Clinical trial NCT05866926
Conditions: Amyotrophic Lateral Sclerosis
Sponsor: Ferrer Internacional S.A.
Start date: 2023-03-06; Completion date: 2024-02-22
Enrollment: 201 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
A multicenter, open-label extension study to investigate the long-term safety of FAB122 in patients with Amyotrophic Lateral Sclerosis

Detailed description:

Arms: arm 1: Drug: FAB122 Daily dose 100 mg

Data presented for the FAB122 study group correspond to subjects receiving FAB122 in the ADORE study as well as the ADOREXT study (FAB122-FAB122). arm 2: Drug: FAB122 Daily dose 100 mg

Data presented for the placebo study group correspond to subjects receiving placebo in the ADORE study and FAB122in the ADOREXT study (placebo-FAB122).
Interventions: intervention 1: FAB122
Intervention descriptions: intervention 1: FAB122 Daily dose 100 mg

Protocol documents:
Prot_000.pdf: 
Ferrer Internacional, S.A. 
 
FAB122-CT-2201 
 
 
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Confidential  
CLINICAL STUDY PROTOCOL 
 
 
Title 
 
A multicenter, open-label extension study to investigate the long-term safety 
of FAB122 in patients with Amyotrophic Lateral Sclerosis 
 
ADOREXT (ALS trial with Daily ORal Edaravone EXTension) study 
 
 
THE SPONSOR STUDY CODE: FAB122-CT-2201 
EudraCT NUMBER:  2022-003050-32 
 
 
 
Sponsor: 
Ferrer Internacional, S.A. 
 
Barcelona, Spain 
 
 
 
 
Study Drug Name:  
FAB122 
Development Phase: 
PHASE III Extension 
Date of Protocol: 
10/07/2023 
 
 
 
 
 
 
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. 
 


Ferrer Internacional, S.A. 
 
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Confidential  
DOCUMENT VERSION HISTORY 
 
Date 
Version 
Reason for Revision 
17/10/2022 
1.0 
Initial 
10/07/2023 
1.1 SWE 
Updates as per request from the Regulatory 
Authorities and Ethics Committees from several 
countries 
Minor grammatically changes and correction of 
inconsistencies. 
Updates in the wording of several sections for better 
understanding 
 
Corrected typos: CSF, Screening 
3.2.2 Updates in the wording of endpoint for survival 
3.2.2 Addition of secondary endpoint (SVC) 
4. Updated wording about study duration  
5.2 Updates in wording of incl. criteria. Addition of 
wording about inc/excl criteria for patients only in follow 
up for vital status 
5.3 Addition of exclusion criteria section 
6 (Table 1): clarification (footer) for patients only in vital
status FU, Addition of lab parameters in footer of table 
1 in line with table 2. 
6. Addition of wording about participants follow up in 
case not attending site visits 
6.1 Section re-worded to clarify baseline assessments 
of the main study can be used. 
6.2&6.3: updates to align with Table 1 
6.4 New section added to clarify procedures for 
patients only in vital status follow up 
6.5. Discontinuation criteria updated  
7.1.2 typo in compliance corrected (100%)  
7.1.3 IMP shipment re-worded 
9.8 section updated in line with 6.5 
11.3.1 added wording to clarify analysis 
11.3.4 added wording to clarify analysis 
11.3.4 SVC added in the analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL APPROVAL SIGNATURES
Sponsor Signatures
Declaration of Sponsor
Study title: A multicenter, open-label extension study to investigate the long-term 
safety of FAB122 in patients with Amyotrophic Lateral Sclerosis
Version number: 1.1 SWE
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
Clinical Development
Diagonal 549
Date
08029 Barcelona
Spain
Name: Nuria Albareda
Ferrer Internacional, S.A.
Signature
Clinical Development
Diagonal 549
Date
08029 Barcelona
Spain
Name: Lubia Álvarez
Ferrer Internacional, S.A.
Signature
Clinical Development
Diagonal 549
Date
08029 Barcelona
Spain
Name: Cristina Tarragó
Ferrer Internacional, S.A.
Signature
Clinical Development
Diagonal 549
Date
08029 Barcelona
Spain


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


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Investigator Signature Page 
 
Declaration of Investigator 
Study title: A multicenter, open-label extension study to investigate the long-term 
safety of FAB122 in patients with Amyotrophic Lateral Sclerosis 
 
Version number:1.1 SWE  
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: Lubia Álvarez
Address: 
Ferrer Internacional, S.A.
Diagonal 549
08029 Barcelona
Spain
Mob.
+34 636 842 234
E-mail:
lalvarez@ferrer.com
Name: Nuria Albareda
Address: 
Ferrer Internacional, S.A.
Diagonal 549
08029 Barcelona
Spain
Mob.:
+34 649 442 389
E-mail:
nalbareda@ferrer.com
Name: Cristina Tarragó 
Address: 
Ferrer Internacional, S.A.
Diagonal 549
08029 Barcelona
Spain
Mob.
+34 620 295 263
E-mail:
ctarrago@ferrer.com
Name: Lubia Álvarez
Address: 
Ferrer Internacional, S.A.
Diagonal 549
08029 Barcelona
Spain
Mob.
+34 636 842 234
E-mail:
lalvarez@ferrer.com


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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 
 
 
 


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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 .............................................................................................................10 
LIST OF FIGURES ...........................................................................................................10 
ABBREVIATIONS ............................................................................................................11 
1. 
SYNOPSIS ..............................................................................................................14 
2. 
INTRODUCTION .....................................................................................................19 
2.1. Background and rationale ..................................................................................19 
2.2. Risk-Benefit Assessment ...................................................................................25 
3. 
OBJECTIVES AND OUTCOMES MEASURES .......................................................26 
3.1. Objectives .........................................................................................................26 
3.1.1. Primary Objective ..................................................................................26 
3.1.2. Secondary Objectives ............................................................................26 
3.2. Endpoints ..........................................................................................................26 
3.2.1. Primary Endpoint ...................................................................................26 
3.2.2. Secondary Endpoints ............................................................................26 
3.2.3. Safety Endpoints ...................................................................................27 
4. 
STUDY DESIGN ......................................................................................................28 
5. 
STUDY POPULATION ............................................................................................29 
5.1. Study Participants .............................................................................................29 
5.2. Inclusion Criteria................................................................................................29 
5.3. Exclusion Criteria ..............................................................................................30 
6. 
STUDY PROCEDURES ..........................................................................................31 
6.1. Eligibility Assessment ........................................................................................33 
6.2. Baseline Assessments ......................................................................................33 
6.3. Rest of visits ......................................................................................................34 
6.4. Phone contacts .................................................................................................35 
6.5. Early Discontinuation/Withdrawal of Participants ...............................................36 
7. 
STUDY INTERVENTIONS .......................................................................................38 
7.1. Investigational Medicinal Product(s) (IMP) Description ......................................38 
7.1.1. Packaging and Labelling ........................................................................39 
7.1.2. Compliance with Trial Treatment ...........................................................39 
7.1.3. Accountability of the Trial Treatment......................................................39 


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7.1.4. Concomitant Medication ........................................................................40 
7.2. Other Treatments (non-IMPS) ...........................................................................40 
8. 
PARAMETERS AND METHODS OF ASSESSMENT .............................................41 
8.1. Parameters ........................................................................................................41 
8.1.1. ALSFRS-R .............................................................................................41 
8.1.2. Survival Time .........................................................................................41 
8.1.3. Lung Function ........................................................................................41 
8.1.4. Staging of Disease Progression .............................................................41 
8.1.5. Health Status .........................................................................................41 
8.1.6. Cognition ...............................................................................................42 
8.2. Safety Parameters .............................................................................................42 
8.2.1. Physical and neurological examination ..................................................42 
8.2.2. Laboratory Parameters ..........................................................................43 
8.2.3. ECG ......................................................................................................43 
8.2.4. Vital Signs .............................................................................................43 
9. 
SAFETY REPORTING ............................................................................................44 
9.1. Definitions .........................................................................................................44 
9.1.1. Adverse Event .......................................................................................44 
9.1.2. Adverse Reaction ..................................................................................44 
9.1.3. Unexpected Adverse Reaction ..............................................................45 
9.2. Severity Assessment .........................................................................................45 
9.3. Serious Adverse Event ......................................................................................45 
9.4. Assessment of Causality ...................................................................................46 
9.5. Reporting Adverse Events .................................................................................46 
9.6. Reporting Serious Adverse Events ....................................................................47 
9.6.1. Adverse Event Follow-up .......................................................................47 
9.7. Expedited Reporting ..........................................................................................48 
9.8. Pregnancy .........................................................................................................48 
10. 
HEALTH ECONOMICS ...........................................................................................50 
11. 
STATISTICS ............................................................................................................52 
11.1. Statistical Analysis Plan (SAP) ..........................................................................52 
11.2. Sample Size Determination ...............................................................................52 
11.3. Description of Statistical Methods ......................................................................52 
11.3.1. Analysis Populations .............................................................................52 
11.3.2. Demographics, baseline characteristics .................................................52 
11.3.3. Subject Disposition ................................................................................52 
11.3.4. Efficacy Analysis....................................................................................52 
11.3.5. Safety Analysis ......................................................................................53 
12. 
DATA MANAGEMENT ............................................................................................55 


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12.1. Case Report Form .............................................................................................55 
12.2. Source Data ......................................................................................................55 
12.3. Data Processing ................................................................................................56 
12.4. Central Data Monitoring .....................................................................................56 
13. 
QUALITY ASSURANCE PROCEDURES ................................................................57 
13.1. Monitoring .........................................................................................................57 
14. 
ETHICS AND REGULATORY CONSIDERATIONS ................................................58 
14.1. Approvals ..........................................................................................................58 
14.2. Ethical Conduct of the Study .............................................................................58 
14.3. Participant Information and Confidentiality.........................................................58 
15. 
FUNDING AND INSURANCE..................................................................................59 
16. 
PUBLICATION POLICY ..........................................................................................60 
17. 
ARCHIVING ............................................................................................................61 
18. 
REFERENCES ........................................................................................................62 
19. 
Annexes .................................................................................................................70 
Annex 1, ALS Functional Rating Scale  revised (ALSFRS-R) ...................................70 
Annex 2: Cost Questionnaire .....................................................................................72 
 
LIST OF TABLES  
Table 1: Study Scheduled Visits ...................................................................................... 31 
Table 2: Overview of laboratory assessments .................................................................. 34 
Table 4: The theoretical quantitative composition of FAB122 granules for oral solution in 
sachet .............................................................................................................................. 38 
 
 
LIST OF FIGURES 
 
Figure 1: Posible mechanism of action of edaravone ....................................................... 24 
 


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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 
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 
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 
EQ-5D-5L 
EuroQoL  5 Dimensions  5 Levels 
fALS 
familial Amyotrophic Lateral Sclerosis 
FBR 
Future Biomedical Research 
FDA 
Food and Drug Administration 
FAB122 
Ferrer New Product 122* (FNP122) 
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 
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 
OLE 
Open-label extension 
P75EDC 
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 


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PLS 
Primary Lateral Sclerosis  
PMM 
Pattern Mixture Model 
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 
VAS 
Visual Analogue Scale 
WBC 
White blood cell  
WFN 
World Federation of Neurology 
WHO 
World Health Organisation 
* It substitutes prior codification FAB122 (Ferrer Advanced Biotherapeutics 122) 


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1. 
SYNOPSIS 
TITLE: 
A multicenter, open-label extension study to investigate the long-term safety 
of FAB122 in patients with Amyotrophic Lateral Sclerosis 
THE SPONSOR STUDY 
CODE: 
FAB122-CT-2201 
EudraCT NUMBER: 
2022-003050-32 
SPONSOR: 
Ferrer Internacional, S.A. 
Barcelona, Spain 
 
STUDY PHASE: 
PHASE III Extension 
STUDY DESIGN: 
Multicenter, multinational, open-label Phase III extension study to investigate 
the long-term safety of 100 mg FAB122 once daily as oral formulation in ALS 
patients. 
All patients participating in the ADORE study will be invited to roll over to 
FAB122 and to participate in ADOREXT. Patients that discontinued treatment 
in the main ADORE study for other than safety reasons, will be also invited to 
re-start treatment with FAB122 in the OLE study. The duration of this open 
label extension (OLE) will be until the product is commercially available at 
each participant country, provided good tolerance and safety is proven. The 
sponsor could also make the decision to terminate the study at any time, in 
case the objectives of the main study (ADORE) are not met. 
Patients not willing to continue receiving active treatment in the extension 
study or that had already discontinued study treatment during the course of 
the main ADORE study for safety reasons, will be asked to be contacted by 
phone and followed up for vital status. 
Subjects rolling over active treatment will visit the clinic at Baseline (Visit 6 or 
8 of the main study (+ 6 weeks in case the OLE is not fully set up) and every 
3 months thereafter. 
 
STUDY PARTICIPANTS:  
Study Population  
ALS patients from main ADORE study 
Inclusion Criteria  
Patients who meet all of the following criteria, will be eligible for the study: 
1. who completed the full study period in the main ADORE study 
(FAB122-CT-2001);  
2. whom the investigator has no concern and judges tolerable for
receiving  treatment with FAB122 from a risk and benefit point of 
view;  
3. a female subject should not be able to become pregnant up to
30 days after the last dose of FAB122 and needs to meet at least 
one of the following criteria: 
- 
female subject who is not of reproductive potential is eligible 


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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 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 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 
mone-releasing system, 
bilateral tubal occlusion or vasectomised partner.  
4. a male patient must: 
- 
agree he will not donate sperm during the period he will be 
using FAB122, AND use a condom during sexual intercourse 
with pregnant or non-pregnant women of childbearing 
potential (WOCBP) partner even if he is vasectomized and 
until 104 days after the last dose, . 
- 
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), intrauteri
ths, 
intrauterine 
hormone-releasing 
system, 
bilateral 
tubal 
occlusion or vasectomised partner; 
5. providing informed consent. 
 
Exclusion Criteria 
Patients who meet any of the following criteria, will not be eligible for the 
study: 
1. Patient who has a medical condition (e.g. cardiac, pulmonary, 
gastrointestinal, musculoskeletal, or psychiatric illness) or personal 
circumstances which, in the opinion of the investigator, will make 
initiation or continuation of treatment with FAB122 not tolerable for 
them from a risk and benefit point of view. 
2. Patient who discontinued study drug prematurely in the double-blind 
phase of the study (ADORE Study) for safety reasons. 


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3. Patient who has received any other investigational drug within the 
period between last visit of the main study and first visit of the 
extension study (i.e. another trial, managed access program, open 
label extension or early access program) 
4. - History of known hypersensitivity to edaravone or to any of the 
excipients. 
For patients  who do not take FAB122 but are only followed up by phone, 
only inclusion criteria #1 and #5 will apply.   
SAMPLE SIZE: 
No formal size calculation has been done for the extension study. 
The main study plans to include approximately 300 patients. It is anticipated 
that 200-225 patients might be included in this extension study. 
PLANNED STUDY 
PERIOD: 
Approximately 3 years (up to the product is commercially available). Product 
commercialization is country dependent, thus study ending will differ between 
countries. The sponsor may terminate the study at any moment in case the 
objectives of the main study (ADORE) are not met) 
STUDY SITES  
Approximately 38 sites  
OBJECTIVES AND OUTCOME MEASURES:  
PRIMARY OBJECTIVE: 
To evaluate the long-term safety of FAB122 in patients with ALS. 
SECONDARY 
OBJECTIVES:  
1. To evaluate the effect of treatment with FAB122 on overall survival;  
2. To evaluate the effect of treatment with FAB122 on disease 
progression in patients with ALS; 
3. To evaluate the effect of treatment with FAB122 on cognitive
functioning; 
4. To evaluate the effect of treatment with FAB122 on quality of life 
(QoL). 
PRIMARY ENDPOINT:  
Nature, frequency and severity of Treatment Emergent Adverse Events. 
SECONDARY 
ENDPOINTS: 
1. Mortality-adjusted change from baseline in ALSFRS-R total score 
until the end of the study;  
2. Overall survival, defined as time to death from any cause or 
respiratory insufficiency (insufficiency defined as tracheostomy or 
the use of non-invasive ventilation for 
 
consecutive days);  
3. Change from baseline in SVC until the end of the study; 
 
4. Mean change in norm-standardized ECAS total score; 
5. Change from baseline in the total score on the ALS Assessment


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Questionnaire-40-Item (ALSAQ-40) until the end of the study; 
6. Change from baseline in EuroQoL  5 Dimensions  5 Levels (EQ-
5D-5L) until the end of the study; 
7. Change from baseline in Health related QoL Visual Analogue Scale 
(VAS) score until the end of the study; 
8. Change 
from 
baseline 
in 
the 
prognostic 
ALS 
biomarker
neurofilament light (NFL); 
9. Change from baseline in the ALS biomarkers creatinine and 
creatinine kinase; 
10. Change from baseline in the ALS biomarker Urinary extracellular
domain of neurotrophin receptor p75 (Urinary P75ECD); 
11. Change 
from 
baseline 
of 
oxidative 
stress 
biomarker 
8-
hydroxyguanosine (8-OHdG); 
12. Cost-Utility analysis of treatment with FAB122. 
 
SAFETY ENDPOINTS  
1. 
Parameters derived from in vital signs and 12-lead electrocardiogram 
(ECG); 
2. 
Parameters derived from laboratory tests (hematology, biochemistry, 
urinalysis); 
3. 
Proportion of patients that drop out due to adverse events.    
 
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. 
 
STATISTICAL METHODS: 
 
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). 
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. 
Difference in survival curves will be evaluated using a log-rank test, stratified 
for randomization factors. The effect of treatment will be expressed as hazard 
ratio. In case of non-proportional hazards, we will estimate the difference in
restricted mean survival time (RMST).  
Changes in the in ALSFRS-R score, ALSAQ-40, SVC, EQ-5D-5L, and VAS


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score over time will be presented descriptively. 
 
 


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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).  
The crude worldwide ALS prevalence is 4.42 (95% CI 3.92 4.96) per 100,000 population 
and the worldwide incidence is 1.59 (95% CI 1.39 1.81) per 100,000 person-years. In 
West Europe the prevalence is 9.62 (95% CI 4.80 16.10); and the incidence is 2.76, (95% 
CI 2.00 3.64) per 100.000 person-years. (Global variation in prevalence and incidence of 
amyotrophic lateral sclerosis: a systematic review and meta-analysis - PubMed (nih.gov)). 
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, more than 40 genes have been identified to date, which together 
account for about 15% of cases (Recent advances in the diagnosis and prognosis of 
amyotrophic lateral sclerosis - PubMed (nih.gov)). 
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., 


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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 
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 behavioral 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). The most widely used instrument to measure function in ALS clinical 


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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 1). 
Pharmacological and non-pharmacological treatment options 
There are limited pharmacological options in the treatment of ALS; 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) 
. 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, anticonvulsants (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 


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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. 
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 
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. Distinguishing pathogenic features of neurodegenerative diseases as 
ALS include high reactive oxygen species (ROS) levels and mitochondrial dysfunction 
(Barber, 2006 and Smith, 2019).    
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. Edaravone is a free 


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radical scavenger that has demonstrated cellular protective properties in animals and 
humans. Owing to its antioxidant activity, edaravone modulates oxidative damage in 
various diseases, especially neurodegenerative diseases (Hardiman, 2017b). 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). 
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 
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 part of the underlying multifactorial 
pathogenic mechanisms of ALS (Franco et al., 2013; Rossi et al., 2013; Zoccolella, 2009). 
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 later 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). Radicava ORS
 as an oral 
formulation of edaravone, with the same intermittent posology of Radicava iv formulation 
and based on a bioavailability study, was approved by FDA in May 2022, for the treatment 
of ALS, as well (Radicava and Radicava ORS). Based on the initial results achieved with 
the intravenous edaravone formulation in ALS patients, Treeway initiated in Europe a 
phase I clinical development program with edaravone daily oral formulation (FAB122), in 
, that was followed by Ferrer phase III 
pivotal study, ADORE. 


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Figure 1: Possible 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 
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). 
Rationale for the Current Study 
As ALS is a rapidly progressive and fatal disease, this study is designed as an open-label 
extension (OLE) study to provide longer term access to daily oral edaravone to patients 
who have demonstrated a good tolerance in the ADORE trial (either FAB122 or placebo 
arm) during 48 weeks and up to 72 weeks.  
The good tolerance for each patient who could be included in the current OLE study will be 
evaluated by the investigator, according to the individual favourable benefit/risk ratio which 
will be based on the available data.  
This OLE study will also assess longer term safety, survival and therapeutic potential of 
daily oral edaravone.  
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 


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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).  
Biobank 
Blood samples will be stored in a central biobank located in Barcelona, Biobanc IGTP-
HUGTP. Institut de Recerca Germans Trias i Pujol (IGTP). Campus Can Ruti, for a 
maximum of 10 years. 
Patients will have the right to withdraw their samples from storage at any time. 
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 and iv edaravone 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 (FAB122 
IB).  
Overall, the safety and efficacy of edaravone administered by oral and intravenous routes 
have been demonstrated in many clinical trials in healthy volunteers and ALS patients. 
Also, a phase III clinical trial (ADORE) with daily oral edarovone is being conducted by 
Ferrer in 300 patients with ALS.  
At the time of writing of this version of the protocol, all patients have been recruited in the 
main study ADORE and there are patients participating for up to 72 weeks. No safety 
concerns have been raised during the monthly safety data review by the Data Safety 
Monitoring Board (DSMB). The DSMB specially reviewed the data related to potential 
neurotoxicity and concluded that there is low incidence of neuropathies and abnormalities 
detected in NCS assessments.  
Therefore, the expected clinical benefits from the participation in the current OLE study for 
selected patients overcome the potential risks.  
 


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3. 
OBJECTIVES AND OUTCOME MEASURES  
3.1. 
Objectives  
3.1.1. 
Primary Objective  
To evaluate the long-term safety of FAB122 in patients with ALS. 
3.1.2. 
Secondary Objectives  
1. To evaluate the effect of treatment with FAB122 on overall survival;  
2. To evaluate the effect of treatment with FAB122 on disease progression in 
patients with ALS; 
3. To evaluate the effect of treatment with FAB122 on cognitive functioning; 
4. To evaluate the effect of treatment with FAB122 on quality of life (QoL). 
3.2. 
Endpoints  
3.2.1. 
Primary Endpoint  
Nature, frequency and severity of Treatment Emergent Adverse Events. 
3.2.2. 
Secondary Endpoints  
1. Mortality-adjusted change from baseline in ALSFRS-R total score until the end of 
the study;  
2. Overall survival, defined as time to death from any cause or respiratory 
insufficiency (insufficiency defined as tracheostomy or the use of non-invasive 
;  
3. Change from baseline in SVC until the end of the study; 
4. Mean change in norm-standardized ECAS total score; 
5. Change from baseline in the total score on the ALS Assessment Questionnaire-
40-Item (ALSAQ-40) until the end of the study; 
6. Change from baseline in EuroQoL  5 Dimensions  5 Levels (EQ-5D-5L) until 
the end of the study; 
7. Change from baseline in Health related QoL Visual Analogue Scale (VAS) score 
until the end of the study; 
8. Change from baseline in the prognostic ALS biomarker neurofilament light (NFL); 
9. Change from baseline in the ALS biomarkers creatinine and creatinine kinase; 


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10. 
Change from baseline in the ALS biomarker Urinary extracellular domain of 
neurotrophin receptor p75 (Urinary P75ECD); 
11. 
Change from baseline of oxidative stress biomarker 8-hydroxyguanosine (8-
OHdG); 
12. 
Cost-Utility analysis of treatment with FAB122. 
3.2.3. 
Safety Endpoints 
1. Parameters derived from vital signs and 12-lead electrocardiogram (ECG); 
2. Parameters derived from laboratory tests (hematology, biochemistry, urinalysis); 
3. Proportion of patients that drop out due to adverse events. 


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4. 
STUDY DESIGN  
Multicenter, multinational, open-label Phase III extension study to investigate the long-term 
safety of 100 mg FAB122 once daily as oral formulation in ALS patients. 
All patients who participated in the ADORE study will be invited to roll over to FAB122 and 
to participate in ADOREXT study. Patients that discontinued treatment in the main ADORE 
study for other than safety reasons, will be also invited to re-start treatment with FAB122 in 
the OLE study. The duration of this open label extension (OLE) will be until the product is 
commercially available at each participant country, provided good tolerance and safety is 
proven. The sponsor could also make the decision to terminate the study at any time in 
case the objectives of the main study (ADORE) are not met. 
Patients not willing to continue receiving active treatment in the extension study or that had 
already discontinued study treatment during the course of the main ADORE study for 
safety reasons, will be asked to be contacted by phone and followed up for vital status. 
Double-blinding to original treatment assignment in the main ADORE study will be 
maintained. 
Subjects rolling over active treatment will visit the clinic at Baseline (whenever possible, 
Visit 6 or 8 of the main study) and every 3 months thereafter. 
End of study at each participant country is defined as the time when the product is 
commercially available; or prematurely in case the objectives of the main study are not 
met, at the time when the main study results show a negative benefit /risk ratio. Other 
reason for premature ending of the study would be in case that the product is not 
authorized by the local/regional authorities, at the time when the rejection is received. 
 


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5. 
STUDY POPULATION 
5.1. 
Study Participants   
ALS patients from main ADORE study.  
5.2. 
Inclusion Criteria 
All patients:  
1. who completed the full study period in the main ADORE study (FAB122-CT-
2001);  
2. whom the investigator has no concern and judges tolerable  receiving treatment 
with FAB122 from a risk and benefit point of view;  
3. a female subject should not be able to become pregnant up to 30 days after the 
last dose of FAB122 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 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 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 de
intrauterine hormone-releasing system, bilateral tubal occlusion or 
vasectomised partner.  
4. a male patient must: 
- agree he will not donate sperm during the period he will be using FAB122  
AND use a condom during sexual intercourse with pregnant or non-
pregnant women of childbearing potential (WOCBP) partner even if he is 
vasectomized until 104 days after the last dose. 
- 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 


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-releasing system, bilateral tubal 
occlusion or vasectomised partner; 
5. providing informed consent. 
 
 
will be eligible and enrolled.  
 
5.3. 
Exclusion Criteria 
Patients who meet any of the following criteria, will not be eligible for the study: 
 
1. Patient who has a medical condition (e.g. cardiac, pulmonary, gastrointestinal, 
musculoskeletal, or psychiatric illness) or personal circumstances which, in the 
opinion of the investigator, will make initiation or continuation of treatment with 
FAB122 not tolerable for them from a risk and benefit point of view. 
2. Patient who discontinued study drug prematurely in the double-blind phase of the 
study (ADORE Study) for safety reasons. 
3. Patient who has received any other investigational drug within the period between 
last visit of the main study and first visit of the extension study (i.e. another trial, 
managed access program, open label extension or early access program) 
4. History of known hypersensitivity to edaravone or to any of the excipients. 
For patients who do not take FAB122 but are only followed up by phone, only inclusion 
criteria #1 and #5 will apply.   


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6. 
STUDY PROCEDURES  
All the study procedures are presented in the following table: 
Table 1: Study Scheduled Visits  
 
Baseline1 
 
 
V1
D1 
W0 
V2-N 
End of Trial4 
Every 3 months (±1 
week)
Administrative procedures 
 
 
ICF 
X 
 
ICF for FBR 
X 
 
In/exclusion assessment 
X 
 
Dispensing study 
medication 
X 
X 
Clinical Procedures 
 
 
Physical examination 
X 
X6 
Vital Signs  
X 
X 
Weight 
X 
X 
12-lead ECG 
X 
X6 
Neurological examination
X 
X6 
(S)AE monitoring 
X 
X 
Prior/Concomitant 
medication 
X 
X 
Laboratory procedures 
 
 
Chemistry2/ 
Haematology2/Urinalysis2
X
X 
Vitamin B6 monitoring3
X 
X 
Urine Pregnancy Test
X 
X 
Blood/urine sampling for 
biomarkers7 
X 
X8 
Blood sampling for 
genotyping for FBR (if 
consented) 
X 
 
ALS evaluation procedures 
 
 
ALSFRS-R
X 
X 
SVC 
X 
X 
ALSAQ-40 
X 
X 
EQ-5D-5L/VAS 
X 
X 
ECAS 
X 
X6 
King
MiToS 
X 
X 
Cost questionnaire 
X 
X 
Vital Status Follow Up5 
 
X 
Study Drug Administration  
X 
 
V=visit 
 
1. 
Baseline visit is V6 or V8 of the main study. 
finalization in the main ADORE study, baseline visit could take place up to 6 weeks after finalization. For patients 
who do not take FAB122 but are only followed up by phone, only ICF will be obtained.  


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2. 
Hematology: hematocrit, hemoglobin, RBC (red blood cell count & parameters), WBC (white blood cell count 
inclusive differential count), platelet (thrombocytes). Biochemistry: total protein, alkaline phosphatase, AST 
(aspartate transaminase), ALT (alanine transaminase), GGT (Gamma-glutamyl transpeptidase), direct and total 
bilirubin, blood urea nitrogen (BUN), creatinine (serum), sodium, potassium, chloride, calcium, bicarbonate, LDH 
(lactate dehydrogenase), CK (creatinine kinase), eGFR (estimated glomerular filtration rate), uric acid and fasting 
glucose, activated partial thromboplastin time (aPTT), prothrombin time (PTT) and fibrinogen..   
Urinalysis or dipstick: Blood, Glucose, Protein, Specific gravity, Ketone, pH, Nitrite, Leukocytes, Bilirubin, 
Urobilinogen, Microscopic exam, if abnormal results are noted. 
3. 
PLP levels will be monitored and, if necessary, supplementation of vitamin B6 (pyridoxine (100 mg/day)) will be 
prescribed. 
4. 
When patient withdraws consent, is not able to attend the study visits any more or is discontinued. 
5. 
Only for patients not taking IMP, phone conctact. For patients who do not take FAB122 but are only followed up by 
phone, only vital status will be collected. The rest of assessments will not be done. 
6. 
Every 6 months. 
7. 
Blood biomarkers:  neurofilament light chain (NfL). Serum creatinine and serum creatine kinase will be measured in 
biochemistry lab testing. Urine biomarkers: 8-hydroxy-2 -deoxyguanosine (8-OhdG), extracellular domain of 
neurotrophin receptor p75 (p75ECD). 
8. 
Every 12 months. 
Follow up of patients unable to attend to one onsite study visit 
In case that, on an ad hoc basis, due to ALS progression, the subject is not able to attend 
the clinic or perform specific testing such as SVC, at least ALSFRS-R score and adverse 
events will be collected (if necessary by telephone). Study medication will be provided to 
the patient as detailed in section 7.1.4. On site visit for key safety assessments needs to 
be performed as soon as possible (max. up to 6 months from last visit) to assess vital 
signs and perform physical exam, ECG and laboratory assessments.  
Follow up of patients unable to attend to more than one onsite study visit 
If, in the judgment of the site Investigator, the participant cannot reasonably be expected to 
travel to the clinic, the minimum data required to continue on study medication are 
laboratory tests (hematology, biochemistry and urinalysis or dipstick as per local lab 
standards), adverse event reporting and ALSFRS-R. 
The monitoring of ALSFRS-R and AEs may continue by telephone according to the 
nominal visit schedule. 
Laboratory samples for safety assessments may be obtained through a local laboratory, 
and results will be reviewed by the site investigator and the medical monitor. These data 
are to be obtained at least every 6 months until the patients withdraw, reaches the 
endpoint or the study completes, whichever occurs first. 
In case the site has an established procedure in place to perform visits at the home of the 
participant, the sponsor will assess the adequacy of the procedure in order to be used in 
the ADOREXT study. If the procedure is deemed adequate to guarantee 
 safety 
and the integrity of the data, home visits by the delegated site staff can be performed. 


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If the patient becomes unfit for travel, this information and the procedures to be followed to 
ensure the safety assessment of the patients must be documented in the source data. If 
no accommodations can be made for adequate safety monitoring, patients will be 
withdrawn from study medication. 
The following sections provide details regarding the procedures to be performed at each 
study visit: 
6.1. 
Eligibility Assessment 
All subjects who completed the full study period in the main ADORE study, will sign the 
extension study-specific consent form. The procedures for Visit 6 or 8 of the main ADORE 
study will be considered for the baseline visit for the extension study. In case the 
study, baseline visit could take place up to 6 weeks after finalization. Study assessments 
performed at Visit 6 or 8 of the main study can be used as baseline assessments of the 
open label extension ADOREXT study within the allowed 6 weeks period.   
A signed copy of the informed consent form (ICF) should be provided to each consenting 
subject and with the original to be retained in the sub
 
Baseline Assessments 
6.2. 
Baseline (Visit 1) 
The following procedures, performed at Visit 6 or 8 of the main study, will be considered as 
baseline procedures for the extension study:  
 
Review inclusion and exclusion criteria. 
 
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, respiratory 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). 
 
Blood samples for routine clinical labs (clinical chemistry, haematology). See 
table 2 for lab assessments. 
 
Blood sampling for biomarkers: 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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Urine samples for urinalysis or dipstick testing 
 
Urine pregnancy test only in women of childbearing potential. 
 
Plasma pyridoxal 
-phosphate (PLP) levels, and, if necessary, vitamin B6 
supplements (pyridoxine (100 mg/day)) will be prescribed. 
 
ALS evaluation procedures: ALSFRS-R, Slow Vital Capacity (SVC), ALSAQ-40, 
EQ-ED-5L, VAS, 
staging system and, MiToS 
 
Cost questionnaire. 
 
Adverse Events monitoring. 
 
ECAS. 
 
Study drug administration 
 
Dispense study medication 
 
6.3. 
Rest of visits 
Every 3 months and up to the product is marketed, subjects will attend the study site and 
the following procedures will be performed: 
 
Review ongoing concomitant medications.  
 
Complete physical examination (every 6 months). 
 
Neurological examination (every 6 months). 
 
Weight. 
 
Vital signs measured with the subject in a supine/semi-supine position (for at 
least 5 minutes prior), including blood pressure, pulse rate, respiratory 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) (every 6 months). 
 
Blood samples for routine clinical labs (clinical chemistry, haematology). See 
table 2 for lab assessments. 
 
Urine samples for urinalysis or dipstick testing.  
 
Blood sampling for biomarkers: neurofilament light (NFL) (every 12 months). 
 
Urine collection for biomarkers: urinary extracellular domain of neurotrophin 
receptor p75 (Urinary P75ECD) and oxidative stress biomarker 8-
hydroxyguanosine (8-OHdG) (every 12 months). 
 
Urine pregnancy test only in women of childbearing potential. 
 
Plasma pyrid
-phosphate (PLP) levels, and, if necessary, vitamin B6 
supplements (pyridoxine (100 mg/day)) will be prescribed. 
 
ALS evaluation procedures: ALSFRS-R, Slow Vital Capacity (SVC), ALSAQ-40, 
EQ-5D-5L, VAS, King  staging system and, MiToS.  
 
Adverse Events monitoring. 
 
ECAS (every 6 months). 
 
Vital status (tracheostomy or initiation of non-invasive ventilation for more than 
20 hours a day for more than 10 consecutive days) / Date of death. Cost 
questionnaire 
 
Dispense study medication 
 


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6.4. 
Phone contacts 
Patients not willing to receive or continue receiving active treatment in the extension study 
or that had already discontinued study treatment during the course of the main ADORE 
study for safety reasons, will be asked to be contacted by phone every three months and 
followed up for vital status. These patients will not undergo the baseline assessments or 
any other study procedures. 
Table 2: Overview of laboratory assessments 
 
Haematology 
Chemistry 
Urinalysis/Dipstick 
Haematocrit 
Bilirubin 
(direct) 
and 
Bilirubin 
(total) 
Blood 
Haemoglobin 
Alkaline phosphatase 
Glucose 
RBC 
Alanine aminotransferase (ALT) 
Protein 
Platelet count 
Aspartate aminotransferase (AST) Specific gravity  
WBC 
Bicarbonate 
Microscopic 
exam, 
if 
abnormal results are noted 
Differential count:  
Calcium 
Ketone 
 Basophils 
Chloride 
PH 
 Eosinophils 
Creatinine 
Nitrite 
 Lymphocytes 
gammaGT (GGT) 
Leukocytes 
 Monocytes 
Glucose 
Bilirubin 
 Neutrophils 
Potassium 
Urobilinogen 
 Large Unstained cells 
Sodium 
 
 
Uric Acid 
 
 
Total protein 
 
 
Urea (BUN) 
 
 
eGFR 
 
 
Activated partial thromboplastin 
time (aPTT) 
 
 
Prothrombin Time (PTT) 
 
 
Fibrinogen 
 
 
Lactate dehydrogenase (LDH) 
 
 
Creatinine kinase (CK) 
 
 
Vitamin B6 
 
 
Blood and urine samples for routine clinical chemistry, haematology and urinalysis/dipstick 
will be analysed locally. 
Vitamin B6 will be analysed by a central laboratory. 
Instructions for handling, shipment and storing of blood and urine samples for Biomarkers 
testing will be described in a separate laboratory manual.


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6.5. 
Early Discontinuation/Withdrawal of Participants 
Subjects may withdraw consent at any time for any reason or be discontinued from the 
extension 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.   
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.   
 
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. 
A subject must be discontinued from study treatment (but should continue to be monitored 
in the study) for any of the following reasons: 
1) Key safety assessment cannot be performed. 
2) The subject becomes pregnant during the study. 
3) 
the best interest of the subject to 
discontinue. 
4) Serious adverse event considered related to the IMP 
5) Severe Neurotoxicity considered related to the IMP 
6) Any other severe adverse event considered related to the IMP at the discretion of 
the investigator. 
7) Acute renal failure (creatinine clearance of less than 30 mL/min)  
8) Severe liver disorder defined as:  
a. ALT/AST 
. 
b. ALT/AST 
. 
c. ALT/AST 
 believed to be related to liver injury or 
hypersensitivity.  
d. ALT/AST 
/AST and with symptoms believed to be related to 
liver injury or hypersensitivity. 
e. ALT/AST 
/AST < 8xULN that persists more than two weeks. 
9) Acute lung injury with pyrexia, cough, dyspnoea and chest X-ray abnormality. 
10) Rhabdomyolysis.  
11) Disseminated intravascular coagulation (DIC). 
12) Hypersensitivity reaction 
13) Anaphylactic reaction/shock 
14) Thrombocytopenia 
a. Platelets <20 10^9/L or >100010^9/L  
b. Platelets between 20 and 50 10^9/L if in the investigator judgement the patient 
present risk of any kind of bleeding or haemorrhage. 
15) Neutropenia 
 
 


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The Sponsor reserves the right to terminate the extension study at any time if continuation 
of the protocol would present a potential safety risk to the subjects or in case that after the 
analysis of the main ADORE study it is concluded that there is no clinical benefit for the 
patients. 
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 
. 
 
 
 
 
 


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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 
 
Each sachet of the active treatment contains the following composition given in the table 3:  
Table 3: 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 
 


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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 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 gastrostomy and feeding tube if applicable.  
7.1.1. 
Packaging and Labelling  
The label(s) for the investigational product 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. 
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 compliant 
with treatment when > 80%-100% of the total scheduled doses since the last clinic visit are 
administered. 
Investigational product used in this study will be monitored for compliant usage throughout 
the trial by the Sponsor or their designee. 
7.1.3. 
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.  


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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 accordance with local regulations, in case it is necessary, and the site has not a specific 
procedure in place to deliver drugs directly to patients, IMP can be delivered directly to 
patient
lidated direct to patient service provided by the Sponsor.  
7.1.4. 
Concomitant Medication 
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 patients management.  
7.2. 
Other Treatments (non-IMPS) 
Riluzole (100 mg/day or less) may be used as background (add-on) therapy.  
 
 
 


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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. 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 over the study period, 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 each in-clinic 
visit. 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 Ki
m 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.  
8.1.5. 
Health Status  
ALSAQ40: The Amyotrophic Lateral Sclerosis Assessment Questionnaire is a patient 
reported outcome (PRO) designed to determi
th 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 


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questionnaire will be provided in the local language of the patient. The ALSAQ40 
questionnaire will be completed by the patient at each study visit 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 five 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 each study visit 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. 
8.1.6. 
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 each study visit.   
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. 
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 baseline visit. 
The BMI will be calculated.  


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Neurological examination will be performed by qualified personnel according to the 
Schedule of Events to asses 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 all clinical laboratory tests conducted during the study must be assessed by 
the investigator to assess pati
 
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
nitor. Any additional relevant laboratory 
results obtained by the investigator during the course of this study will be reported to the 
Sponsor or its representative. 
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.  
 
 


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9. 
SAFETY REPORTING 
Adverse events will be recorded (using MEDRA version 23.0) 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 
i
 
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. 
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 
ct 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). 


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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 Invest
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. 
9.2. 
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. 
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. 
The term 
efers 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 (i.e., no place to stay, live too far away to come for 
hospital visits, respite care) will not be considered inpatient hospitalizations. 


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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 subject
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.  
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 
 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 


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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 i
the database. 
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. For 
Germany, SAEs must be reported immediately (without undue delay) after site awareness, 
as per German ordinance (§ 12 (4) GCP-V). 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
e (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 
esentative 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 the subjec
ndition. 
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. 


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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. 
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
macovigilance (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
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. 
Pregnancy  
According to the recommendations on the CTFG contraception guidance, highly effective 
contraception measures are required for this study. All females patients who are of 
reproductive potential will be requested 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 (oral, injectable, implantable), , intrauterine device in pla
months, intrauterine hormone-releasing system, bilateral tubal occlusion or vasectomised 
partner. 
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.  
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. 


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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 
 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 2). The consented patients 
will complete the questionnaire at baseline and every 3 months thereafter. up to 
the end of the study.   
 eCRF: Some data will be gathered form the 
hospitalizations, concomitant medications, and occurrence of AEs.  
The following cost parameters will be considered for the cost-utility analysis:  
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.   
An ad-hoc cost questionnaire will be completed at Baseline and every 3 months thereafter. 
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 


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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.  
11.2. 
Sample Size Determination  
No formal size calculation has been done for the extension study. 
The main study plans to include approximately 300 patients. It is anticipated that 200-225 
patients might be included in this extension study. 
All subjects who completed the full study period in the main ADORE study and providing 
informed consent to comply with extension trial procedures are eligible to participate in this 
extension study. 
11.3. 
Description of Statistical Methods 
11.3.1. 
Analysis Populations  
Safety Analysis Set: The safety analysis set will consist of all subjects who receive at least 
1 dose of IMP in the extension study.  
11.3.2. 
Demographics, baseline characteristics 
Demographics and medical history will be retrieved from the main ADORE study. 
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.  
11.3.4. 
Efficacy Analysis 
Descriptive statistics (median, and the 25th and 75th percentiles with 95% confidence 
intervals) and Kaplan-Meier curves will be provided for patients participating in the 
extension study and patients that consented to only follow their vital status.  
The primary aim of the analysis is to evaluate the difference between patients originally 
randomized to FAB122 versus those originally randomized to placebo using the extended 
follow-up data from the open-label phase. The difference in overall survival between 
patients originally randomized to FAB122 versus those originally randomized to placebo  
will be evaluated using a log-rank test, stratified for randomization factors. The effect of 
treatment will be expressed as hazard ratio. In case of non-proportional hazards, we will 
estimate the difference in restricted mean survival time (RMST).  


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In addition, we will explore the effect of treatment switching in the placebo arm using a 
rank preserving structural failure time model (RPSFTM) and inverse probability of 
censoring weights (IPCW). Details of the analyses will be provided in the SAP.  
 
Changes in the in ALSFRS-R score, SVC, ALSAQ-40, EQ-5D-5L, and VAS score over 
time will be presented descriptively. 
11.3.5. 
Safety Analysis 
Safety evaluations will be based on the incidence, severity, and type of AEs and clinically 
significant changes in th
xamination 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.  
11.3.5.1. 
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.  
11.3.5.2. 
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). 
11.3.5.3. 
Concomitant Medication 
All concomitant medications will be summarized by medication class or ATC classification.  
11.3.5.4. 
Laboratory Parameters 
Clinical laboratory tests (including re-check values if present) will be listed chronologically. 
 values above 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. 
11.3.5.5. 
ECG 
From the 12-lead ECG data, HR, PR, RR, 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. 


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11.3.5.6. 
Vital Signs 
Vital signs, including blood pressure, pulse rate, respiratory rate, pulse oximetry and 
temperature will be summarized at each time point, using descriptive statistics and will be 
presented graphically.  
 


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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, Ethics 
Committee and Regulatory Authorities 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 Inve
iginal patient clinical source 
documents generated at the s
gin
cording of the 
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, phys
s, 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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12.3. 
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 eCRFs. 
 
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 eCRFs, 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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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 patient information leaflet consent includes information that data will be recorded, 
collected processed and may be transferred (to EU and non-EU countries). In case data 
will be transferred outside of the EU the sponsor safeguards for an adequate level of 
protection of the data.  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. 
The patient can take any time needed to decide whether to participate in the study. If the 
patient requires more time to decide, the investigator may schedule a date with the patient 
to re-discuss. 
 


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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. 
The patient will be reimbursed for travel expenses for visits to the study site and back, as 
well as drinks and meals for the patient and accompanying person during the respective 
study visits in the clinic. Reimbursement will be made against receipt or mileage 
allowance. 
 


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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 eCRFs, 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 (25 years, as per CTR: article 58 of the 
EU- ordinance 536/2014). 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 Sponsor
g. 
All data will be stored in a purpose-built data base for the study.  
 


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18, 
40 48. 
https://doi.org/10.1080/21678421.2017.1361441 
The Writing Group on behalf of the Edaravone (MCI-186) ALS 19 Study Group. 2017 b, 
2017. Open-label 24-week extension study of edaravone (MCI-186) in amyotrophic 
lateral sclerosis. Amyotroph. Lateral Scler. Front. Degener. 18, 55 63. 
https://doi.org/10.1080/21678421.2017.1364269 
The Writing Group on behalf of the Edaravone (MCI-186) ALS 19 Study Group. 2017 c, 
2017. Safety and efficacy of edaravone in well defined patients with amyotrophic 
lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet 
Neurol. 16, 505 512. https://doi.org/10.1016/S1474-4422(17)30115-1 
Treeway, 2019. Treeway 
 C1.04. A single dose, randomized, two-period, cross-over 
study to evaluate the absolute bioavailability and pharmacokinetics of a new oral 
formulation of TW001 in healthy subjects. (Synoptic Study Report). The 
Netherlands. 
Treeway, 2017a. Treeway - C1.01. An open-label, cross-over pilot study to evaluate the 
effect of a single dose of TW001 on the oxidative stress and pharmacokinetics with 
and without food in patients with amyotrophic lateral sclerosis. (Synoptic Study 
Report). The Netherlands. 
Treeway, 2017b. Treeway - C1.02. A randomized, open-label study to evaluate the 
pharmacokinetics and safety of multiple doses of TW001 and the effect of food on 
the pharmacokinetics of TW001 in healthy subjects. (Synoptic Study Report). The 
Netherlands. 
Turner, M.R., Barnwell, J., Al-Chalabi, A., Eisen, A., 2012. Young-onset amyotrophic 
lateral sclerosis: historical and other observations. Brain 135, 2883 2891. 
https://doi.org/10.1093/brain/aws144 
van Es, M.A., Hardiman, O., Chio, A., Al-Chalabi, A., Pasterkamp, R.J., Veldink, J.H., van 
den Berg, L.H., 2017. Amyotrophic lateral sclerosis. Lancet Lond. Engl. 390, 2084
2098. https://doi.org/10.1016/S0140-6736(17)31287-4 
Verber, N.S., Shepheard, S.R., Sassani, M., McDonough, H.E., Moore, S.A., Alix, J.J.P., 
Wilkinson, I.D., Jenkins, T.M., Shaw, P.J., 2019. Biomarkers in Motor Neuron 
Disease: 
A 
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Watanabe, Kazutoshi, Watanabe, Kazuhiko, Kuwahara, T., Yamamoto, Y., 1997. Free 
Radical-induced Oxidation Products of 3-Methyl-1-phenyl-2-pyrazolin-5-one (MCI-
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https://doi.org/10.5650/jos1996.46.797 
Westeneng, H.-J., Debray, T.P.A., Visser, A.E., van Eijk, R.P.A., Rooney, J.P.K., Calvo, 
A., Martin, S., McDermott, C.J., Thompson, A.G., Pinto, S., Kobeleva, X., 
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Gromicho, M., Körner, S., Ringer, T.M., Rödiger, A., Gunkel, A., Shaw, C.E., 
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J., Ludolph, A.C., Petri, S., de Carvalho, M., Van Damme, P., Talbot, K., Turner, 
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19. 
ANNEXES  
Annex 1, 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 
4 None
3 Intermittent use of BiPAP 
2 Continuous use of BiPAP 
1 Continuous use of BiPAP during day and night 


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1 Provides minimal assistance to caregiver 
0 Unable to perform any aspect of task 
0 Invasive mechanical ventilation by intubation or 
tracheostomy 
6. Dressing and hygiene 
 
 
4 Normal function 
 
3 Independent; can complete self-care with effort
or decreased efficiency 
 
2 Intermittent assistance or substitute methods 
 
1 Needs attendant for self-care 
 
0 Total dependence 
 
 
 
 
 
 


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  Annex 2: 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 at the visit every 3 months. 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)  
 


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Instructions for filling out the cost diary  
 
Please fill out this diary before visits every 3 months. 
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. 
 on to the next question. If 
lease 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.  
 
Please note:  
make statements which are related to your disease (ALS, motor neurone disease).  
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. 
 the following questions apply to the period of the last 3 months. 
12 weeks ago 
8 weeks ago 
Last 4 weeks 
Day 1. 
Day 1. 
Day 1. 


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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, 
ADOREXT Trial Group 


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Quarterly questionnaire (From ____.____.____ to ____.____.____) (DD-MM-YYYY) 
 
CLINICAL VISITS & HOSPITALISATIONS 
1. During the last 3 months, 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 
 complete 
the subsequent table 
A. If you have 
move on to question 
number 2. 
1 
2 
 
Table A. If 
ive? (e.g. lab test, filled prescription) 
 
GP and specialist 
visits (specialization) 
Number of 
contacts during the last 3 
months 
What was done? 
How often? 
General practitioner 
 
_____________________ 
 
est 
 
 
tomography 
resonance imaging 
 
 
_________
_________
_________
_________ 
Nurse 
_____________________ 
 
test 
 
ephone call 
ter 
tomography 
resonance imaging 
 
 
_________
_________
_________
_________ 
Neurologist 
_____________________ 
 
 
 
 
tomography 
resonance imaging 
 
 
_________
_________
_________
_________ 
Psychologist  
_____________________ 
 
 
 
 
_________
_________
_________
_________ 


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tomography 
resonance imaging 
__________ 
 
Ambulatory care 
in hospital 
_____________________ 
 
 
 
 
tomography 
resonance imaging 
 
 
_________
_________
_________
_________ 
Emergency 
department 
_____________________ 
 
 
cription filled 
 
tomography 
resonance imaging 
 
 
_________
_________
_________
_________ 
Other (please specify) 
__________________ 
_____________________ 
 
 
led 
l 
uter 
tomography 
resonance imaging 
 
 
_________
_________
_________
_________ 
Other (please specify) 
__________________ 
_____________________ 
 
 
lled 
 
 
tomography 
tic 
resonance imaging 
 
 
_________
_________
_________
_________ 
 
2. During the last 3 months, 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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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 
 
 
________________
_ 
 
 
 
________________
_ 
 
 
 
________________
_ 
 
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 3 months, 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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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 3 months, 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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From ___.___.___ 
Until ___.___.___ 
 
 
 
From ___.___.___ 
Until ___.___.___ 
 
 
 
From ___.___.___ 
Until ___.___.___ 
 
 
 
SPECIALIZED EQUIPMENT & DEVICES 
5. During the last 3 months, 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. 
 
If you had any adaptations done to your home but did not pay for it please specify who 
 
 
Medical Aids 
(examples) 
Dida you have to 
pay anything? 
Provided by 
 
 
 
 
 
lift 
____________________________
_ 
____________________________
_ 
 
 
 
 
 
 
 
 
 
 
__________
__________
__________
__________
__________
__________
__________ 
 
__________ 
__________
__________
__________
__________
__________ 
__________
__________ 
 
__________ 
ks 
 
____________________________
_ 
 
 
 
 
__________
__________
__________ 
__________
__________
__________ 


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N/A 
__________ 
 
 
e bathroom/shower 
ations 
____________________________
_ 
 
s 
____________________________
_ 
 
____________________________
_ 
 
 
ouse) 
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 3 months, 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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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 3 months, 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 
please 
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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If you have checked 
to question number 10. 
If you have 
move on to question 
number 13. 
 
10. If you returned to work in the last 3 months, is it the same 
employment that you had before your illness? 
 
 
 
1 
2 
 
11. During the last 3 months, 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 
se 
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 3 months, 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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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 on medical 
 
 
Stude
 
 
1 
 
2 
3 
4 
 
14. During last 3 months 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 
have finished the 
questionnaire. 
 
1 
2 
16. Is your health-related insurance policy/plan public or 
private? 
 
 
 
1 
2 
 
17. Please tell us what it covers by ticking one or more of the 
Health care costs (i.e. 
1 


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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-2201 
Clinical Study Reference: ADOREXT 
 
Final SAP v1.0, 19 April 2024 
 
TMP-516A Statistical Analysis Plan Template
Version 2.0, Document Number:  iDD-000074  
Page 1 of  19 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
(Short) study title:  
ADOREXT (ALS trial with Daily ORal Edaravone EXTension) 
study 
Name of the sponsor:  
Ferrer Internacional, S.A. 
Protocol identification:
FAB 122-CT-2201
Version and date of SAP:
Final v1.0, 19APR2024 
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-2201 
Clinical Study Reference: ADOREXT 
 
Final SAP v1.0, 19 April 2024 
 
TMP-516A Statistical Analysis Plan Template
Version 2.0, Document Number:  iDD-000074  
Page 2 of  19
 
 
VERSION HISTORY
 
Version
Date
 History list  
1.0 
19 Apr 2024
Final version 
 


Ferrer Internacional, S.A.
Protocol ID: FAB 122-CT-2201
Clinical Study Reference: ADOREXT
Final SAP v1.0, 19 April 2024
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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:  Nicola Lama, PhD, Certara
______________________ 
Signature 
______________ 
Date
Sponsor contact: 
Name, title, company:  Núria Bordas, Clinical Development Lead at Ferrer Internacional
______________________ 
Signature 
______________ 
Date
Nicola Lama, PhD, Certara
Núria Bordas, Clinical Development Lead at Ferrer Internacional


Ferrer Internacional, S.A.
Protocol ID: FAB 122-CT-2201
Clinical Study Reference: ADOREXT
Final SAP v1.0, 19 April 2024
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Version 2.0, Document Number: iDD-000074                                                                                   Page 4 of  19
Name, title, company:  Carolina Cernadas, MD, BSc, Clinical Development Biostatistician Lead 
at Ferrer Internacional
______________________ 
Signature 
______________ 
Date
Carolina Cernadas, MD, BSc, Clinical Development Biostatistician Lead 
,
,
p
y
at Ferrer Internacional


Ferrer Internacional, S.A. 
 
Protocol ID: FAB 122-CT-2201 
Clinical Study Reference: ADOREXT 
 
Final SAP v1.0, 19 April 2024 
 
TMP-516A Statistical Analysis Plan Template
Version 2.0, Document Number:  iDD-000074  
Page 5 of  19 
 
 
TABLE OF CONTENTS
Version history................................................................................................................................ 2
Approval page................................................................................................................................. 3
Table of contents............................................................................................................................. 5
List of abbreviations ....................................................................................................................... 7
1
General .................................................................................................................................. 9
2
Study Information.................................................................................................................. 9
2.1
Study Objective(s) ..................................................................................................... 9
2.2 
Design of the Study ................................................................................................. 10
2.3 
Study medication ..................................................................................................... 10
2.4
Sample size.............................................................................................................. 10
2.5 
Study assessments.................................................................................................... 10
3
Subjects for Analysis........................................................................................................... 11
3.1 
Analysis populations................................................................................................ 11
3.1.1
Modified Intent-to-treat (mITT and mITTe) Analysis Sets.............................. 11
3.1.2
Safety Analysis Set Extension (SAFe)............................................................. 11
3.2 
Protocol deviations .................................................................................................. 11
3.3 
Data Review Meeting .............................................................................................. 11
4
Study endpoints ................................................................................................................... 11
4.1 
Primary endpoint ..................................................................................................... 11
4.2 
Secondary endpoint(s) ............................................................................................. 11
4.3
Safety endpoint(s).................................................................................................... 12
5
Statistical Analysis .............................................................................................................. 12
5.1 
General considerations ............................................................................................ 12
5.2 
Missing or excluded data ......................................................................................... 13
Mapping of unscheduled or early termination visits ............................................................. 14
5.3 
Interim analysis........................................................................................................ 14
5.4 
Baseline characteristics ............................................................................................ 14
5.4.1
Inclusion/exclusion criteria............................................................................... 14
5.4.2
Demographics................................................................................................... 14
5.4.3
Disposition ........................................................................................................ 14
5.4.4
Medical history and Concomitant Medication ................................................. 15


Ferrer Internacional, S.A. 
 
Protocol ID: FAB 122-CT-2201 
Clinical Study Reference: ADOREXT 
 
Final SAP v1.0, 19 April 2024 
 
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5.4.5
Other screening data......................................................................................... 15
5.5
Statistical analysis primary and secondary efficacy endpoints ............................... 15
5.5.1
Primary analysis ............................................................................................... 15
5.5.2
Secondary analysis ........................................................................................... 15
5.5.2.1
Overall Survival and ‘Survival Time’ ..................................................... 15
5.5.2.2
ALSFRS-R questionnaire........................................................................ 15
5.5.3
Other efficacy endpoints and examinations ..................................................... 16
5.6
Safety and tolerability evaluation............................................................................ 16
5.6.1
Adverse events.................................................................................................. 16
5.6.2
Other safety endpoints and examinations ......................................................... 16
5.7
Scheduled visits, dosing and treatment compliance................................................ 16
6
Changes from protocol and other relevant remarks ............................................................ 16
7
Data receipt.......................................................................................................................... 17
8
Technical details.................................................................................................................. 17
8.1 
Programming conventions ....................................................................................... 17
8.2 
Coding ..................................................................................................................... 17
8.3 
Analysis software .................................................................................................... 17
8.4 
Presentation of tables, listings, graphs..................................................................... 17
9
Tables, listings, graphs ........................................................................................................ 18
9.1 
General ..................................................................................................................... 18
9.2 
In-text tables and graphs.......................................................................................... 18
9.3
End-of-text tables and graphs.................................................................................. 18
9.4 
Listings .................................................................................................................... 19
 


Ferrer Internacional, S.A. 
 
Protocol ID: FAB 122-CT-2201 
Clinical Study Reference: ADOREXT 
 
Final SAP v1.0, 19 April 2024 
 
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Version 2.0, Document Number:  iDD-000074  
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LIST OF ABBREVIATIONS
8-OHdG
8-hydroxyguanosine
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-Item
BMI
Body Mass Index 
 
CI
Confidence Interval
 
CRF
Case report form
 
CSR
Clinical Study Report
 
DSMB
Data Safety Monitoring Board  
 
EQ-5D-5L 
EuroQoL – 5 Dimensions – 5 Levels
 
GCP 
Good Clinical Practice
 
ICH
Internation Conference on Harmonisation 
 
ITT
Intent-To-Treat
 
MedDRA
Medical Dictionary for Regulatory Activities 
 
mITT
Modified Intent-To-Treat 
 
NFL
Neurofilament light
 
OLE
Open label extension 
 
P75ECD
Neurotrophin receptor p75
PDF
Portable Document Format 
 
PEG
Percutaneous Endoscopic Gastrostomy
PNG
Portable Network Graphics 
 
PT 
Preferred Term 
 
Q1
Lower quartile
 
Q3
Upper quartile
 
QoL
Quality of life
 
RMST
Restricted Mean Survival Time 
 
RTF
Rich Text Format
 
SAE
Serious Adverse Event
 


Ferrer Internacional, S.A. 
 
Protocol ID: FAB 122-CT-2201 
Clinical Study Reference: ADOREXT 
 
Final SAP v1.0, 19 April 2024 
 
TMP-516A Statistical Analysis Plan Template
Version 2.0, Document Number:  iDD-000074  
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SAF
Safety analysis population
 
SAP
Statistical Analysis Plan
SAS
Statistical Analysis Software
SD
Standard Deviation
SOC 
System Organ Class
 
SVC 
Slow Vital Capacity
 
TEAE
Treatment Emergent Adverse Event
VAS
Visual Analogue Scale
WHO
World Health Organisation 
 
 


Ferrer Internacional, S.A. 
 
Protocol ID: FAB 122-CT-2201 
Clinical Study Reference: ADOREXT 
 
Final SAP v1.0, 19 April 2024 
 
TMP-516A Statistical Analysis Plan Template
Version 2.0, Document Number:  iDD-000074  
Page 9 of  19
 
 
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-2201 by Certara.  
This plan is written in agreement with protocol versions (see table), and case report form (CRF) 
version 3.0, dated 28 Nov 2023. 
Version*
Date
V2.0 ITA & NL
24/01/2023 
V1.1 FRA
03/04/2023 
V2.1 RUS
11/05/2023
V1.1 ESP
01/06/2023 
V1.1 POL
01/06/2023 
V1.1 POR
07/06/2023 
V1.1 GBR
06/07/2023 
V1.1 BEL
06/07/2023 
V1.3 IRL 
06/07/2023 
V1.1 GER
10/07/2023 
V1.1 SWE
10/07/2023 
*see Protocol versions tracker for more details
The protocol and the (annotated) CRF are the primary source for this document, together with 
the relevant Good Clinical Practice (GCP) and International Council on Harmonization (ICH) 
guidelines. Furthermore, sponsor requirements for reporting will be considered. 
Additional changes or updates of those documents or requirements may result in a new version 
of the reporting/statistical analysis plan. This study-SAP is to be finalized prior to database lock 
for study FAB 122-CT-2201. 
The statistical analysis and summary tabulations described in this SAP will provide the basis of 
the results sections of the clinical study report (CSR) for this trial. 
2
STUDY INFORMATION 
2.1 
Study Objective(s) 
The primary objective of this study is to evaluate the long-term safety of FAB122 in patients 
with Amyotrophic Lateral Sclerosis (ALS). 
The secondary objectives of this study are as follows: 
 To evaluate the effect of treatment with FAB122 on overall survival 


Ferrer Internacional, S.A. 
 
Protocol ID: FAB 122-CT-2201 
Clinical Study Reference: ADOREXT 
 
Final SAP v1.0, 19 April 2024 
 
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To evaluate the effect of treatment with FAB122 on disease progression in patients with 
ALS 
To evaluate the effect of treatment with FAB122 on cognitive functioning
To evaluate the effect of treatment with FAB122 on quality of life (QoL).
Due to study early termination, some analysis planned in the protocol will not be performed (see 
Section 6). This SAP focuses on a subset of analyses related to objectives of safety, overall 
survival, and disease progression. 
2.2
Design of the Study
This is a multicenter open-label Phase III extension study to investigate the long-term safety of 
100 mg FAB122 once daily as oral formulation in ALS patients. 
All patients participating in the main study (ADORE) study will be invited to roll over to FAB122 
and to participate in ADOREXT. Patients that discontinued treatment in the main ADORE study 
for other than safety reasons, will be also invited to re-start treatment with FAB122 in the open 
label extension (OLE) study. The duration of this OLE was planned to be until the product is 
commercially available at each participant country, provided good tolerance and safety is proven. 
The sponsor could also make the decision to terminate the study at any time in case the objectives 
of the ADORE study are not met. 
Patients not willing to continue receiving active treatment in the extension study or that had already 
discontinued study treatment during the course of the ADORE study for safety reasons, will be 
asked to be contacted by phone and followed up for vital status.  
Subjects rolling over the active treatment will visit the clinic at Baseline (whenever possible, visit 
6 or 8 of the main study + 6 weeks in case the OLE is not fully set up) and every 3 months 
thereafter. 
2.3 
Study medication 
Patients will receive 100 mg FAB122 granules for oral solution in single sachets, which has to be 
dissolved in 100 mL water prior to administration.
2.4
Sample size
No formal size calculation has been done for the extension study. The main study plans to include 
approximately 300 patients. It is anticipated that 200-225 patients might be included in this 
extension study.
All subjects who completed the full study period in the main ADORE study and providing 
informed consent to comply with extension trial procedures are eligible to participate in this 
extension study. 
2.5
Study assessments
The schedule of assessments is available in Table 1 of the study protocol. 
 
 


Ferrer Internacional, S.A. 
 
Protocol ID: FAB 122-CT-2201 
Clinical Study Reference: ADOREXT 
 
Final SAP v1.0, 19 April 2024 
 
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3
SUBJECTS FOR ANALYSIS
3.1
Analysis populations
3.1.1
Modified Intent-to-treat (mITT and mITTe) Analysis Sets
The mITT analysis set includes all patients who were randomized in the ADORE study and 
received at least 1 dose of investigational product regardless of any protocol deviation (see 
Section 6). The mITT population will be used for the analysis of efficacy variables, and 
statistical analysis will be done “as randomized” in ADORE study. The mITT is considered the 
primary analysis population for efficacy. 
The mITTe analysis set refers to the subset of patients of mITT who enrolled in ADOREXT.
3.1.2
Safety Analysis Set Extension (SAFe) 
The SAFe population includes all patients enrolled in ADOREXT who have received at least one 
dose of the investigational drug during the extension study, 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”. Although all patients will be treated with FAB122 in 
ADOREXT, data will be presented also using the randomization groups of ADORE study. 
3.2 
Protocol deviations  
Following Sponsor review of the protocol deviations, none was found as impacting safety and no 
formal analysis of protocol deviations was found as required following early termination of the 
study. 
3.3
Data Review Meeting
Not applicable / not in the scope of this SAP following early termination of the study. 
4 
STUDY ENDPOINTS 
The primary, secondary and safety endpoints of this study are reported in the sections below. 
Due to study early termination, some analysis planned in the protocol will not be performed (see 
Section 6). Focus of this SAP are the primary endpoint, the overall survival and survival time.
The ALSFRS-R score will also be described. 
4.1 
Primary endpoint 
The primary endpoint is the nature, frequency and severity of Treatment Emergent Adverse 
Events (TEAEs). 
4.2 
Secondary endpoint(s)
 ALSFRS-R and mortality-adjusted change from baseline in ALSFRS-R total score until 
the end of the study 
 Overall Survival, defined as time from study treatment start in ADORE study to death 
from any cause
 Survival time, defined as time from study treatment start in ADORE study to the 
occurrence of respiratory insufficiency (insufficiency defined as tracheostomy or the use 


Ferrer Internacional, S.A. 
 
Protocol ID: FAB 122-CT-2201 
Clinical Study Reference: ADOREXT 
 
Final SAP v1.0, 19 April 2024 
 
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Version 2.0, Document Number:  iDD-000074  
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of non-invasive
 or death from any 
cause
 Change from baseline in SVC until the end of the study 
 Mean change in norm standardized ECAS total score
Change from baseline in the total score on the ALS Assessment Questionnaire-40-Item 
(ALSAQ-40) until the end of the study 
Change from baseline in EuroQoL – 5 Dimensions – 5 Levels (EQ-5D-5L) until
the end of the study 
Change from baseline in Health related QoL Visual Analogue Scale (VAS) score
until the end of the study 
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)
Cost-Utility analysis of treatment with FAB122
4.3
Safety endpoint(s)
 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
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 will be replaced by <0.001. 
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 in 
ADOREXT study, unless otherwise specified. Typically, baseline data are collected at Visit 6 or 
8 of the ADORE study. In case this value is missing for a specific patient in ADOREXT CRF 
data, but an earlier measurement is collected in ADORE study data, this value will be used as 
baseline instead. Unscheduled measurements are excluded as baseline value.


Ferrer Internacional, S.A. 
 
Protocol ID: FAB 122-CT-2201 
Clinical Study Reference: ADOREXT 
 
Final SAP v1.0, 19 April 2024 
 
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5.2
Missing or excluded data
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. 
 
Data of patients from site 5806 will not be included in the ADOREXT analysis, following GCP 
findings, in accordance with the analysis performed in ADORE study.  
 
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. 
 
 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.  
  
ALS history and randomization data will be inherited from ADORE analysis datasets.
 
 


Ferrer Internacional, S.A. 
 
Protocol ID: FAB 122-CT-2201 
Clinical Study Reference: ADOREXT 
 
Final SAP v1.0, 19 April 2024 
 
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Mapping of unscheduled or early termination visits 
When visit assessments are missing, repeat assessments may be mapped to the appropriate visit 
in the database by the DM vendor, when appropriate. For these unscheduled assessments 
following a missing protocol visit or assessment, 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 by the Sponsor as appropriate. 
The data of early withdrawal may 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 by the Sponsor as 
appropriate. 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. 
5.3 
Interim analysis 
Not applicable. 
5.4 
Baseline characteristics 
5.4.1 Inclusion/exclusion criteria 
Not applicable / not in the scope of this SAP following early termination of the study.  
5.4.2 Demographics 
Descriptive tabulations of the data for demographics and ADORE baseline characteristics will be 
made for the SAFe. 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, including ALS history data, using data 
from ADORE baseline. 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. 
5.4.3 Disposition 
To present disposition, summaries will be provided for all randomized, enrolled in extension, 
treated in extension, and completed extensions along with reasons for early discontinuation. 
Completion status will be derived from CRF form “Study Completion”. Additionally, the 
number/percentage of patients in the mITT and SAFe will be presented. The patient disposition 
will be presented per treatment group and overall. 
 


Ferrer Internacional, S.A. 
 
Protocol ID: FAB 122-CT-2201 
Clinical Study Reference: ADOREXT 
 
Final SAP v1.0, 19 April 2024 
 
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5.4.4
Medical history and Concomitant Medication 
Not applicable / not in the scope of this SAP following early termination of the study. 
5.4.5 Other screening data 
Not applicable following early termination of the study. 
5.5 
Statistical analysis primary and secondary efficacy endpoints 
All efficacy analysis will be conducted on the mITT set, unless otherwise specified.  
5.5.1 Primary analysis 
Not applicable, no primary endpoint for efficacy is included in this study. 
5.5.2 Secondary analysis 
5.5.2.1 Overall Survival and ‘Survival Time’ 
Time to event endpoints for overall survival and survival time definitions are reported in Section 
4.2. Patients who early terminated the ADOREXT study for reasons different from death will be 
considered as still alive and with no respiratory insufficiency event at the time of study 
discontinuation, unless otherwise specified in the survival follow-up CRF form. Endpoints will be 
derived by combining the survival data from ADORE and ADOREXT. 
Descriptive statistics including median, Q1/Q3 quartiles with 95% confidence intervals will be 
tabulated. Endpoints will be also summarized with the use of the Kaplan-Meier method. 
The difference between the groups randomized in ADORE to FAB122 and placebo will be 
evaluated descriptively by means of a stratified log rank test. Hazard ratios and 95% confidence 
intervals will be estimated with the use of a stratified Cox proportional-hazards regression model 
with treatment group as the sole explanatory variable. 
The difference between the groups will also be assessed using restricted mean survival time 
(RMST) analysis. Considering the duration of the ADOREXT study, the RMST will be performed 
up to the largest observation time from the pooled ADORE and ADOREXT data, adjusting for the 
stratification variables. 
Randomization strata from ADORE study will be used for the stratified analysis. No adjustment 
will be performed for the treatment cross over following enrollment in ADOREXT study. 
5.5.2.2 ALSFRS-R questionnaire
Descriptive statistics for absolute and change from extension baseline in total ALSFRS-R score 
will be presented by treatment group in summary tables.  
Results will also be presented for the following subscales:
 Bulbar function (questions 1-3 of the ALSFRS-R)
 Fine motor function (questions 4-6 of the ALSFRS-R) 


Ferrer Internacional, S.A. 
 
Protocol ID: FAB 122-CT-2201 
Clinical Study Reference: ADOREXT 
 
Final SAP v1.0, 19 April 2024 
 
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Gross motor function (questions 7-9 of the ALSFRS-R)
Respiratory function (questions 10-12 of the ALSFRS-R)
Only patients included in the mITTe will be included in the summaries.
5.5.3
Other efficacy endpoints and examinations 
Not applicable / not in the scope of this SAP following early termination of the study. 
5.6 
Safety and tolerability evaluation 
All safety presentations will be created using the SAFe population. 
5.6.1 Adverse events 
A treatment emergent adverse event (TEAE) is defined as an adverse event that appears at or 
after first dosing of extension. 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 treatment discontinuation, any AE leading to 
death. 
All TEAEs and those leading to death will be tabulated. 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 be tabulated busing 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 premature treatment 
discontinuation and Serious TEAEs. These summary tables will be presented by decreasing 
frequency of occurrence based on SOC and PT. 
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.  
5.6.2 Other safety endpoints and examinations 
Not applicable / not in the scope of this SAP following early termination of the study. 
5.7 
Scheduled visits, dosing and treatment compliance 
Not applicable / not in the scope of this SAP following early termination of the study. 
6 
CHANGES FROM PROTOCOL AND OTHER RELEVANT REMARKS  
Due to study early termination, some analysis planned in the protocol will not be performed. 
This SAP focuses on a subset of analyses related to objectives of safety, overall survival, and 


Ferrer Internacional, S.A. 
 
Protocol ID: FAB 122-CT-2201 
Clinical Study Reference: ADOREXT 
 
Final SAP v1.0, 19 April 2024 
 
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Version 2.0, Document Number:  iDD-000074  
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disease progression. In particular, analysis will be performed for the primary endpoint, the 
overall survival and survival time. The ALSFRS-R score will also be described. 
Overall survival and survival time endpoints definition will be updated to align with ADORE 
study. ALSFRS-R is also added to the secondary endpoints as it will be analyzed without 
mortality adjustment. 
The mITT analysis set was not originally planned in the study protocol and included in the SAP 
to perform survival analysis combining ADORE and ADOREXT data.  
7 
DATA RECEIPT 
All data will be received per transfer agreements. The received files will be imported into SAS 
and will be programmed into analysis datasets, before programming of the tables, listings and 
figures is done. The analysis datasets will not be checked against CDISC standards. 
8
TECHNICAL DETAILS 
8.1
Programming conventions
8.2
Coding
Coding of adverse events will be performed by the Data Management provider. Adverse events 
are coded with the MedDRA coding system. 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. Concomitant medications and medical history are not in the scope of this SAP. 
8.3
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.
8.4
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 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.


Ferrer Internacional, S.A. 
 
Protocol ID: FAB 122-CT-2201 
Clinical Study Reference: ADOREXT 
 
Final SAP v1.0, 19 April 2024 
 
TMP-516A Statistical Analysis Plan Template
Version 2.0, Document Number:  iDD-000074  
Page 18 of  19 
 
 
9
TABLES, LISTINGS, GRAPHS 
9.1 
General 
A detailed list of tables, graphs and listings is presented, if applicable, per report section in 
sections 9.2, 9.3 and 9.4. 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. 
9.2 
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.
9.3 
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. 
Table /graph 
number 
Contents of table/graph 
14.1 Demographic Data Summary figures and tables
14.1.1
Demographics
14.1.2
Baseline Characteristics
14.1.3 
ALS-specific history
14.1.4 
Disposition
14.2 Efficacy Data Summary Figures and Tables 
14.2.1.1
Survival time: descriptive statistics
14.2.1.2
Survival time: Kaplan-Meier curves 
14.2.1.3
Survival time: statistical analysis results (RMST) 
14.2.2.1
Overall survival: descriptive statistics
14.2.2.2
Overall survival: Kaplan-Meier curves 


Ferrer Internacional, S.A. 
 
Protocol ID: FAB 122-CT-2201 
Clinical Study Reference: ADOREXT 
 
Final SAP v1.0, 19 April 2024 
 
TMP-516A Statistical Analysis Plan Template
Version 2.0, Document Number:  iDD-000074  
Page 19 of  19 
 
 
14.2.2.3
Overall survival: statistical analysis results (RMST)
14.2.3.1
Descriptive statistics for absolute values and change from baseline ALSFRS-R 
total score and function domains 
14.3 Safety Data Summary figures and tables – 14.3.1 Displays of Adverse Events 
14.3.1.1
Overview adverse events
14.3.1.2
Treatment emergent adverse events by SOC and PT 
14.3.1.3
Treatment emergent serious adverse events by SOC and PT
14.3.1.4
Treatment emergent adverse events leading to treatment discontinuation by SOC 
and PT
14.3 Safety Data Summary figures and tables – 14.3.2 Listings of Deaths, Other Serious and 
Significant Adverse Events 
14.3.2.1
Deaths
14.3.2.2
TEAEs 
9.4
Listings 
Listings are not in the scope of this SAP.