistical analysis primary and secondary endpoints ............................................. 22
5.6.1
Primary analysis ............................................................................................... 22
5.6.2
Secondary analysis ........................................................................................... 23
5.6.3
Additional analysis ........................................................................................... 27
5.6.4
Exploratory analysis ......................................................................................... 27
5.7 
Safety and tolerability evaluation............................................................................ 28
5.7.1
Adverse events.................................................................................................. 28
5.7.2
Clinical laboratory............................................................................................ 29
5.7.3
Vital Signs ........................................................................................................ 30
5.7.4
ECG .................................................................................................................. 30
5.7.5
Prior and concomitant medication.................................................................... 30
5.7.6
Physical examination........................................................................................ 31
5.7.7
Nerve conduction study (NCS) ........................................................................ 31
5.7.8
Other examinations ........................................................................................... 31
5.8 
Scheduled visits, Dosing and Treatment Compliance ............................................. 31
5.8.1
Visit dates ......................................................................................................... 31
5.8.2
Dosing and treatment compliance .................................................................... 31
6
Changes from protocol and other relevant remarks ............................................................ 32
7
COVID-19 details................................................................................................................ 32
8
Data receipt.......................................................................................................................... 32
9
Technical details.................................................................................................................. 33
9.1 
Programming conventions ....................................................................................... 33
9.2 
Coding ..................................................................................................................... 37
9.3 
Analysis software .................................................................................................... 37
9.4 
Presentation of tables, listings, graphs..................................................................... 37
10
Tables, listings, graphs ........................................................................................................ 37
10.1 
General ..................................................................................................................... 37
10.2 
In-text tables and graphs.......................................................................................... 38
10.3 
End-of-text tables and graphs.................................................................................. 38
10.4 
Listings .................................................................................................................... 41


Ferrer Internacional, S.A.
Protocol ID: FAB 122-CT-2001
Clinical Study Reference: ADORE 
 
07 December 2023 
 
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LIST OF ABBREVIATIONS
8-OHdG 
8-hydroxyguanosine
ADaM
Analysis Data Model 
 
AE
Adverse Event
 
AESI
Adverse Event of Special Interest  
 
ALS  
Amyotrophic Lateral Sclerosis
ALSFRS-R  
ALS Functional Rating Score – revised
ALSAQ-40 
ALS Assessment questionnaire 40 
 
ALT
Alanine transaminase 
 
ANCOVA
Analysis of Covariance 
 
aPTT
Activated partial thromboplastin time 
AR(1)
First order Autoregression
AST
Aspartate transaminase
 
BDRM 
Blind Data Review Meeting 
 
BMI
Body Mass Index 
 
BUN
Blood urea nitrogen  
 
CAFS
Combined Assessment of Function and Survival 
 
CDISC 
Clinical Data Interchange Standards Consortium 
 
CI
Confidence Interval
 
CK
Creatinine kinase
CS
Compound Symmetry
 
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
 
CTL
Clinical Trial Lead
 
DM
Data Manager 
 
DSMB
Data Safety Monitoring Board  
 
ECAS 
Edinburgh Cognitive and behavioural ALS Screen 
 
ECG
Electrocardiogram 
 
eGFR
Estimated Glomerular Filtration Rate
 
EQ-5D-5L 
EuroQoL – 5 Dimensions – 5 Levels
 
FCS
Fully Conditional Specification
 
GGT 
Gamma-glutamyl transpeptidase 
 
GLM
Generalized Linear Model
 


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Protocol ID: FAB 122-CT-2001
Clinical Study Reference: ADORE 
 
07 December 2023 
 
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HCT
Haematocrit 
 
HGB
Haemoglobin 
 
HHD
Hand-held dynamometer
HR
Heart Rate
ICE
Intercurrent Event
 
ICH
Internation Conference on Harmonisation 
 
LDH 
Lactate dehydrogenase 
 
ITT
Intent-To-Treat
MAR
Missing At Random
MCAR 
Missing Completely At Random
 
MedDRA
Medical Dictionary for Regulatory Activities 
 
MiToS
Milano-Torino staging system
 
mITT
Modified Intent-To-Treat
MMRM
Mixed Model for Repeated Measures
NCS 
Nerve Conduction Study 
 
NFL
Neurofilament Light 
 
P75ECD
Extracellular domain of neurotrophin receptor p75 
 
PDF
Portable Document Format 
 
PEG
Percutaneous Endoscopic Gastrostomy
 
PK
Pharmacokinetic(s)
 
PM 
Project Manager 
 
pMI
Placebo Multiple Imputation
PNG
Portable Network Graphics 
 
PP
Per Protocol
PT 
Preferred Term 
 
PTT
Prothrombin Time 
 
QoL
Quality of Life  
 
Q1
Lower quartile
 
Q3
Upper quartile
 
RBC
Red Blood Cells
 
RMST
Restricted Mean Survival Time 
 
RTF
Rich Text Format
 
SAE
Serious Adverse Event
 
SAF
Safety analysis population
 
SAP
Statistical Analysis Plan
 


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Protocol ID: FAB 122-CT-2001
Clinical Study Reference: ADORE 
 
07 December 2023 
 
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SAS
Statistical Analysis Software
 
SD
Standard Deviation 
 
SDTM
Study Data Tabulation Model
SOC
System Organ Class
SVC 
Slow Vital Capacity
 
TEAE
Treatment Emergent Adverse Event
 
VAS
Visual Analogue Scale
 
WBC
White blood cell 
WHO
World Health Organisation
 


Ferrer Internacional, S.A.
Protocol ID: FAB 122-CT-2001
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1
GENERAL
This Statistical Analysis Plan (SAP) describes in detail the methods and presentation of the data 
analyses which will be conducted for study FAB 122-CT-2001 by Certara. Any references to PK 
analyses in this SAP are under responsibility of the involved PK scientist from the client, and 
analysis details are therefore not specified in this SAP. This plan is written in agreement with 
protocol version 4.0, dated 24 May 2023, and blank CRF version 3.0, dated 21 June 2023, the 
relevant GCP-ICH guidelines and sponsor requirements. 
Since a separate DSMB-SAP will be developed for the DSMB analyses, this full study-SAP is to 
be finalized prior to database lock and unblinding for study FAB 122-CT-2001. 
The protocol and the (annotated) CRF are the primary source for this document, together with 
the relevant GCP-ICH guidelines. Furthermore, sponsor requirements for reporting will be taken 
into account. Additional changes or updates of those documents or requirements may result in a 
new version of the reporting/statistical analysis plan. 
2
STUDY INFORMATION 
2.1 
Study Objective(s) 
The primary objective of this study is to assess the effect of treatment with 100 mg of FAB122 
on disease progression in patients with ALS.
The secondary objectives of this study are as follows:
 To evaluate the effect of treatment with FAB122 on survival
 To evaluate the safety and tolerability of FAB122 
 To evaluate the effect of treatment with FAB122 on quality of life (QoL) 
 To evaluate the effect of treatment with FAB122 on cognitive functioning 
 To evaluate the pharmacokinetics (PK) of FAB122. 
The exploratory objectives of this study are as follows:
To evaluate the PK interaction of FAB122 and riluzole
To explore and identify biomarkers that inform the statistical understanding of ALS 
and/or their therapeutic treatments.
2.2
Design of the Study
This is a multicenter, multinational, double-blind, randomized (2:1), placebo-controlled Phase III 
study to investigate the efficacy and safety of 100 mg FAB122 (former TW001) once daily as oral 
formulation in approximately 300 ALS patients (200 FAB122, 100 Placebo).
Patients will receive double-blind treatment up to a maximum of 72 weeks. The study is planned 
to continue until the last randomized patient has reached 48 weeks of follow-up (or has reached 
an intercurrent event) AND the first one third (100) of the randomized patients has reached 72 
weeks of follow-up (or has reached an intercurrent event). 


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Protocol ID: FAB 122-CT-2001
Clinical Study Reference: ADORE
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2.3
Study medication
Patients will receive 100 mg FAB122 or matched placebo for 48 or 72 weeks. Riluzole (100 
mg/day or less) may be used as background (add-on) therapy, where patients should be on stable
doses at the start of the study and for at least 30 days before the initiation of study drug.
2.4
Sample size
The sample size estimation is based on the primary endpoint: the change from baseline in 
ALSFRS-R score after 48 weeks. A difference of 3.0 points between FAB122 treatment arm and 
placebo is assumed with a (pooled) standard deviation of 7.5 and an allocation ratio of 2:1 
(FAB122:Placebo). With these assumptions, a total sample size of 300 (200 patients on FAB122 
and 100 on placebo) is needed to achieve 90% power to detect the difference of 3.0 points between 
the two treatment groups at a 5% (2-sided) level of significance. 
For further details on the background of these assumptions, refer to the protocol.


Ferrer Internacional, S.A.
Protocol ID: FAB 122-CT-2001
Clinical Study Reference: ADORE
07 December 2023
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2.5
Study assessments


Ferrer Internacional, S.A.
Protocol ID: FAB 122-CT-2001
Clinical Study Reference: ADORE
07 December 2023
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Ferrer Internacional, S.A.
Protocol ID: FAB 122-CT-2001
Clinical Study Reference: ADORE 
 
07 December 2023 
 
TMP-516A Statistical Analysis Plan Template
Version 2.0, Document Number:  iDD-000074  
Page 13 of  42 
 
 
3
SUBJECTS FOR ANALYSIS
3.1
Analysis populations
3.1.1
Intent-to-treat (ITT) Analysis Set 
The ITT analysis set consists of all randomized patients. The ITT population will be used for the 
analysis of efficacy variables, and statistical analysis will be done “as randomized”.
3.1.2 
Modified Intent-to-treat (mITT) Analysis Set 
The mITT analysis set includes all patients who were randomized for this study and received at 
least 1 dose of investigational product regardless of any protocol deviation. The mITT 
population will be used for the analysis of efficacy variables, and statistical analysis will be done 
“as randomized”. The mITT is considered the primary analysis population. 
3.1.3 
Per protocol (PP) Analysis Set 
The PP population includes a subset of the mITT population. Patients with major protocol 
deviations that might impact the primary endpoint will be excluded from this population. These 
deviations will be determined before database lock and unblinding. The PP population will be 
used in the analysis of efficacy variables.
3.1.4 
Safety (SAF) population 
The SAF population includes all randomized patients who have received at least one dose of the 
investigational drug, irrespective of satisfying other criteria. This population will be used for the 
analysis of safety and tolerability, and statistical analysis will be done “as treated”. 
3.1.5
Pharmacokinetics (PK) population 
The PK population includes all patients who received the investigational drug and provided 
evaluable PK data. The PK population will be used for the analysis of the PK assessments only. 
3.2 
Protocol deviations 
Major protocol deviators will be identified to the extent possible by individuals responsible for 
data collection/compliance, and its analysis and interpretation. In the course of the study, all 
protocol deviations will be collected, and during the Blind Data Review Meeting (see section 
3.3) the major and minor deviations and the consequences regarding the analysis 
populations/statistical analysis will be assessed. Any patients or data values excluded from 
analysis will be identified, along with their reason for exclusion. In general, outlier data will not 
be excluded. A dataset will be created and used for tabular/listing presentations. 
3.3 
Blind Data Review Meeting 
The patients will be classified during the (Blinded) Data Review Meeting (BDRM) to the 
analysis populations using the protocol deviations. Invitees to this meeting are the Sponsor 
Medical Representative (CTL or delegate), the Sponsor Project Manager (PM), the Sponsor PK 
scientist, Julius Clinical PM, Julius Clinical Data Manager (DM) and the Certara lead 
statistician, but more roles can be invited if considered necessary. Input to this meeting will be 
supplied by the involved Data Management Department or the responsible PM at least one week 
in advance of the meeting: a blinded list of all protocol deviations (including missing and outlier 
data), with specific detailing and description regarding the deviation, preferably in excel. 


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This meeting will be held in a blinded manner. The goal of this meeting is to reach consensus on 
minor and major protocol deviations. In case of a major deviation impacting the primary or 
secondary endpoints, the specific patient will be excluded from the PP population, either 
completely or from a specific time point onwards. The meeting must be held prior to database 
lock and unblinding.  
The decisions taken during this meeting will be documented by the PM (or a delegate as agreed) 
and sent for review to all parties involved as soon as possible after the meeting, but before 
database lock. If all parties involved agree, then the document is finalized, signed and stored 
before database lock by the PM. 
 
4 
STUDY ENDPOINTS 
4.1 
Hierarchical multiple testing 
A hierarchical multiple testing procedure will be used to evaluate superiority of the primary 
endpoint, followed by the evaluation of superiority of the key secondary endpoints. A fixed 
sequence stepwise multiple testing procedure at the 0.05 level will be performed in the following 
pre-specified hierarchical order:  
I. 
Primary endpoint: change from baseline ALSFRS-R score after 48 weeks.
II. 
Key secondary endpoint: CAFS at 48 weeks
III. 
Key secondary endpoint: Survival time (death, tracheostomy or initiation of non-invasive 
ventilation for more than 20 hours a day for more than 10 consecutive days) over 72 
weeks  
Each step will be considered confirmatory if all previous steps were successful (i.e. if superiority 
was achieved). If any of the previous steps were unsuccessful, the subsequent steps are regarded 
as exploratory. 
4.2 
Primary endpoint 
The primary endpoint is the change from baseline in Amyotrophic Lateral Sclerosis Functional 
Rating Scale – Revised (ALSFRS-R) score after 48 weeks. 
4.3 
Secondary endpoint(s) 
All secondary endpoints will be analyzed at 48 weeks including all patients, and additionally at 
72 weeks for the subset of patients who reach 72 weeks (or ICE) as a subgroup analysis. The 
exception will be the planned main analysis for the key secondary endpoint of survival time (see 
below). This analysis will include data up to 48 weeks for all patients and up to 72 weeks for the 
subgroup of patients with planned extended follow-up. Analyses conducted at earlier time-points 
are informative but of lower relevance. 
Key secondary endpoints 
 Combined assessment of function and survival (CAFS) at 48 and 72 weeks; 
 Survival time, i.e. time to death, tracheostomy or initiation of non-invasive ventilation for 
more than 20 hours a day for more than 10 consecutive days, over 72 weeks. 
Efficacy 


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Change from baseline in ALSFRS-R score after 24, and 72 weeks;
The slope of the decrease in ALSFRS-R score over time at 24, 48 and 72 weeks;
Change from baseline in ALSFRS-R score after 24, 48 and 72 weeks on: 
o
Bulbar function (question 1-3 of the ALSFRS-R);
o
Fine motor function (question 4-6 of the ALSFRS-R)
o
Gross motor function (question 7-9 of the ALSFRS-R)
o
Respiratory function (question 10-12 of the ALSFRS-R) 
Time to a 3, 6, 9 and 12 points change from baseline in ALSFRS-R score;
Proportion of subjects with change from baseline in ALSFRS-R score at 24, 48 and 72 
-1, change 
-
-2 etc.; 
Time to change in staging of disease progression (King’s staging system and MiToS) or 
death over 72 weeks; 
Overall survival: Proportion of subjects alive (survival rate) after 24, 48 and 72 weeks;
Proportion of subjects alive and no tracheostomy1, or no initiation of non-invasive 
ventilation for more than 20 hours a day for more than 10 consecutive days after 24, 48, 
and 72 weeks; 
Change from baseline in slow vital capacity (SVC, liters) at 24, 48 and 72 weeks;
Change from baseline in the overall mega score for the hand-held dynamometer (HHD) 
at 24, 48 and 72 weeks.
QoL 
 Change from baseline in the total score on the ALS Assessment Questionnaire-40-Item 
(ALSAQ-40) Form at 24, 48 and 72 weeks;
 Change from baseline in EuroQoL – 5 Dimensions-5 Levels (EQ-5D-5L) questionnaire 
score at 24, 48 and 72 weeks. 
 Change from baseline in Health related QoL Visual Analogue Scale (VAS) score at 24, 
48 and 72 weeks. 
Cognition 
-
Specific, and ECAS (Edinburgh Cognitive and behavioural ALS Screen) total score;
Change from baseline for ALS Specific, ALS Non-Specific, and ECAS total score at 24, 
48 and 72 weeks; 
 
-Specific, and 
ECAS total score. 
 
Pharmacokinetics
(Population) PK parameters of FAB122 and riluzole  
4.4
Exploratory endpoint(s)
Pharmacokinetics
PK interaction between FAB122 and riluzole 
 
1 Defined as tracheostomy due to trouble breathing as per item 12 of the ALSFRS-R. 


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Biomarkers
Change from baseline in the prognostic ALS biomarkers neurofilament light (NFL) and 
heavy chain (NFH) 
Change from baseline in the surrogate ALS biomarkers creatinine and creatine kinase
Change from baseline in the surrogate ALS biomarker Urinary extracellular domain of 
neurotrophin receptor p75 (Urinary P75ECD)
Change from baseline of oxidative stress biomarker 8-hydroxyguanosine (8-OHdG)
Health economics  
Cost-Utility analysis of treatment with FAB122.
4.5
Safety endpoint(s)
 
 Nature, frequency and severity of Treatment Emergent Adverse Events;
 Parameters derived from in vital signs and 12-lead electrocardiogram (ECG);
Parameters derived from laboratory tests (hematology, biochemistry, urinalysis);
Proportion of subjects that drop out due to adverse events.   
 
5 
STATISTICAL ANALYSIS
5.1
General considerations 
Raw data (in listings) will be presented in the same precision as received. Appropriate rounding 
will be performed for the summary statistics: arithmetic mean, median, SD (standard deviation) 
and confidence limits will be presented with one more decimal than the original data; minimum 
and maximum values will be presented with the same precision as the original data. In frequency 
tables, percentages will be presented with 1 decimal. P-values will be presented with 3 decimals, 
and those smaller than 0.001 wil
 
Descriptive statistics presented in general summary tables will be the number of non-missing 
observations (n), mean, SD, minimum, median and maximum for quantitative data. For 
categorical data, frequency counts and percentages will be determined. The denominator when 
calculating percentages will be the number of patients in the applicable analysis population. 
Descriptive statistics will be displayed for all visits that a measurement is collected on, even if 
the endpoint is only referring to limited visits for the analysis. 
 
Baseline is defined as the last value measured prior to first study treatment administration, unless 
otherwise specified. In case this value is missing for a specific patient, but an earlier 
measurement (e.g. screening) is present, this value will be used as baseline instead. Unscheduled 
measurements are excluded as baseline value.  
 
If available in the database, data for screening failures will not be presented in summary tables, 
except for disposition and end-of-study displays. Data for screening failures will be listed as 
available. 
 


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For patients that are unable to attend the clinic on a study visit due to ALS progression, at least 
ALSFRS score, AEs and concomitant medication data are collected. These data may be collected 
by telephone and are considered of the same quality as performed during live visits. 
If a patient is not able to attend the site for two consecutive visits, then IMP will be discontinued 
at the 2nd missed visit, but participation in the trial and data collection can continue via 
telephonic visits to collect ALSFRS-R, AE and concomitant medication. It is assumed that data 
collected via telephone visits is of same quality as the data collected via site visits.
For QoL questionnaires: in case of technical issues with the ePRO device, these can be 
completed on a paper version as a backup. The data collected per paper are considered of the 
same quality as collected with the ePRO device. 
 
5.2 
Missing or excluded data or intercurrent events
Efficacy data – intercurrent events
The intercurrent events during the study can be broadly classified as terminal and non-terminal 
intercurrent events. Death or “real” loss to follow-up are considered terminal intercurrent events,
wherein there is absolutely no data available for these patients after the occurrence of the event. 
The other intercurrent events are non-terminal, where there is a possibility of collecting data 
from these patients after the occurrence of the intercurrent event (ICE). 
Note that per design of the study, only 100 patients will be followed until week 72. The non-
available data for the ~200 patients between week 48 and 72 will not be considered as ICE.
Regarding intercurrent events, following ICH E9 (R1), two types of strategies will be applied for 
the primary statistical analysis performed for the primary endpoint and utilizing the primary 
analysis population (mITT). 
The “Treatment Policy” strategy will be applied to the following intercurrent events: 
 Treatment discontinuation due to adverse events. 
 Treatment discontinuation due to lack of efficacy. 
 Other unforeseen treatment related reasons (i.e. due to efficacy or safety issues). 
 Rescue medication. 
 Non-treatment-related reasons, other than those already specified earlier. This includes 
situations like patients moving to another location for treatment unrelated reasons. Note 
that the “Treatment Policy” strategy might not be applicable if there are real lost-to-
follow-up cases after doing all efforts to retrieve the data. 
For deaths, the Treatment Policy cannot be applied, and missing data imputation will be used for 
the statistical analyses. 
The “Treatment Policy” strategy implies that the efficacy observed assessment (including those 
collected after the occurrence of the intercurrent event) will be used regardless of the occurrence 
of an intercurrent event.  
The “Composite” strategy will be applied to the following intercurrent events. 


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Related2 death (or death with unknown reasons). It is expected that the rate of death at 52 
. A non-substantial but lower 
rate is expected in the experimental arm.
“Real” lost to follow-up. These are cases where there is lost to follow-up after reasonable 
attempts to contact the patient have been made and all efforts to retrieve the data have 
failed. 
The “Composite” strategy for handling these events will be applying a conservative scenario 
using the 95% worst percentile combined with multiple imputation (the intercurrent event is 
explicitly taken into account and made part of the outcome by this imputation, conditioned on 
timepoint). This method uses the imputation of a conservative value representing the 95th worst 
percentile. 
Efficacy data – missing 
To evaluate the impact of missing data and of the earlier handling methods, a number of 
sensitivity analyses will be performed for the primary endpoint utilizing the primary analysis 
population (mITT).  
 As treatment multiple imputation: For any patient with missing values, the estimates 
for the missing assessments will be based on the actual treatment group of that patient. 
One-hundred imputations will be performed. A predicted mean matching based on a 
monotone regression (in case the missing data pattern is monotone) or on a fully 
conditional specification regression (in case the missing data pattern is arbitrary and non-
monotone) will be applied. The predicted mean matching method imputes an observed 
value which is closest to the predicted value from the simulated regression model for 
each missing value. It ensures that imputed values are plausible and might be more 
appropriate than the regression method if the normality assumption is violated. The 
regression model will condition on observed values of the primary outcome measured at 
other time points (including baseline measurements) and possible other covariates that 
are related to the missing data pattern and/or primary endpoint. The statistical model for 
the primary endpoint will then be applied to each imputed dataset separately. The 
estimated parameters will be pooled using Rubin’s combining rules. This analysis will be 
applied under the assumption of data missing at random (MAR).
Tipping-point analysis: The tipping point is defined as the difference in the change from 
baseline in ALSFRS-R score at week 48 between FAB122 and placebo at which the 
study conclusion (i.e. the statistical significance) changes. This analysis is done to 
explore the impact of MNAR data and is therefore a sensitivity analysis under the 
assumption of MNAR. Missing data are imputed over a range of possible scenarios for 
treatment effect, in order to identify the scenario (or tipping point) that reverses the study 
conclusion as obtained in the original MAR/MCAR analysis. To find this tipping point a 
systematic shift will be applied to the (as-treated) imputed values (i.e. a MNAR 
adjustments in the multiple imputation process) in the FAB122 treatment arm. These 
shifts will cover a large enough range, in steps of 0.2 to find the value for which the 
analysis shows a change in significance of the primary hypothesis test, the tipping point. 
For each shift the primary analysis method will be repeated on the 20 multiple imputed 
data sets. In case such a tipping point has an unrealistic value (as per clinical decision), 
this will support the treatment effect found in the primary analysis.  
 
2 All deaths (including unrelated) are meant here, as it is safe to assume all deaths are related to ALS. In case of 
unrelated deaths, this will be very small number. 


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Hybrid approach: With the hybrid approach the missing weeks for patients who 
discontinued due to AE or lack of efficacy will be imputed using the placebo-based 
pattern imputation under the MNAR assumption and under the assumption of monotone 
missing data. All other discontinuation/missing will be imputed using multiple 
imputation by treatment group using a multivariate stepwise approach using a fully 
conditional specification (FCS) regression method (Rubin, 1987), assuming the missing 
data pattern is arbitrary and non-monotone. Missing baseline values, if any, will be 
imputed using age and time since diagnose. Subsequent visits will be imputed using data 
of all previous weeks in a stepwise fashion. Twenty imputations will be performed.
 Completer analysis: This analysis includes only patients who have completed the study 
up to week 48, and those patients who died prior to 48 weeks assuming they would 
otherwise have completed the study up to 48 weeks. 
 Per Protocol and ITT Analysis: This analysis will include patients from the PP and the 
ITT analysis sets. The same missing data imputation and ICE strategy as for the mITT 
analysis will be applied to these sensitivity analyses. 
For presentation of descriptive statistics of efficacy data, no imputation or sensitivity analysis 
will be included, and data will be presented ‘as is’. All these analyses will be done on data 
available at the visit considered. In summary tables, the number of patients without missing data 
will be presented (per visit, if applicable) unless otherwise specified. In calculations of 
percentages, the denominator will be the number of patients in the applicable analysis 
population. 
 
Safety data 
Using the most conservative approach, missing/incomplete information related to AEs will be 
handled as listed below, to indicate an AE as being treatment emergent or presented having a 
certain intensity/causality. Note that imputed dates/times or intensity/causality will not appear in 
data listings, but only in descriptive statistics tables (where applicable). 
 
 In case of (partially) missing onset dates, the AE will be handled as follows:  
o If full start date is available, and on or after first dosing date, the AE is considered 
treatment emergent. 
o In case full stop date is available and prior to first dosing date, the AE is 
considered prior. 
o If the day part of the start date is missing: 
 The AE is considered treatment emergent if the month and year of the start 
date are the same or after the month and the year of the first dosing date. 
o If the day and month part of the start date are missing: 
 The AE is considered treatment emergent if the year of the start date is the 
same or after the year of the first dosing date. 
o In case the start date is completely missing: 
 If stop date is fully available and on/after the first dosing date, the AE is 
considered treatment emergent. 
 If the stop date is partially missing, but the month and year (or year alone 
in case of missing month) are after the month and year (or year alone) of 
the first dosing date, the AE is considered treatment emergent. 
o In case full start date and full stop date are missing, the AE is considered 
treatment emergent. 
 


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In case intensity is missing for a certain TEAE, it will be regarded as severe. 
In case causality is missing for a certain TEAE, it will be regarded as related. 
In case seriousness is missing for a certain AE, then this is discussed and addressed prior 
to database lock and unblinding in agreement with the sponsor and the Data Management 
vendor. 
Regarding prior/concomitant medication, a similar approach will be followed for partially 
missing dates, as will be done for AEs as described above.  
Using the most conservation approach, missing/incomplete information regarding medical 
history/ALS history will be handled as follows to calculate the duration of symptom onset: 
 If only the day part of the date of diagnosis is missing, then the first of the month is 
imputed for the start date.
 If the day and month part of the date of diagnosis is missing, then 01 January is imputed 
for the start date.
If the complete date is missing, then no imputation can be performed, and this will need to be 
discussed and addressed prior to database lock and unblinding in agreement with the sponsor and 
the Data Management vendor.
Other
Based on the BDRM, certain values can be decided to be excluded from analyses. These values 
will be listed, but not included in descriptive statistics, plots or statistical analyses. This may be 
(outlier) data that are a result of unambiguous measurement errors. 
5.3
Mapping of unscheduled or early termination visits 
When visit assessments are missing, repeat assessments performed within the agreed time 
window of +/- 7 days will be mapped to the appropriate visit in the database by the DM vendor. 
Repeat assessments performed outside of these agreed time windows are collected in the 
database using an unscheduled visit. For these unscheduled assessments following a missing 
protocol visit, mapping will be done to the (closest) protocol visit at which the applicable 
assessment should have been performed before the date of unscheduled visit.  
In case of a repeated or additional assessments for non-missing assessments, mapping will only 
be done for replacement if this is clearly agreed (at patient and visit level) with the client and 
specified by DM vendor (e.g. because it replaces an erroneous measure collected at the actual 
visit), and as such will be used in statistical data presentations. These agreements will be 
documented during the BDRM. 
For patients that withdraw early from the trial, an early termination visit is scheduled 7-14 days 
after withdrawal, for which the same procedures as for visit 8 will be performed. The data of this 
early withdrawal will be mapped to the most appropriate scheduled post-baseline visit as 
applicable per assessment, to be agreed together with the DM vendor and the client on 
occurrence. The documentation of these agreements is to be finalized during the BDRM. For 
early termination visits in general mapping will be done to the closest protocol visit at which the 
applicable assessment should be performed after the date of early termination. 
5.4 
Interim analysis 
No formal interim analysis is planned, however interim safety and efficacy results will be shared 
with a DSMB following a specific DSMB SAP and DSMB charter. 


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5.5
Baseline characteristics
5.5.1
Inclusion/exclusion criteria 
An individual patient listing of deviations from the inclusion and exclusion criteria will be 
presented.  
5.5.2 
Demographics
Descriptive tabulations of the screening data for demographics will be made. Demographic data 
(including weight and height measurements) per treatment group and overall will be presented. 
Appropriate descriptive statistics for age, height, weight, BMI, race, ethnicity and gender will be 
given. Descriptive statistics will be n, arithmetic mean, SD, median, minimum and maximum for 
quantitative data. For qualitative data, frequency counts and percentages will be determined. The 
summary will be created for each efficacy analysis population separately. Additionally, 
demographic data will be listed.  
5.5.3 
Baseline characteristics 
The patient baseline characteristic “substance use” and the stratification groups (the slope 
ALSFS-R score from the time of first symptoms until screening, concomitant use of riluzole) 
will be summarized per treatment group and overall using the safety population. Baseline 
characteristics will also be listed. 
5.5.4 
Disposition 
To present disposition, a summary of all included, randomised, treated and completed3 patients 
will be created. Number/percentage screened will be included as well, if available in the 
database. Additionally, in the same summary, the number/percentage of patients in the ITT, 
mITT, PP, PK and SAF will be presented and the frequency/percentage per reason for non-
completion will be added. The patient disposition will be presented per treatment group and 
overall. 
 
Additionally, a listing displaying all disposition information (including reasons for withdrawal 
and reasons for exclusion from the PP population) on a per patient level will be created. This 
listing will include exposure time for each patient, calculated from date of first dose until end of 
treatment, and follow-up time for each patient, calculated from date of first dose until end of 
study. 
5.5.5 
Medical history 
Medical history will be tabulated per System Organ Class (SOC) and Preferred term (PT) 
according to the Medical Dictionary for Regulatory Activities (MedDRA) terminology list and 
presented as number/percentage of patients in each SOC and PT for the SAF. SOC and PT will 
be presented in descending order of frequency of occurrence based on SOC and PT. These data 
will also be listed on a per patient level. 
 
3 A patient is considered to complete the study if he/she completed the 72 week treatment period OR if she/he 
completed at least 48 week of treatment at study completion (i.e. after the last patients have completed the study up 
to at least 48 week). Note that this is a different selection of patients then for the ‘Completer Analysis’ as defined as 
one of the sensitivity analyses. 


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5.5.6
ALS history 
Collected information on ALS history will be summarized as appropriate. ALS duration will be 
determined based on the baseline data and the date of onset. In case of (partially) missing onset 
date, the imputation rules per section 5.2 will be followed. 
5.5.7
Other screening data 
Not applicable. 
5.6 
Statistical analysis primary and secondary endpoints 
The primary analysis population is the mITT for the primary and all secondary endpoints. 
Analyses of the primary endpoint based on the ITT and PP will also be undertaken to provide 
supplementary information on efficacy. Statistical analysis on secondary endpoints will be 
considered explorative in nature and will only be done for the mITT.
For each of the primary and secondary endpoints descriptive statistics will be presented for 
original values and change from baseline values on a per-visit basis, for each treatment arm and 
overall. All individual primary and secondary endpoint data will be listed as well. 
No multiple corrections will be applied: a hierarchical approach is used as per section 4.1 and all 
other endpoints are considered strictly explorative.  
5.6.1 
Primary analysis 
The primary endpoint is defined as the change from baseline in total ALSFRS-R score after 48 
weeks (primary timepoint).  
For the primary analyses, a placebo (reference) multiple imputation (pMI) will be applied to 
impute missing data for any patients (i.e. from both treatment arms) who discontinue treatment 
early, irrespective the reason for drop-out (only when due to intercurrent events with unknown 
cause), and for which no data was collected after treatment discontinuation. The pMI method 
assumes the statistical behavior of placebo- and drug-treated patients after dropout is the 
statistical behavior of placebo-treated patients. A total of 20 imputed data sets will be created. 
Before applying the statistical model to the primary endpoint, intercurrent events will be handled 
following the rules specified in Section 5.2. 
The primary endpoint will be analyzed using a mixed model for repeated measures (MMRM), 
considering ALSFRS-R is assessed at multiple timepoints. The average treatment effect (lsmeans) 
and the treatment difference (estimand) of the change from baseline ALSFRS-R total score at 48 
weeks will be extracted from the results from this model and presented together with the 95% 
confidence interval and p-value. Other timepoints will also be presented. 
The model will include factors for treatment, time, treatment-by-time interaction, the stratification 
factor concomitant use of riluzole (yes/no), baseline ALSFRS-R score and the stratification factor 
slope of disease progression  as fixed effects. An unstructured (UN) covariance matrix will be used 
in the model. If the model does not converge, the structure will be adapted to respectively AR(1), 
Toeplitz or Compound Symmetry (CS). The results of the 20 imputed data sets will be combined 
to obtain the final estimate of the treatment difference with 95% confidence interval and p-value. 
An example SAS code which can be used as basis is as follows: 


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class trt time riluse;  
model cfb=trt time trt*time riluse base disslope / ddfm=kr;  
repeated time/ subject=patient type=un; 
lsmeans trt*time/cl; 
run; 
Sensitivity analyses using the mITT population will be performed for the primary endpoint as 
described in Section 5.2. The same model will be used to each of the imputed datasets separately
after applying the imputation techniques. The estimated parameters of the imputed datasets will 
be pooled using Rubin’s combining rules to obtain a final result of the treatment difference with a 
95% confidence interval and p-value. 
Descriptive statistics will be presented for ALSFRS-R total score, including change from 
baseline. 
5.6.2 
Secondary analysis 
All secondary endpoints at 72 weeks will be analyzed for the subgroup of patients who reach 72 
weeks (or ICE). Analysis will be done for the full patient group until week 48, and a separate 
analysis will be done for the subgroup until week 72. 
Key secondary endpoints 
No sensitivity analysis or intercurrent event correction will be applied for any of these key 
secondary endpoints. 
Combined assessment of function and survival (CAFS) at week 48 and 72 
CAFS is used to compare each study patient’s outcome to others in the trial in a series of pairwise 
comparisons, based on function (i.e. ALSFRS-R score) and survival. See section 9.1 for relevant 
derivations. For each pairwise comparison, a study patient is assigned a score and then the summed 
scores are ranked for all patients. 
Descriptive statistics for CAFS ranks will be made but are difficult to interpret as mean values 
depend on the size of the study. Descriptive statistics will also include mean difference in ranks 
with a 95% CI. 
The difference between treatments CAFS ranks will be assessed using the Gehan-Wilcoxon rank 
test (also known as the Generalized Wilcoxon test) or, in case of relevant differences in baseline 
characteristics (as per factors included in the ANCOVA model mentioned), by using an ANCOVA 
model. 
Regarding the Gehan-Wilcoxon rank test: if the analysis indicates a statistically significant effect, 
then the separate analysis of function and survival (as described below in the other secondary 
endpoints section) can provide insight whether the improved outcome for the group was driven by 
prolonged survival, improved function, or both. In case of an ANCOVA model: a General Linear 
Model (GLM) will be utilized with treatment, baseline ALSFRS-R score and stratification factors 
(slope of disease progression, concomitant use of riluzole) as covariates.  
ALSFRS-R score values for patients who survived but have a missing week 48 score will be 
imputed following to the imputation defined in section 5.6.1, before the CAFS score will be 


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Clinical Study Reference: ADORE 
 
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determined. The GLM will omit any (other) patients with missing data from the analysis. The duration 
from symptom onset is calculated from the medical history data.  
In case of GLM, subsequent component analyses of function and survival will be used to determine 
which parameter(s) drive the overall effect on the CAFS results. The direction and magnitude of 
the function and survival components of the CAFS will inform the interpretation of the results. 
‘Survival Time’
‘Survival Time’, i.e. time to death4 or time to reaching the criteria for respiratory insufficiency is 
the other key secondary endpoint. The criteria for respiratory insufficiency are defined as 
tracheostomy or initiation of non-invasive ventilation for more than 20 hours a day for more than 
10 consecutive days, over 48 weeks or 72 weeks, respectively. Descriptive statistics (median and 
Q1/Q3 quartiles with 95% confidence intervals) and Kaplan-Meier curves will be provided. The 
difference between oral FAB122 and placebo will be assessed using restricted mean survival time 
(RMST) analysis for the time point week 48 (and another one for week 72 for the subgroup of 100 
patients), adjusting for the stratification variables. The RMST analysis provides robust estimates 
even when the proportional hazard function is violated.  
SAS PROC LIFETEST with option RMST will be used for this analysis. 
In addition, a Cox regression model and a stratified log-rank test will also be applied as supportive 
analysis, including factors for treatment and stratification variables. Patients that complete the 
study and those that discontinue due to reasons other than death or due to reaching the criteria for 
respiratory insufficiency will be considered censored.   
Other secondary endpoints
The following secondary endpoints will also be presented, as applicable. No sensitivity analysis, 
intercurrent event correction or imputation methods will be applied for any of these endpoints. 
ALSFRS-R score
Absolute and change from baseline in total ALSFRS-R score after 24 (full group and subgroup)
and 72 weeks (subgroup only) will be presented by treatment group in summary tables. Note that 
results after 12, 48 and 60 weeks for full group/subgroup as available will also be presented by 
treatment group in the same summary table. The statistical analysis is as described in the section 
on the primary endpoint. 
The proportion of patients with change from baseline in ALSFRS-R score at 24, 48 and 72 weeks 
will be presented in categories for each treatment group. C
-
-
-2 etc. A Chi-squared test will be performed, and 
the p-value added to the table. 
The slope of the decrease in ALSFRS-R total score over time at 24, 48 and 72 weeks will be 
calculated and presented in summary tables. Per treatment arm, slopes will be determined using 
an MRMM model on the change from baseline, with independent variables treatment group, 
baseline value, time and treatment*time interaction. Slopes for each treatment group and slope 
difference between treatments will be presented. No individual per-patient slopes will be 
presented. 
 
4 Where date of death is taken from the Survival follow-up form. 


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Clinical Study Reference: ADORE 
 
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Change from baseline in ALSFRS-R subscale scores will also be calculated after 24, 48 and 72 
weeks for the following subscales: 
 Bulbar function (question 1-3 of the ALSFRS-R);
Fine motor function (question 4-6 of the ALSFRS-R);
Gross motor function (question 7-9 of the ALSFRS-R) 
Respiratory function (question 10-12 of the ALSFRS-R);
Summary statistics for the change from baseline in the above subscale scores will be presented by 
treatment group and overall, again separately for the full group and the subgroup.
In addition, a similar statistical model as for the primary endpoint will be utilized for analyzing 
the change from baseline for the subscale scores. 
Time to event - change from baseline or death 
Time to event, being a change from baseline of 3, 6, 9 and 12 points or death in ALSFRS-R 
score over 48 or 72 weeks, respectively, will be calculated and summarized by median values 
with 95% confidence intervals. In addition, the Hazard Ratio with 95% CI will be presented. 
Comparisons between treatment groups will be done using a Logrank test. 
Overall Survival 
Proportion of patients alive (survival rate) after 24, 48 and 72 weeks for full group and subgroup 
as available will be presented by treatment groups and overall. Kaplan-Meier plots will be 
presented, and treatment groups will be compared using a log-rank test. 
Progression free survival
Proportion of patients alive and no tracheostomy, or no initiation of non-invasive ventilation for 
more than 20 hours a day for more than 10 consecutive days after 24, 48 and 72 weeks will be 
presented by treatment group. Kaplan-Meier plots will be presented, and treatment groups will be 
compared using a log-rank test. 
Staging of disease progression 
Data from staging of disease progression (King’s scaling system, MiToS) after 12, 24, 60, 72 
weeks as compared to baseline will be presented per visit by treatment group and overall, in 
summary tables using frequency and percentages. Frequency and percentages of patients showing 
a decline of  1 stage from baseline will be presented as well. 
Kaplan-Meier curves will be created to present time to decline of 1 stage from baseline in both 
staging systems over 48 weeks or 72 weeks, respectively. A log-rank test will be used to 
determine the difference between study arms. Patients lost to follow-up will be censored. Days 
of maintaining the baseline stages will be presented per treatment arm and group/subgroup, 
including differences between treatment groups. 
 
See section 9.1 for relevant derivations for King’s scaling system and MiToS. 
 
Slow Vital Capacity (SVC)


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Relevant derivations for the SVC are presented in section 9.1. 
Descriptive statistics for absolute value and change from baseline in slow vital capacity (SVC, 
liters) at 24, 48 and 72 weeks will be presented in by treatment group and overall. A similar 
statistical model as for the primary endpoint will be utilized for analyzing the change from 
baseline. 
Hand-held dynamometer 
Derivations for the HDD megascore are presented in section 9.1. 
Descriptive statistics for absolute value and change from baseline in the overall mega score for the 
hand-held dynamometer (HHD) at 24, 48  and 72 weeks will be presented by treatment group and 
overall. A similar statistical model as for the primary endpoint will be utilized for analyzing the 
change from baseline for the overall mega score. Subscores (per muscle and per muscle group) 
will only be included in the listings. 
QoL
The following QoL parameters will be calculated and presented by treatment group and overall
in summary tables.  
 Absolute values and change from baseline in the total score on the ALS Assessment 
Questionnaire-40-Item (ALSAQ-40) and the five scale scores at 24, 48 and 72 weeks. Scale 
scores will also be presented based on range, using frequency and percentages. A similar 
statistical model as for the primary endpoint will be utilized for analyzing the change from 
baseline for the total score only. Derivations for the ALSAQ-40 are presented in section 
9.1. 
 EuroQoL – 5 Dimensions-5 Levels (EQ-5D-5L) questionnaire score 24, 48 and 72 weeks.
Frequency and percentage of each level will be presented for each timepoint on each of the 
dimensions, per treatment. Relevant derivations for the EQ-5D-5L are presented in section 
9.1. The per patient 5-digit number will only be presented in the listing. 
Absolute values and change from baseline Health related QoL Visual Analogue Scale 
(VAS) score at 24, 48 and 72 weeks. Data from all visits collected will be presented in the 
summary. A similar statistical model as for the primary endpoint will be utilized for 
analyzing the change from baseline.
Cognition
The following cognition parameters will be presented by treatment group in summary tables. 
Results on the cognitive subdomains will only be presented in listings. 
 Proportion of patient
-Specific, 
and ECAS (Edinburgh Cognitive and behavioral ALS Screen) total score;  
 Absolute values and change from baseline for ALS Specific, ALS Non-Specific, and ECAS 
total score at 24, 48 and 72 weeks. 
 
 
-Specific, and ECAS 
total score. 


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Pharmacokinetics
The Population PK parameters of FAB122 and riluzole will be presented by the PK vendor, and 
analysis is specified in a separate PK analysis plan. A separate PK report may be created by the 
PK vendor and added to the Clinical Study Report. 
5.6.3 
Additional analysis 
As an additional (supportive) analysis, the joint assessment of change in functional decline5 and 
overall mortality using a joint modelling (i.e. shared-parameter) framework over 48 weeks (all 
patients) and 72 weeks (subgroup of 100 patients) will be determined. The statistical model will 
combine ALSFRS-R score and survival6, using a linear mixed model and a Cox model, as 
submodels combined into a non-linear mixed model using the SAS procedure PROC NLMIXED. 
Parameter estimates and standard errors will be presented. Initial values for the parameters in the 
joint model may be based on the resulting parameter estimates of the two submodels, as described 
before for ALSFRS-R and survival. Example SAS code is available as reference in the publication 
of Vonesh e.a., 2006.  
5.6.4 
Exploratory analysis 
PK analysis
All summary tables, plots, listings, and analyses of the PK concentration data and parameters will 
be done by the PK vendor. PK listings containing the dates and times of the sample collection will 
be created by Certara.
The data for the PK concentration and the calculated PK parameters received according to the 
agreed data transfer specifications may be converted to CDISC format by Certara (if not done by 
the PK vendor) and can be supplied back to the PK scientist for use in the PK analyses.  
Biomarkers
The following biomarkers will be summarized by treatment group as exploratory endpoints: 
 Change from baseline in the prognostic ALS biomarker neurofilament light (NFL)  
Change from baseline in the ALS biomarkers creatinine and creatinine kinase
Change from baseline in the ALS biomarker Urinary extracellular domain of 
neurotrophin receptor p75 (Urinary P75ECD) 
Change from baseline of oxidative stress biomarker 8-hydroxyguanosine (8-OHdG)
For NFL also the geometric mean and geometric mean ratio will be presented, using log-
transformed (based on natural logarithm) data. The geometric mean is calculated as the exponent 
of the mean of the log transformed data. The geometric mean ratio is the ratio of two geometric 
means. 
Furthermore, a listing will be created presenting all data that are out of reference range on a per-
patient level, including any available unscheduled measurements. The investigator has judged 
the out-of-range values on their clinical significance, and this information will be added as well. 
Information regarding age at screening and gender will be added to this listing. 
 
5 Vonesh EF, Greene T, Schluchter MD. Shared parameter models for the joint analysis of longitudinal data and event times. Stat Med. 2006; 25: 
143 – 63 
6 R.P.A. van Eijk et al.  Joint modeling of endpoints can be used to answer various research questions in randomized clinical trials. Journal of 
Clinical Epidemiology 147 (2022): 32-39


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Cost-utility analysis
In this study, an exploratory cost-utility analysis for treatment with FAB122 will be conducted 
based on the data from the cost questionnaire providing direct and indirect costs associated with 
the disease, and information from eCRF data existing of hospitalizations, concomitant medication 
and occurrence of AEs.  
The following cost parameters are considered for the cost-utility analysis among study groups:  
 Number of contacts classified per specialist and type of contact. 
 Number of hospitalizations related to ALS classified per unit of stay and length of stay. 
 Specialized equipment / Devices cost per type of Medical Aid. 
 Paramedical treatment visits (i.e. physical therapy, rehabilitation, occupational therapist, 
speech and language therapist, or otherwise specified by the patient). 
 Formal care (i.e. health professional) and informal care (i.e. familiar/friend): duration and 
cost per type of service and overall.
 Employment situation.  
 Occurrence of AEs in each group (see section 5.7.1, note: no costs are collected for this).  
Descriptive statistics will be displayed for each of the categories above as well as for the costs by 
category and over all categories for each patient, where costs will be presented in euros. As 
applicable, duration of a hospitalization (in days) will be presented as average over the patients as 
well as the total summed duration over all patients per treatment group. Adding of costs and 
calculation from local tariff to euro will be done via programming, using input from client and DM 
vendor on used currency and exchange rates to be used by time of Database lock. 
It should be noted that most cost-utility analysis fields are free text (in local language), which may 
make it complicated to derive all the above directly from the data. Also, in the data collected, there 
is no clear indication whether or not hospitalizations are related to ALS and total costs collected 
are not consistently entered. Specific data handling strategies may be discussed with the client and 
the DM vendor, otherwise descriptive statistics will be limited to items as collected, where free 
text fields will only be listed (without translation).
5.7
Safety and tolerability evaluation
 All safety presentations will be created using the SAF population. 
5.7.1 
Adverse events
A treatment emergent adverse event (TEAE) is defined as an adverse event that appears during 
or after first study treatment. In case of (partially) missing start/stop dates, refer to Section 5.2. 
An AE overview table will be created displaying the number of patients (and percentage) 
experiencing a treatment-emergent adverse event (TEAE) and the number of TEAEs for: Any 
TEAE, Any mild/moderate/severe TEAE, Any unrelated/related TEAE, Any serious AE, Any 
serious TEAE, and Any TEAE leading to study discontinuation. 
SUSARs will be reported by the pharmacovigilance vendor.  
All TEAEs are tabulated by System Organ Class (SOC) and Preferred Terms (PTs) within each 
SOC according to the MedDRA terminology list. TEAEs will also be tabulated by severity 
(mild/moderate/severe) and by relationship to study medication (related/unrelated), using 
frequency counts (number of patients with at least one event, and number of events) and 
percentage of patients with the event. Similar tables will be created for TEAEs leading to 


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premature discontinuation, Serious TEAEs and TEAEs of special interest. These summary tables 
will be presented by decreasing frequency of occurrence based on SOC and PT. 
The summary tables will be accompanied by individual patient listings of all AEs including 
information on AE number, actual AE description, date of start and end of AE (or ongoing), PT 
(MedDRA), SOC (MedDRA), severity, relationship, pre-existing (yes/no), seriousness, special 
interest, action taken and outcome. Pre-existing AEs are not considered to be treatment 
emergent. AEs starting prior to administration of the study drug will only be listed. 
Separate listings will be created for AESIs, SAEs, and deaths. 
For summary tables, an AE is considered related if the causality to the study medication is 
classified as either ‘‘Probably Related’ or ‘Possibly Related’, where a missing relationship is 
also considered related. Otherwise, it will be considered unrelated for summary tables. The 
original description will be used in listings. 
5.7.2 
Clinical laboratory 
The following laboratory safety data are collected for this study: 
Hematology 
Chemistry 
Urinalysis 
Other 
Haematocrit (HCT)
Bilirubin (direct) and Bilirubin 
(total) 
Blood
-human chorionic 
-hCG)
Haemoglobin (HGB)
Alkaline phosphatase 
Glucose
Hepatitis B surface antigen 
(HBsAg)
RBC
Alanine aminotransferase 
(ALT)
Protein
Hepatitis C virus antibody 
(HCV-Ab)
Platelet count
Aspartate aminotransferase 
(AST) 
Specific 
gravity  
HIV antibody (HIV-Ab) 
WBC
Bicarbonate
Microscopic 
exam, if 
abnormal 
results are 
noted
Plasma vitamin B6 levels 
Differential count: 
- 
Basophils 
- 
Eosinophils 
- 
Lymphocytes 
- 
Monocytes 
- 
Neutrophils 
Calcium
Ketone
Cystatin C
Chloride
PH
Creatinine
Nitrite
GammaGT (GGT)
Leukocytes
Fasting Glucose
Bilirubin
Potassium
Urobilinogen
Sodium
Uric Acid
 
 
Total protein 
 
 
Urea (BUN) 
 
 
eGFR
 
 
Activated partial 
thromboplastin time (aPTT)
 
Protrombin Time (PTT)
 
 
Fibrinogen 
 
 
Lactate dehyrdognease (LDH)
 
 
Creatinine kinase (CK)
 
Laboratory safety data will be summarized using descriptive statistics over time, and listed per 
visit and treatment group, using protocol visits. Change from baseline will be calculated and 


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presented as well for quantitative data, using the same summary statistics. The categorical data of 
urinalysis will be summarized by treatment and time in frequency tables by variable. If 
applicable, laboratory safety data collected as additional/unscheduled assessments (i.e. apart 
from those per protocol) will only be listed and will not be used in summary statistics. 
For laboratory safety data, all recorded and determined laboratory safety data will be listed. 
Safety laboratory parameters will be presented in the tables and listings in the same 
(standardized) units as supplied. Since data will be provided in both conventional as SI units, SI 
units will be used for presentation purposes. 
It should be noted that Creatinine and Creatinine Kinase are also part of the Biomarker analysis 
and will therefore be presented twice for different analysis populations. 
5.7.3
Vital Signs 
Vital sign data will present measurements for height, weight, BMI, systolic and diastolic blood 
pressure, pulse rate, respiratory rate, pulse oximetry and temperature. Vital signs (absolute values 
and change from baseline) will be summarized (n, mean, SD, median, minimum and maximum) 
and listed per visit, per treatment group and overall, using protocol visits. Mean (SD) of absolute 
values for vital signs data (blood pressure, pulse rate and respiratory rate) will also be presented 
graphically through time.  
If applicable, vital sign measurements collected as additional/unscheduled assessments (i.e. apart 
from those per protocol) will only be listed and will not be used in summary statistics or 
graphical presentations.
5.7.4
ECG
From the 12-lead ECG data, HR, PR interval, QRS interval, QT interval, RR interval and QTcF 
will be reported for each visit and summarized using descriptive statistics. Change from baseline 
will be calculated as well, using the same summary statistics. Mean (SD) temporal profiles for 
12-lead ECG (QT, QTcF) will be presented graphically. Clinically significant findings will only 
be listed. 
If applicable, ECG measurements collected as additional/unscheduled assessments (i.e. apart 
from those per protocol) will only be listed and will not be used in summary statistics. 
5.7.5
Prior and concomitant medication  
The use of concomitant medication will be listed for all patients: included will be the medication 
generic name, WHO coding information, dose, route of administration, start and stop date, 
frequency and reason for administration, as well as information if given for an AE. 
Differentiation will be made between prior and concomitant medication, by creating two separate 
listings.  
Separate frequency tables will be presented for prior and concomitant medication per 
Standardized Medication Name as provided.
If a medication is started and stopped prior to the first dosed of study medication, then it is 
considered prior medication. In other instances, it is considered concomitant. In case of 
(partially) missing start/stop dates, refer to Section 5.2. 


Ferrer Internacional, S.A.
Protocol ID: FAB 122-CT-2001
Clinical Study Reference: ADORE 
 
07 December 2023 
 
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5.7.6
Physical examination 
All abnormalities reported by the physical examinations will be listed.  
5.7.7 
Nerve conduction study (NCS) 
NCS consists of the following assessments: Hand Temperature (oC), Foot Temperature (oC), 
SRAR, SNAP (µV) and SCV (m/s). The latter two have been determined for locations Median 
Nerve, Ulnar Nerve, Radial Nerve, Sural Nerve. Descriptive statistics will be presented for all 
assessments, irrespective of being performed per NCS protocol or quality assessment result. The 
following descriptive displays will be presented: 
- 
Descriptive statistics per visit and treatment arm, including change from baseline. 
- 
Mean +/- SD plots versus time
- 
Shift from baseline categories (presenting frequencies and percentages per visit and 
treatment arm) 
- 
and treatment arm) 
- 
Normal/abnormal classification results (presenting frequencies and percentages per visit 
and treatment arm)
Information on high/low/normal categorization is presented in section 9.1.
In case of multiple measurements for a specific visit, repeats have occurred because of a 
measurement being not quality approved. In those instances, the last repeated value will be used 
for the descriptive statistics. All collected values will be listed.
5.7.8
Other examinations 
Any other data collected will be presented in listings.  
5.8 
Scheduled visits, Dosing and Treatment Compliance 
5.8.1 
Visit dates  
A listing with actual visit dates will be presented.
5.8.2
Dosing and treatment compliance
Relevant dosing information, scheduled and actual dosing dates, drug accountability and 
treatment compliance will be listed for each patient.  
A frequency tabulation of compliance below 80%, 80-120% (inclusive), and above 120% will be 
presented. Compliance will be determined using the drug accountability information collected in 
the database. The total number of sachets dispensed minus the total number of full sachets 
returned is considered the actual amount of trial medication taken. This should automatically 
include the number of missed doses. Sachets not returned will be considered not taken, from 
conservative perspective, and will be subtracted from this total number. The duration between 
the first dose date and the last dose date is considered the period over which the study medication 
has been taken and is the theoretical amount of trial medication taken (based on intake of one 
sachet per day). Percentage compliance is then calculated as ((actual – not returned)/theoretical) 
*100%. 


Ferrer Internacional, S.A.
Protocol ID: FAB 122-CT-2001
Clinical Study Reference: ADORE 
 
07 December 2023 
 
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6
CHANGES FROM PROTOCOL AND OTHER RELEVANT REMARKS  
The hybrid approach for missing data (Section 5.2) uses placebo-based pattern imputation under 
the MNAR assumption instead of last observation carried forward for patients who discontinued 
due to AE or lack of efficacy. 
Several clarifications have been made to the sensitivity analyses. 
A few minor typing errors have been corrected (e.g. creatine kinase instead of creatinine kinase) 
For CAFS, the protocol states that “A rank-ANOVA will be used as a sensitivity analysis”. 
However, the CAFS are already ranked data and already analyzed via ANCOVA, so this specific 
analysis has been removed. Furthermore, it has been added that either a Gehan-Wilcoxon rank 
test or an ANCOVA or will be performed, based on assessment of baseline differences, as per 
literature reference. Lastly, for the analysis it is mentioned in the protocol that “the same 
covariates as the primary efficacy analysis” will be included. This is not completely true, as the 
time and time*treatment interaction will not be included in the ANCOVA model, hence the 
variables are slightly different. 
There are a few patients (# 3) that have been mis-randomized in the study and, consequently, did 
not receive study treatment. According to the definition, these patients still belong to the ITT 
population, being a secondary analysis population in this study. In principle no imputation will 
be applied for these patients for the primary endpoint and missingness is assumed to be MAR 
(missing at random). If the number of mis-randomized patients is larger than anticipated, a pMI 
approach will be considered for imputation of the baseline values. 
There are several patients for who the CTCAE toxicity grade has been collected. These data will 
only be present in the CDISC files and the relevant listings, and not used in any descriptive 
statistics tabulations. 
7 
COVID-19 DETAILS  
This study is conducted during the COVID-19 pandemic. A number of data capture decisions may 
need to be taken due to national, local, or site-specific restrictions imposed, with the primary need to 
prioritize the safety of clinical study teams and patients, and to maintain the integrity of the 
study/data collection.  
 
The details of potential COVID-19 impact on the study’s procedures and activities will be provided 
in the Risk Management Plan of the study and other applicable study plans (i.e: monitoring plan).  
Screening and Baseline assessment will always be done in clinic. Every effort should be made to 
perform these visits, depending on local regulations. The contingency would only be applicable 
for the randomized/ongoing patients. In case of sanitary restrictions, the following assessment 
might be performed at patient’s home by the site study team personnel or by a validated Home 
Nursing services provider, provided by the sponsor. 
Any impact on the data and the statistical analyses will be assessed during the trial. 
8 
DATA RECEIPT 
All data will be received per transfer agreements. The received files will be imported into SAS 
and will be programmed to CDISC standards (SDTM and ADaM) using the latest FDA accepted 
versions, before programming of the tables, listings and figures is done.  


Ferrer Internacional, S.A.
Protocol ID: FAB 122-CT-2001
Clinical Study Reference: ADORE
07 December 2023
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9
TECHNICAL DETAILS
9.1
Programming conventions
CAFS
To calculate7 a patient’s CAFS, each patient is scored on their relative function and time of death 
as compared to other patients (irrespective of treatment arm) in the trial. The summary CAFS score 
for each patient is the sum of the comparisons (-1, 0, +1) against all other patients. For each 
pairwise comparison of patients, the patient who shows a better score receives a +1, and the one 
who shows a worse score receives a -1. In the case of a tie, no points are added or subtracted 
(scoring is 0). If both patients die, the one surviving longer fared better; if only one survives then 
that patient fared better; and if both patients survive, the one with the smaller decline in ALSFRS-
R from baseline fared better. If a patient discontinues early (only after first applying the imputation 
rule to ALSFRS-R), comparison to each other patient 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 patients. This way, a higher CAFS score indicates a better outcome.
Next, each patients’ summated score (the so-called function/survival score) is ranked, where
ranking is done on week 48 (for all patients and the subgroup) and week 72 (for the subgroup of 
100 patients) separately. In general, the ranking has the following characteristics: 1) the first 
patient who dies will have the lowest score and is ranked the lowest; 2) the last to die is ranked 
above all others who die; 3) among survivors, the patient with the greatest decline in ALSFRS-R 
is ranked just above the last patient who died; 4) the surviving patient with the least decline in 
ALSFRS-R is ranked highest; 5) when comparing ALSFRS-R decline among two survivors, the 
decline is measured at the longest time that both were followed. The average rank score is then 
calculated for each treatment group. A higher mean rank score indicates that patients in that 
treatment group, on average, have a better outcome. 
Comparison should be done per patient based on their last observed follow-up time if lack of 
follow-up is due to logistic/administrative issues. This can only be assessed if the reason is clearly 
specified as being a logistic reason in the database.
King’s scaling system
The King’s system consists of five stages, ranging from 1 to 5, and is based on disease burden as 
measured by clinical involvement and significant feeding or respiratory failure, with stage 1 
being symptom onset and stage 5 being death.
Based on the Kings Staging System data as collected in the CRF, the King’s stage per visit can 
be determined as follows, where the highest stage is selected for each patient. 
If deceased, then Stage is 5
If any nutritional (4a) or respiratory (4b) failure, then Stage is 4
Count the number of regions (Bulbar, Upper limbs, Lower limbs) and this sum will be 
either Stage 1, 2 or 3.
7 Berry, J. e.a. “The Combined Assessment of Function and Survival (CAFS): A new endpoint for ALS clinical 
trials”, Amyotrophic lateral sclerosis and frontotemporal degeneration; Volume 12, 2013-issue 3, pages 162-168.


Ferrer Internacional, S.A.
Protocol ID: FAB 122-CT-2001
Clinical Study Reference: ADORE
07 December 2023
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MiToS
MiToS is not collected per CRF but needs to be composed from the ALSFRS-R based on four 
key domains (walking/self-care, swallowing, communicating and breathing). Each domain has a 
threshold score reflecting the loss of function in the specific ALSFRS-R subscores as presented 
in the table below. Subscores of each item below the threshold are assigned a function score of 1
(meaning functional loss), while subscores above the threshold are assigned a function score of 
0.  MiToS stages are determined as the sum of those function score values across the four 
domains and includes 6 stages on functional ability. Where 2 items are used (with OR or AND), 
scoring is to be based on either one or both item scores as indicated. The sum illustrates how 
many functional domains are lost. The 6 MiToS stages are defined as: stage 0 presents no loss of 
function in any domain; stages 1–4 represent the loss of independence of function in 1, 2, 3 or 4 
domains, respectively, and stage 5 is death.
Table: Thresholds scores
ALSFR-S domain
Item(s)
Threshold & functional score
Movement
(8) Walking 
: functional score=1
OR (6) Dressing and hygiene
: functional score=1
Swallowing
(3) Swallowing
: functional score=1
Communicating
(1) Speech 
: functional score=1
AND (4) Handwriting
: functional score=1
Breathing
(10) Dyspnea 
: functional score=1
OR (12) Respiratory insufficiency
: functional score=1
SVC


Ferrer Internacional, S.A.
Protocol ID: FAB 122-CT-2001
Clinical Study Reference: ADORE
07 December 2023
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Values are determined for three trials; the highest value of the three trials will be used for the 
descriptive statistics and statistical analysis. 
HDD megascore
Patients’ muscle strength is measured bilaterally using HHD for two muscle groups: Elbow 
Flexion and Hip Flexion. Muscle strength is evaluated three times for each measured body 
location. For each, the highest value of the two most closely related values will be identified and 
presented. “Two most closely related” is defined as the two values closed to the mean of the 
three trials – from these two, the highest value will be selected for further use.
For calculation of individual muscle scores, the selected muscle strength is transformed as a 
percent change from baseline using the equation: [(post-baseline value – baseline value) / 
baseline value] x 100. The transformed muscle strength will be set to missing if the baseline 
value is zero.
The HDD mega-score is a composite score that averages strength across muscle groups. It is 
calculated as the mean of the non-missing transformed muscle strength scores among the four 
measured body locations, i.e., from the two muscle groups measured bilaterally. The overall
HDD mega-score is calculated as follows. The maximum muscle strength will be standardized 
using a z-score transformation. For this standardization, data of a healthy population (N=228)8
will be used. The table below provides the z-score transformations applicable, and those z-scores 
present the individual HDD mega-score per muscle. The HDD mega-score for each muscle 
group is determined by averaging the two z-scores within the muscle group. The overall HDD 
mega-score is the average of the four z-scores determined.
Muscle
Z-score transformation
Left Elbow Flexion
Z=(X-34.79)/11.51
Right Elbow Flexion
Z=(X-34.99)/11.77
Left Hip Flexion
Z=(X-43.88)/15.86
Right Hip Flexion
Z=(X-44.43)/15.61
ALSAQ-40
The ALSAQ-40 consists of 40 items/questions, referring to the patient’s condition during the 
past 2 weeks and the answers are given on a five-point Likert scale (0=never, 1=rarely, 2=some-
times, 3=often, 4=always or cannot do at all). These items are combined to provide 5 
dimensions/scales - physical mobility (Q1-Q10), activities of daily living and independence
(Q11-Q20), eating and drinking (Q21-Q23), communication (Q24-Q30), and emotional reactions
(Q31-Q40). For each scale a summary score is calculated, ranging from zero (best health status) 
to 100 (worst health status) according to the formula9:
Computations are therefore as follows for each scale for each patient, where a missing score will 
lead to a missing dimension for that specific patient.
8 Table e-1 from Jeremy M. Shefner, e.a. Quantitative strength testing in ALS clinical trials. Neurology Aug 2016, 87 (6) 617-
624.
9 ALSAQ User Manual, August 2020


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Clinical Study Reference: ADORE 
 
07 December 2023 
 
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Scale
Computation 
physical mobility
100 x (
i / 40)
activities of daily living and independence
i / 40)
eating and drinking 
i / 12) 
communication 
i / 28) 
emotional reactions
i / 40)
The interpretation of score ranges for the 5 scales are as follows: 
 
Range
Interpretation
0-19
No problems
20-39 
Problems rarely
40-59
Problems sometimes
60-79
Problems often
80-100 
Problems always/ nearly always or unable to do at all 
Although not specified in the scoring manual, a total score for the ALSAQ-40 will be derived as 
the mean of the 5 scales (yielding a range of possible scores of 0 to 100. The total score will be 
missing for a patient if one of the scales/dimensions is missing. 
EQ-5D-5L
The EQ-5D descriptive system comprises five dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 5 levels (no problems, slight 
problems, moderate problems, severe problems, extreme problems) and is scored as a 1-digit 
number (ranging 1-5, respectively) expressing the level for that dimension. The digits for the five 
dimensions can be combined into a 5-digit number that describes the patient’s health state (e.g. 
1-1-3-4-5).  
Nerve conduction study (NCS) 
Normal ranges for NCS are defined as below. Values below the lower limit are considered LOW, 
values above the upper limit HIGH, and otherwise (if not missing) values are considered to be 
NORMAL.
Parameter
Age group
Lower limit 
Upper limit 
Hand Temperature (ºC) 
- 
30 
37 
Foot Temperature (ºC)
- 
30 
37 
Median Nerve – SNAP Amp (µV)
11 
- 
5
- 
Median Nerve – SCV (m/s) 
- 
30 
70 
Ulnar Nerve – SNAP Amp (µV) 
11 
- 
40 - 
 
7
- 
5
- 
Ulnar Nerve – SCV (m/s) 
- 
30 
70 
Radial Nerve – SNAP Amp (µV)
11 
- 
40 - 
 
7
- 
5
- 
Radial Nerve – SCV (m/s) 
- 
30 
70 
Sural Nerve – SNAP Amp (µV) 
8
- 
40 - 
 
5
- 
2
- 


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Clinical Study Reference: ADORE 
 
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Sural Nerve – SCV (m/s)
-
30
70
Sural-Radial Amp Ratio (SRAR)
0.45
-
40 - 
 
0.32
- 
0.19
- 
Percentage change from baseline will be calculated as (value – baseline)/baseline.
9.2
Coding
Coding of adverse events, concomitant medication and medical history will be performed by the 
Data Management (DM) provider. Adverse events and medical history are coded with the 
MedDRA coding system. Concomitant medication is coded according to the WHO drug code 
and the ATC class code. The DM vendor will use the latest versions available at time of database 
lock, as per DM documentation. Coding will be supplied as part of the data transfer. 
9.3
Analysis software 
The statistical analysis and reporting will be done using SAS® for WindowsTM version 9.4. SAS 
tabular output (tables and listings) will be saved in RTF format. SAS graphs will be saved in 
PNG format. Both will be imported into Word® and supplied to the Medical Writer for use in the 
clinical study report. When the sponsor wants to receive the output before the study report, then 
the Word® document is transferred to PDF and supplied. 
9.4
Presentation of tables, listings, graphs
All output will be generated as SAS tables, graphs and listings. 
All tables and listings will be created such that they fit landscape pages, following the page 
format and margins of the Clinical Study Report (CSR) template to be used. The tables for the 
end-of-text and listings for the appendix will be created using SAS with an RTF output, and font 
Times New Roman size 9 will be used.  
For graphs, in general Swiss font will be used, and output will be as created as PNG plot. Graphs
are preferably created using black, grey and white color, to facilitate black-and-white printing. 
Different line patterns and symbols will be used to differentiate between classification or 
treatment levels. Only if it enhances clarity of the plot, distinct colors can be used instead. 
Graphs will be created such (i.e. taking into account line thickness and font size) that they can be 
presented as two (2) per page in the clinical study report. 
 
10 TABLES, LISTINGS, GRAPHS 
10.1 
General 
A detailed list of tables, graphs and listings is presented, if applicable, per report section in 
sections 10.2, 10.3 and 10.4. Template tables and listings as well as example plots (as received 
from client or extracted from a relevant paper) will be used as a reference for creation of all 
output, and a separate document will be created for this. Table/graph/listing numbering will be 
followed, however, if the data give cause for combining or splitting tables or listings, numbering 
may be adapted as necessary. 


Ferrer Internacional, S.A.
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Clinical Study Reference: ADORE 
 
07 December 2023 
 
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10.2
In-text tables and graphs 
In-text tables and graphs will be designed or extracted by the Medical Writer during creation of 
the Clinical Study Report, based on the tables and graphs created for section 14 of the CSR. 
Upon request of the Medical Writer or the client, in-text tables may be programmed, and details
will be agreed in advance. These in-text tables will also use font Times New Roman.
10.3 
End-of-text tables and graphs 
Following ICH E3 guidelines, all tables and graphs mentioned here will be presented in Section 
14 of the CSR, and tables will be prepared in the order and with section number as stated. Where 
the column Topline is marked, the output will be part of the Topline results to be supplied 
shortly after Database lock and will include the results for the full set (until week 48) as well as 
the subgroup of 100 patients (until week 72) for the secondary analyses. 
Table /graph 
number 
Contents of table/graph 
Topline 
14.1 Demographic Data Summary figures and tables 
 
14.1.1 
Demographics 
X
14.1.2 
Baseline characteristics
X
14.1.3 
Disposition
X
14.1.4 
Medical history
 
14.1.5 
ALS-specific history
X
14.1.6 
Compliance
X
14.2 Efficacy Data Summary Figures and Tables 
 
14.2.1.1-
14.2.1.x
Descriptive statistics for absolute values and change from baseline ALSFRS-R 
total score and function domains
X
14.2.1.x
Mean (SD) plot ALSFRS-R total score
14.2.2.1
Statistical analysis results ALSFRS-R total score (including ICE approaches)
X
14.2.3.1-
14.2.3.5 
Sensitivity analyses for ALSFRS-R total score 
 
14.2.4 
Statistical analysis results ALSFRS-R function domains
 
14.2.5 
Descriptive statistics for categorized change from baseline ALSFRS-R total 
score 
 
14.2.6 
Descriptive statistics for slope of decrease of ALSFRS-R total score
 
14.2.7 
Descriptive statistics for time to change from baseline for ALSFRS-R total 
score, including HR (95% CI) and log-rank test 
 
14.2.8.1
Descriptive statistics for CAFS
X


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Protocol ID: FAB 122-CT-2001
Clinical Study Reference: ADORE 
 
07 December 2023 
 
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14.2.8.2
Statistical analysis results CAFS
X
14.2.9.1
Survival time: descriptive statistics
X
14.2.9.2
Survival time: Kaplan-Meier curves 
X
14.2.9.3
Survival time: statistical analysis results (RMST) 
X
14.2.9.4 -
14.2.9.5 
Survival time: supportive analyses (Cox and log-rank)
 
14.2.10.1 
Overall survival: population alive 
 
14.2.10.2 
Overall survival: Kaplan-Meier curves 
 
14.2.11.1 
Progression-free survival: descriptive statistics
 
14.2.11.2 
Progression-free survival: Kaplan-Meier curves 
 
14.2.12 
Statistical analysis results joint model 
 
14.2.13.1-
14.2.13.3 
Descriptive statistics for King’s staging system 
X
14.2.13.4 
Kaplan-Meier curves King’s staging system
 
14.2.14.1-
14.2.14.3 
Descriptive statistics for MiToS
X
14.2.14.4 
Kaplan-Meier curves MiToS
 
14.2.15.1 
Descriptive statistics for SVC
 
14.2.15.2 
Statistical analysis results for SVC
 
14.2.16.1
Descriptive statistics for HDD mega score 
14.2.16.2
Statistical analysis results for HDD mega score 
14.2.17.1-
14.2.17.6
Descriptive statistics for Quality of Life: ALSAQ-40 (total score and 5 scales) 
 
14.2.17.7
Statistical analysis results for Quality of Life: ALSAQ-40 total score
14.2.17.8 
Descriptive statistics for Quality of Life: EQ-5D-5L
 
14.2.17.9 
Descriptive statistics for Quality of Life: VAS 
 
14.2.17.10
Statistical analysis results for Quality of Life: VAS
 
14.2.18.1-
14.2.18.x 
Descriptive statistics for Cognition (ECAS) 
 
14.2.19.1-
14.2.19.x 
Descriptive statistics for Biomarkers
 
14.2.19.5 
Out of range Biomarkers
 


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Clinical Study Reference: ADORE 
 
07 December 2023 
 
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14.2.20.1-
14.2.20.x
Descriptive statistics for Cost-Utility analysis
 
14.3 Safety Data Summary figures and tables – 14.3.1 Displays of Adverse Events
14.3.1.1
Overview adverse events
X
14.3.1.2
Treatment emergent adverse events
X
14.3.1.3-
14.3.1.5
Treatment emergent adverse events by severity 
X
14.3.1.6-
14.3.1.7 
Treatment emergent adverse events by relationship
X
14.3.1.8
Treatment emergent adverse events leading to premature discontinuation 
X
14.3.1.9
AESIs
X
14.3.1.10 
SAEs
X
14.3 Safety Data Summary figures and tables – 14.3.2 Listings of Deaths, Other Serious and 
Significant Adverse Events 
14.3.2.1
AESIs
 
14.3.2.2
SAEs
 
14.3.2.3
Deaths
 
14.3 Safety Data Summary figures and tables – 14.3.4 Abnormal Laboratory Value Listing (each 
patient) 
 
14.3.4.1
Out of range clinical laboratory
 
14.3.4.2-
14.3.4.7
Descriptive statistics Clinical laboratory – haematology, clinical chemistry, 
urinalysis, serology, vitamin B6
 
14.3.4.8.1
Descriptive statistics Vital signs 
14.3.4.8.2
Mean (SD) plot Vital signs
14.3.4.9.1 
Descriptive statistics ECG 
 
14.3.4.9.2 
Mean (SD) plot ECG 
 
14.3.4.10 
Physical Examination 
 
14.3.4.11.1-
14.3.4.11.x 
Nerve Conduction Study 
 
14.3.4.12-
14.3.4.13 
Prior and concomitant medication
 


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Clinical Study Reference: ADORE 
 
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10.4
Listings 
Following ICH E3 guidelines, all listings mentioned here will be presented in Section 16.2 of the 
CSR, and listings will be prepared in the order and with section number as stated.  
Individual listings will be prepared of all the data collected in the database, following SDTM 
data format. No combining of data other than mentioned in this paragraph will be performed. 
The key variables in the listings (except a few displaying screening data) will be patient number 
and treatment. If applicable, visit number will be listed additionally. Furthermore, a listing 
containing study visit dates will be presented. 
Listing number
Contents of listing
16.2.1 Discontinued patients
16.2.1.1
Inclusion/exclusion criteria – description 
16.2.1.2
Inclusion/exclusion criteria – deviations
16.2.1.3
Patient disposition 
16.2.2 Protocol deviations 
16.2.2 
Protocol deviations 
16.2.3 Demographic and baseline data 
16.2.3.1
Demographics 
16.2.3.2
Randomization
16.2.3.3
Substance use 
16.2.3.4
Medical history
16.2.3.5
ALS history
16.2.3.6
Pregnancy test
16.2.4 Compliance and/or treatment data
16.2.4.1
Treatment exposure 
16.2.4.2
Drug accountability and compliance
16.2.4.3
Study visits
16.2.5 Individual efficacy response data 
16.2.5.1
ALSFRS-R 
16.2.5.2
CAFS 


Ferrer Internacional, S.A.
Protocol ID: FAB 122-CT-2001
Clinical Study Reference: ADORE 
 
07 December 2023 
 
TMP-516A Statistical Analysis Plan Template
Version 2.0, Document Number:  iDD-000074  
Page 42 of  42 
 
 
16.2.5.3
King’s staging system  
16.2.5.4
MiToS 
16.2.5.5
SVC 
16.2.5.6
HDD
16.2.5.7
QoL
16.2.5.8
Cognition (ECAS) 
16.2.5.9
Biomarkers 
16.2.5.10 
Cost-utility 
16.2.5.11 
Survival
16.2.6 Adverse event listings 
16.2.6.1
Adverse events 
16.2.6.2
AEs leading to discontinuation from the study 
16.2.6.3
Vital signs
16.2.6.4
ECG 
16.2.6.5
Physical Examination
16.2.6.6
Neurological examination 
16.2.6.7
Nerve conduction study 
16.2.6.8
Prior and concomitant medication
16.2.7 Listing of individual laboratory measurements by patient
16.2.7.1
Laboratory safety data – haematology
16.2.7.2
Laboratory safety data – clinical chemistry
16.2.7.3
Laboratory safety data – urinalysis 
16.2.7.4
Laboratory safety data – coagulation
16.2.7.5
Laboratory safety data – serology
16.2.7.6
Laboratory safety data – Vitamin B6 
16.2.7.7
General comments