Modulation of the Motor Pathway by Transcranial Pulse Stimulation in People With ALS: a Pilot Randomized Trial
Phase: NA
Conditions: Amyotrophic Lateral Sclerosis (ALS)
Sponsor: Parc de Salut Mar

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Modulation of the motor pathway by Transcranial Pulse Stimulation in people with ALS: a 
pilot randomized trial 
 
Protocol Number: NEU-TPS-ALS-01 
ClinicalTrails.gov number: pending 
Investigational Product: Neurolith 
Phase: Pilot study 
 
Short title: TPS for ALS 
Sponsor: Hospital del Mar Research Institute  
Doctor Aiguader 88 
Barcelona 08003 
SPAIN 
 
 
Protocol Version: 2.1 
Protocol Date: July 22nd , 2024 
 
 
 

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TABLE OF CONTENTS 
1.0 
TRIAL SUMMARY.................................................................................................... 7 
2.0 TRIAL DESIGN.......................................................................................................... 11 
 2.1 Trial Design ......................................................................................................... 11 
 2.2 Trial Diagram........................................................................................................ 11 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)............................................................................... 13 
 3.1 Primary Objective(s) & Hypothesis(es) .................................................................. 13 
 3.2 Secondary Objective(s) & Hypothesis(es)............................................................... 13 
 3.3 Exploratory Objectives...........................................................................................13 
4.0 BACKGROUND & RATIONALE..................................................................................... 14 
 4.1 Background ........................................................................................................... 14 
 
4.1.1 Therapeutic Background ....................................................................................... 14 
 4.2 Rationale................................................................................................................ 17 
 
4.2.1 Rationale for the Trial and Selected Subject Population ....................................... 17 
 
4.2.2 Rationale for Stimulation Protocol...................................................................……18 
 
4.2.2.1 Rationale for the Use of Sham ...................................................................... 18 
 
4.2.2.2 Starting Stimulation Protocol........................................................................ 18 
 
4.2.2.3 Maximum Exposure for This Trial…………....................................................... 18 
 
4.2.3 Rationale for Endpoints ........................................................................................ 18 
 
4.2.3.1 Efficacy Endpoints........................................................................................... 18 
 
4.2.3.2 Safety Endpoints............................................................................................. 18 
 
4.2.3.3 Exploratory Endpoints .................................................................................... 19 
 
4.2.3.6 Planned Exploratory Biomarker Research...................................................... 19 
 
4.2.3.7 Biomarker Analysis.......................................................................................... 19 
 4.3 Benefit/Risk ........................................................................................................... 20 
5.0 METHODOLOGY ........................................................................................................ 20 
 5.1 Entry Criteria.......................................................................................................... 21 
 
5.1.1 Diagnosis/Condition for Entry into the Trial ......................................................... 21 
 
5.1.2 Subject Inclusion Criteria....................................................................................... 21 
 
5.1.3 Subject Exclusion Criteria ..................................................................................... 21 
 5.2 Trial Treatment(s) ................................................................................................. 22 
 
5.2.1 Stimulation Protocol Selection/Modification....................................................... 22 
 
5.2.2 Timing of Therapy Administration......................................................................... 22 
 
5.2.3 Trial Blinding/Masking........................................................................................... 22 
 5.3 Concomitant Treatments/Vaccinations (Allowed) …............................................. 22 
 5.4 Rescue Treatments & Supportive Care.................................................................. 22 
 5.6 Diet/Activity/Other Considerations....................................................................... 22 
 
5.7.1 Diet....................................................................................................................... 23 

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5.7.2 Use of Alcohol, Caffeine, and Tobacco.................................................................. 23 
 
5.7.3 Activity .................................................................................................................. 23 
 5.7 Subject Withdrawal/Discontinuation Criteria......................................................... 23 
 5.8 Subject Replacement Strategy................................................................................ 23 
 
5.9 Beginning and End of the Trial ............................................................................. 23 
 5.10 Clinical Criteria for Early Trial Termination ........................................................... 23 
6.0 TRIAL FLOW CHART ................................................................................................... 25 
7.0 TRIAL PROCEDURES .................................................................................................. 27 
 7.1 Trial Procedures ................................................................................................... 27 
 
7.1.1 Administrative Procedures..................................................................................... 27 
 
7.1.1.1 Informed Consent........................................................................................... 27 
 
7.1.1.1.1 General Informed Consent...................................................................... 27 
 
7.1.1.2 Inclusion/Exclusion Criteria ........................................................................... 27 
 
7.1.1.3 Subject Identification Card ............................................................................. 27 
 
7.1.1.4 Medical History .............................................................................................. 27 
 
7.1.1.5 Prior and Concomitant Treatments Review ................................................... 28 
 
7.1.1.5.1 Prior Treatments...................................................................................... 28 
 
7.1.1.5.2 Concomitant Treatments......................................................................... 28 
 
7.1.1.6  Assignment of Screening Number.................................................................. 28 
 
7.1.1.7 Assignment of Treatment……………………………………........................................ 28 
 
7.1.1.8 Trial Compliance (Treatment)......................................................................... 28 
 
7.1.2 Clinical Procedures/Assessments.......................................................................... 28 
 
7.1.2.1 Physical Assessments/Examinations .............................................................. 28 
 
7.1.2.1.1 Physical Examination/Neurological Examination………………………….…... 28 
 
7.1.2.1.3 Vital Signs................................................................................................. 29 
 
7.1.2.1.4 Body Height/Weight................................................................................ 28 
 
7.1.2.2 Clinical Assessments………………………………................................................... 28 
7.1.2.2.9 Adverse Experience Monitoring............................................................. 30 
 
7.1.4.1 Withdrawal/Discontinuation.......................................................................... 31 
 
7.1.4.2 Blinding/Unblinding ....................................................................................... 31 
 
7.1.4.3 Domiciling ...................................................................................................... 31 
 
7.1.4.4 Calibration of Critical Equipment.................................................................... 31 
 
7.1.5 Visit Requirements................................................................................................. 31 
 
7.1.5.1 Screening........................................................................................................ 31 
 
7.1.5.2 Treatment Period – Visits………………............................................................ 31 
 
7.1.5.3 Post-Treatment Follow-up.............................................................................. 31 
 7.2 Assessing and Recording Adverse Events ............................................................... 33 

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7.2.1 
 Definition of an Over Stimulation for this Protocol and Reporting of Over 
Stimulation Protocol ……………………....................................................................................... 34 
 
7.2.2 
Reporting of Pregnancy and Lactation…………………........................................... 34 
 
7.2.3 
Immediate Reporting of Adverse Events…………………........................................ 35 
 
7.2.3.1 Serious Adverse Events .................................................................................. 35 
 
7.2.3.2 Events of Clinical Interest................................................................................ 35 
 
7.2.3.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting..................36 
 
7.2.4 Evaluating Adverse Events..................................................................................... 36 
 
7.2.5 Investigator Responsibility for Reporting Adverse Events .................................... 41 
8.0 STATISTICAL ANALYSIS PLAN ..................................................................................... 41 
 8.1 Statistical Analysis Plan Summary .......................................................................... 41 
 8.2 Responsibility for Analyses/In-House Blinding ....................................................... 42 
 8.3 Hypotheses............................................................................................................ 42 
 8.4  Analysis Endpoints ................................................................................................ 43 
 
8.4.1 Efficacy and Ancillary Endpoints............................................................................ 43 
 
8.4.2 Safety Endpoints ................................................................................................... 43 
 8.5 Analysis Populations.............................................................................................. 44 
 
8.5.1 Efficacy Analysis Populations ................................................................................ 44 
 
8.5.2 Safety Analysis Population..................................................................................... 44 
 8.6  Statistical Methods................................................................................................ 44 
 
8.6.1 Statistical Methods for Efficacy Analysis............................................................... 44 
 
8.6.2 Statistical Methods for Safety Analysis.................................................................. 45 
 
8.6.3 Summaries of Baseline Characteristics, Demographics, and Other Analyses ……...45 
 
8.6.3.1 Demographic and Baseline Characteristics .................................................... 45 
 8.7  Interim Analysis..................................................................................................... 45 
 8.8 Multiplicity ............................................................................................................ 45 
 8.9 Sample Size and Power Calculations ...................................................................... 45 
 8.11 Compliance (Treatment Adherence) ................................................................... 46 
 8.12 Extent of Exposure................................................................................................ 46 
9.0 LABELING, PACKAGING, AND STORAGE...................................................................... 46 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS.......................................................... 46 
 10.1 Confidentiality.................................................................................................... 46 
10.1.1 Confidentiality of Data ....................................................................................... 46 
10.1.2 Confidentiality of Subject Records........................................................................... 46 
10.1.3 Confidentiality of Investigator Information............................................................. 46 
10.1.4 Confidentiality of IRB/IEC Information..................................................................... 46 
 10.2 Compliance with Financial Disclosure Requirements............................................ 47 
 10.3 Compliance with Law, Audit and Debarment ....................................................... 47 

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 10.4 Compliance with Trial Registration and Results Posting Requirements.................. 48 
 10.5 Quality Management System................................................................................ 48 
 10.6 Data Management................................................................................................ 48 
 10.7 Publications ........................................................................................................ 49 
11.0 LIST OF REFERENCES................................................................................................. 50 
12.0 APPENDICES............................................................................................................. 53 
12.1 List of Abbreviations and Definition of Terms ......................................................... 53 
12.2 Criteria for ALS………………………………….……………….................................................... 55 
12.3 General Neurological Exam...................................................................................... 56 
12.4 Predefined Limits of Change Criteria ....................................................................... 59 
13.0 SIGNATURES............................................................................................................. 61 
 13.1 Investigator.......................................................................................................... 61 
 
 
 

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LIST OF TABLES 
   
Table 1 NEUROLITH Parameters and FDA Guidelines......................................................... 17 
Table 2 Trial Flow Chart...................................................................................................... 27 
Table 3 Evaluating Adverse Events ................................................................................... 39 
Table 4 Statistical Analysis Plan......................................................................................... 42 
Table 5 
Analysis Strategy for Key Efficacy Variables ………………………………………………….… 46 
Table 6 
Analysis Strategy for Safety Parameters ……………………………………………………….… 48 
 
 
 
 
 
 

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LIST OF FIGURES 
           
Figure 1 Trial Design Diagram ................................................................................................ 11 
Figure 2 NEUROLITH Concept ................................................................................................ 13 
Figure 3 NEUROLITH Headband............................................................................................. 13 
Figure 4 NEUROLITH TPS Steering ………………........................................................................ 14 
 
 
 
 

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1.0 TRIAL OUTLINE 
 
Study Title 
Modulation of the motor pathway by Transcranial Pulse Stimulation 
in people with ALS: a pilot randomized trial 
Study Registration 
NEU-TPS-ALS-01 
Study Category  
Interventional 
Investigator sponsored study 
Phase 
Pilot trial  
Background & 
Rationale 
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease 
preferentially damaging the motor pathway, but also other 
cognitive networks, leading to motor paralysis and death in 3-5 
years after diagnosis. At present, treatments only delay by few 
months the progression of the disease (e.g., to ventilatory support). 
For this reason, ALS in an important unmet need that would benefit 
from non-invasive neuromodulation therapies aimed to preserve 
central nervous system (CNS) networks. 
Transcranial Pulse Stimulation (TPS) is a non-invasive 
neuromodulation therapy that deliver ultra-short mechanical waves 
of low intensity to the cortex using neuronavigation. Mechanical 
waves and ultrasounds modulate neuronal activity by activating 
mechanoreceptors on the neuronal membrane, changing neuronal 
excitability (producing either activation or inhibition of excitatory 
(glutamatergic) or inhibitory (GABAergic) neurons depending on the 
stimulation parameters. TPS has shown the ability to slow disease 
progression in patients with other neurodegenerative diseases such 
as Alzheimer disease and Parkinson Disease, suggesting it may 
protect the cortical networks from neurodegeneration. 
Study Design 
Adaptive trial design: Stage 1) Open label study to assess the effects 
(neuromodulation) of TPS on biomarkers in ALS patients; Stage 2) A 
randomized, blinded, sham controlled study to assess the efficacy of 
TPS in patients with ALS 
Objective(s) 
To assess the efficacy of TPS of the motor cortex on biomarkers and 
clinical endpoints in patients with ALS  
Outcome(s) 
Primary:  
Stage 1. Change in the motor cortex excitability threshold from 
baseline to week 8.  
Stage 2. Change from baseline to month 6 in the ALS functional 
rating scale-revised (ALSFRS-R) total score. 
Secondary stage 1:  

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1. Change in the motor cortex excitability (paired-pulse transcranial 
magnetic stimulation (ppTMS): motor evoked potential (MEP) 
amplitudes, resting motor threshold, intra-cortical facilitation (ICF) 
and short intracortical inhibition (SICI)), from baseline to week 4 
2. Change plasma NfL levels from baseline to week 4 and 8 
3. Changes in muscle strength, assessed by MRC sum score from 
baseline to week 4 and 8 
4. Changes in hand-held dynamometry from baseline to week 4 and 
8 
Exploratory stage 1 
1. Changes in candidate biomarkers SOD1, Ataxin 2, C90rf72, 
UNC13A, TDP43, stathmin 2, NfL and NfH levels in extracellular 
vesicles of neuronal origin (nEVs) collected from plasma from 
baseline to week 4 and 8 
Secondary stage 2: 
 
1. Differences (treated vs sham) and change (from baseline to end 
of the study (month 6)) in the slow vital capacity (SVC)  
2. Differences (treated vs sham) and change (from baseline to end 
of the study (month 6)) in plasma NfL levels or other biomarkers  
from exploratory stage 1 if found significant 
3. Differences (treated vs sham) and change (from baseline to end 
of the study (month 6)) in in cortical hyperexcitability (MEP 
amplitudes, resting motor threshold, ICF and SICI) 
4. Changes in muscle strength, assessed by MRC sum score from 
baseline to end of the study (month 6) 
5. Changes in hand-held dynamometry, from baseline to end of the 
study (month 6) 
Exploratory stage 2 
1. Differences (treated vs sham) and change (from baseline to end 
of the study (month 6)) in candidate biomarkers levels in nEVs 
collected from plasma that were informative in stage 1 from 
baseline to week 4 and 8 
Safety endpoints: presence of serious adverse events 
Inclusion / 
Exclusion Criteria 
Inclusion: Patients with diagnosis of sporadic ALS (definite or 
clinically probable) as defined by the World Federation of Neurology 
revised El Escorial criteria, SVC of 50% or greater of estimated 
measure and presence of cortical hyper-excitability in the motor 
cortex as demonstrated by TMS; 21 to 80 years old and male or 
female 
Exclusion: patients with fALS (based on medical history) that are 
unable to tolerate TMS studies or have a contraindication as 
described below 

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Measurements & 
Procedures 
1. ALSFRS-R 
2. SVC 
3. MRC sum score 
4. Hand-held Dynamometry 
5. Motor cortex excitability by TMS 
6. Plasma NfL levels 
7. Blood: isolation nEVs and biomarker quantification (SOD1, Ataxin 
2, C90rf72, UNC13A, TDP43, stathmin 2, NfL and NfH) 
8. Brain MRI for neuronavigation 
9. TPS stimulations (6 sessions of 20 min each in 2 weeks) 
Study Product / 
Intervention 
Neurolith is a medical device delivering transcranial pulse 
stimulations under neuronavigation guidance.  
Controls 
ALS patients allocated to sham stimulations. Sham treated patients 
will be offered to receive TPS therapy in the Open Label Extension 
phase (OLE) of the trial for ethical purposes. 
Number of 
Participants & 
Rationale 
Stage 1: n=10 
Stage 2: n=40 (randomization 2:1 active vs sham stimulation) 
Rationale for sample size: this is an exploratory sample likely to be 
informative for experience in planning for future trials.  
Study Duration: 
24 months 
Stage 1: 6 months 
Stage 2: 3 months recruitment, 6 months randomized phase, 6 
months OLE, 3-month analysis and clinical scientific report 
Timelines: 
Stage 1:  
● First Patient First Visit (FPFV): September 1st , 2024 
● Last Patient Last Visit (LPLV): February 1st, 2025 
Stage 2: 
● First Patient First Visit (FPFV): March 1st , 2025 
● Last Patient Last Visit (LPLV): October 1st, 2026 
Study Schedule: 
Patients are recruited from the ALS center at Hospital del Mar from 
patients diagnosed with ALS and referrals provided by the local ALS 
foundation (Miquel Valls Foundation) 
Stage 1: V1: informed consent, inclusion/exclusion criteria, TMS 
cortex excitability, brain MRI (for neuronavigation) can be 
conducted at any time between Visit 1 and 2; V2: stim; V3: TMS and 
biomarkers assessment week 4; V4: TMS and biomarkers 
assessment week 8. 

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Stage 2: V1: informed consent, inclusion/exclusion criteria, TMS 
cortex excitability, brain MRI (for neuronavigation) can be 
conducted at any time between Visit 1 and 2; V2: randomization 
and baseline; V3-5: stim, biomarkers and scales; V6-V7: open label 
extension 
Study Center: 
ALS center and Neuromodulation center. Hospital del Mar – 
Pompeu Fabra University, Barcelona, Spain 
Statistical Analysis 
Plan 
Considering that this is a pilot study, and no previous data is 
available for this intervention, a convenience sample size of 10 
subjects for the pilot and 40 patients for the randomized phase has 
been defined. Using the results from the CENTAUR trial1 in patients 
with ALS, a sample size of 6 patients per arm provided a 90% to 
detect differences by week 24 with alpha 0.05. 
Changes on ALSFRS-R, motor threshold, biomarker levels before and 
after stimulation will be assessed with ANCOVA test. 
 
A list of abbreviations used in this document can be found in Appendix 12.3. 
 
 

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2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a pilot study for evaluating the efficacy of modulating the motor cortex (M1) with 
Transcranial Pulse Stimulation (TPS)2, 3 delivered by NEUROLITH device in patients with 
sporadic Amyotrophic Lateral Sclerosis (ALS)4. TPS is aimed to reduce cortical 
hyperexcitability and slow disease progression of the upper motor pathway, which will 
reduce the neurodegeneration of the lower motoneuron pathway and delay clinical 
progression. We will include patients with diagnosis of sporadic ALS (definite or clinically 
probable) as defined by the World Federation of Neurology revised El Escorial criteria, slow 
vital capacity (SVC) of 50% or greater of estimated measure and presence of hyper-
excitability in the motor cortex as demonstrated by transcranial magnetic stimulation 
(TMS). Patients 21 to 80 years old and male or female are eligible. Familial ALS is excluded 
from the study. Clinical adverse events and therapeutic effects will be assessed during the 
study. Considering the primary endpoint for stage 1 is the efficacy in reducing cortical 
hyperexcitability, the presence of M1 hyperexcitability at inclusion (baseline) is required. 
The study is composed of 2 stages: stage 1 is an open label study to assess the effects of TPS 
on biomarkers in ALS patients (TMS based hyper-excitability and molecular biomarkers); 
and stage 2 is a randomized, single blinded, sham controlled study to assess the efficacy of 
TPS in regulatory accepted clinical scales and biomarkers in patients with ALS.  
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures. 
2.2 
Trial Diagram 
The trial design is depicted in Figure 1. 
 

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Figure 1 
Trial Design Diagram 
 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 Co- Primary Objective(s) & Hypothesis(es) 
Objectives: 
Stage 1. Change in the motor cortex excitability threshold from baseline to week 8.  
Stage 2. Change from baseline to month 6 in the ALS functional rating scale-revised (ALSFRS-
R) total score. 
Hypothesis: 
TPS stimulation delivered to M1 will decrease cortical hyper-excitability and slow disease 
progression.  
 
3.2 Key Secondary Objective(s) & Hypothesis(es) 
Objectives: 
Secondary stage 1:  
1. Change in the motor cortex excitability from baseline to week 4 
2. Change plasma NfL levels from baseline to week 4 and 8 
3. Changes in muscle strength, assessed by MRC sum score from baseline to week 4 and 8 
4. Changes in hand-held dynamometry from baseline to week 4 and 8 
 
Secondary stage 2: 
1. Differences (treated vs sham) and change (from baseline to end of the study (month 6)) in 
the slow vital capacity (SVC)  
2. Differences (treated vs sham) and change (from baseline to end of the study (month 6)) in 
plasma NfL levels or other biomarkers  from exploratory stage 1 if found significant 
3. Differences (treated vs sham) and change (from baseline to end of the study (month 6)) in 
in cortical hyperexcitability (MEP amplitudes, resting motor threshold, ICF and SICI) 
4. Changes in muscle strength, assessed by MRC sum score from baseline to end of the 
study (month 6) 

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5. Changes in hand-held dynamometry, from baseline to end of the study (month 
6)Hypothesis: 
TPS stimulation delivered to M1 will decrease cortical hyper-excitability and slow disease 
progression.  
 
3.3. Exploratory endpoints 
Exploratory stage 1 
1. Changes in candidate biomarkers SOD1, Ataxin 2, C90rf72, UNC13A, TDP43, stathmin 2, 
NfL and NfH levels in extracellular vesicles of neuronal origin (nEVs) collected from plasma 
from baseline to week 4 and 8 
Exploratory stage 2 
1. Differences (treated vs sham) and change (from baseline to end of the study (month 6)) in 
biomarker levels in nEVs being informative from stage 1 collected from plasma from 
baseline to week 4 and 8 
Hypothesis: 
TPS stimulation changes molecular biomarkers levels in nEVs, which represents the 
cytoplasm content of brain neurons in the previous 12h, as a surrogate endpoint of the 
neurodegenerative process.  
 
3.4. Safety endpoints 
1. Presence of serious adverse events motor cortex excitability, reduce biomarkers of 
neuronal damage and slow disease progression 
Hypothesis: 
TPS is safe and well tolerated in patients with neurodegenerative disease and up to 80 years 
old 
 
4. BACKGROUND & RATIONALE 
4.1 Background 
4.1.1 Therapeutic Background 

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that involves both upper 
and lower motoneurons4. Patients develop a progressive loss of motor function, with a 
mean survival of 3 to 5 years. Other brain circuits are being damaged such as frontal-
temporal pathways leading to cognitive impairment and even to dementia. There is no 
diagnostic biomarker, and its diagnosis is based on clinical criteria, which are periodically 
reviewed and updated5-7 . ALS is a heterogenous disease from the clinical, genetic, and even 
histopathological point of view8 . Furthermore, there are no prognostic biomarkers that 
predict the outcome of the patients. New tools have even been developed to predict the 
progression profile of patients (ENCALS survival model, and the ENCALS risk profile) based 
on gender, age of onset, form, presence or absence of frontotemporal dementia, as well as 
respiratory function9, 10 . Data from sporadic and genetic forms of the disease has taught us 
that several key cellular and molecular pathways are involved in the disease such as 
cytoskeletal dynamics, neuroinflammation, mitochondrial dysfunction, reticulum 
endoplasmic stress and protein homeostasis11, 12 .  
Neuromodulation is intended to activate or restore 
specific neuronal circuits using different types of energy 
at varying frequency. Invasive neurostimulation by 
means of deep-brain electric stimulation for Parkinson’s 
disease and Essential Tremor have already achieved the 
level of validated therapies with high efficacy success 
and widespread usage. By contrast, the level of 
validation and benefits provided by non-invasive 
neurostimulation is very limited. For years, magnetic, 
electric, or light neurostimulation has been tested but 
has shown significant limitations because of lack of 
spatial resolution or low penetration into structures 
deep in the brain, where relevant motor circuits are 
located11.  
Transcraneal Pulse Stimulation (TPS) has been shown to provide an adequate 
neurostimulation platform because it offers high spatial and temporal resolution, as well as 
the excellent safety based on decades of experience with TPS in osteo-muscular, heart and 
kidney diseases2, 3, 13, 14. TPS can be generated with electrohydraulic, electromagnetic, and 
piezoelectric devices. Whereas ultrasounds uses an oscillatory sound wave, TPS uses a 
single sound wave (Figure 1). TPS can achieve significant penetration (8 cm) into the brain 
because of the lower skull absorption, allowing to activate the cortex, including regions 
further from the skull such as the hippocampus, 
insula or cingular cortex (figure 2)13. TPS can 
activate neurons by microcavitation due to the 
sound ultrashort waves. Such membrane 
displacements activate the many 
mechanosensors found in neurons and other 
cells.15 The activation of mechanosensors opens 
ion channels that change neuronal excitability 
and therefore induce either activation or 
Fig.2. TPS beam penetrates 8 cm in the brain covering 
the cortex thickness 
Fig.1. Ultrasound waves vs TPS waves 

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inhibition of neuronal circuits depending on the TPS protocol and the neuronal cell type16. 
For all these reasons, TPS has become a very promising technology for modulating neuronal 
circuits safely and effectively for treating brain diseases such as ALS17-23.  
 
4.1.2. TPS neuromodulation therapy 
The TPS neuromodulation device 
(NEUROLITH) is a medical device for offline 
MRI-guided neuromodulation treatment 
that maintains brain region specific targeting 
based on a neuronavigation system using an 
electromagnetic TPS system (figure 3). The 
Neurolith system has been approved in 
Europe (CE mark) in 2018 for the treatment 
of Alzheimer disease. At present, around 
10,000 patients with Alzheimer disease have 
been exposed to TPS with excellent safety. 
No serious adverse events have been 
reported and the most common adverse 
events are headache or fatigue that 
disappear in 24-48h.  The device directly delivers the ultrashort sound beam to a key 
structure involved with motor modulation such as M1 cortex using a neuronavigation 
system (figure 2). The NEUROLITH device will be comfortably applied at the clinic visit 
where the patient remains sited, the hair 
will be humidified, and ultrasound gel is 
applied to the electromagnetic stimulator. 
The device produces a characteristic 
sound that is not disturbing but 
recognized. No heat, pain, numbness or 
any other sensation is perceived by the 
patient. The system provides a sham 
stimulation option based in the use of a 
membrane containing gas that blocks 
sound transmission, preserving the 
characteristic sound or any other feature 
the patient may notice. 
Prior to first use, every subject will 
undergo an MRI scan to register the location on their temple region relative to the brain 
targets for tailored anatomical registration (figure 4 and 5). NEUROLITH has an external 
control unit containing a battery supply for initial cost efficiency, flexibility in stimulation 
protocols and human clinical study designs. 
Fig.3. Neurolith device is composed by the stimulation 
system (control unit and power source) and 
neuronavigation system 
Fig.4. The neuronavigation system guides TPS stimulation 
using off-line MRI guidance 

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The stimulation involves delivering 1,000 
pulses per cortical region, with a 
maximum of 6,000 pulses per session13. 
The system uses a low energy flux density 
maximum of 0.25 mJ/mm2 accordingly 
with EMA and FDA guidelines (high energy 
is defined as > 0.5 mJ/mm2). Each session 
use to extend for 20 min. The standard 
therapy involves 6 sessions in 2 weeks. 
After completion, single follow-up 
sessions are applied every 2 months. 
 
4.1.3. TPS safety and operation 
specifications 
TPS stimulation of the brain has been shown to be safe and well tolerated in animal and 
studies and clinical practice. So far, round 10,000 patients with Alzheimer disease have 
been treated with TPS (6 sessions in 2 weeks) and 800 have been retreated during follow-up 
(range of re-treatments 3-5) without having observed any serious adverse event13. Common 
adverse events are headaches and fatigue that disappears in 24-48h.  
In addition to TPS, the field of ultrasound stimulation is providing significant amount of data 
supporting the safety of sound waves for neurostimulation. Multiple animal studies have 
analyzed histological changes of tissue following repeated ultrasound exposure within the 
FDA-recommended imaging limits and, to date, no studies have found evidence of tissue 
damage19, 20. A more recent study examined long term effects of ultrasound 
neuromodulation in the brain using nonhuman primates21. The researchers treated animal’s 
brains with focused ultrasound across 129- 147 sessions over the course of two years at a 
semi-regular interval. Across the study, there were no signs of behavioral degradation while 
performing tasks associated with the treated brain region. Furthermore, comparison of MRI 
brain scans before and after the two-year treatment showed no morphological 
abnormalities in these animals. 
In addition to large animal models, histological and report-based safety data has been 
obtained from human neuromodulation studies. Patients scheduled for anterior temporal 
lobe resection for epilepsy treatment had their temporal lobe exposed to a battery of 
focused ultrasound paradigms prior to surgical removal22. Examination of the excised tissue 
revealed no indications of morphological damage or neuronal damage (acidophilic cells). In 
a study with ultrasound parameters comparable to those proposed here in our First-in-
Human study, subjects’ thalamic nuclei were stimulated to reduce pain perception. The 
study found a significant reduction in perception and, critically, no adverse events were 
reported.  
 
4.2 
Rationale 
4.2.1 
Rationale for the Trial and Selected Subject Population 
Fig.5. The software provides controls for intensity, pulse 
number, pulse repetition, total number of pulses and 
neuronavigation 

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NEUROLITH is a non-invasive neuromodulation device, using low intensity TPS (LITPS) to 
stimulate neurons involved in motor control. LITPS stimulates neurons by cavitation that 
activates mechanoreceptors that modulates neuronal excitability and firing. LITPS is safe 
and can penetrate the skull and brain reaching the whole cortex, including deeper regions 
such as the hippocampus, insula or cingulate cortex. Therefore, LITPS is a highly selective 
neurostimulation approach to modulate relevant neuronal networks, in this case the 
networks regulating the motor circuits. Indeed, LITPS has shown extended effects along 
time24. 
Given the potential efficacy of LITPS, and the need for highly effective and safe treatments 
for ALS, this study aims to examine the safety and efficacy of LITPS to modulate motor 
cortex M1 in patients with ALS. 
4.2.2 Rationale for Stimulation Protocols Selection/Regimen 
The stimulation protocols for the current study will be 20 min duration as indicated in the 
CE mark approval. The system uses a low energy flux density maximum of 0.25 mJ/mm2 
accordingly with EMA and FDA guidelines (high energy is defined as > 0.5 mJ/mm2). The 
standard therapy involves 6 sessions in 2 weeks as indicated in the CE mark. After 
completion, single to multiple follow-up sessions can be applied every 2-3 months. 
4.2.2.1 Rationale for the Use of Sham 
In order to assess the efficacy of the therapy in clinical outcomes, comparison between 
active and sham treatment is required. Using sham or placebo for 6 months is accepted for 
patients with ALS as shown in the most recent phase 2 and 3 trials. In order to encourage 
participation and fulfill patients’ expectations, sham treated patients will receive active 
stimulation during the open label extension period (OLE), intended to collect more safety 
data and to assess sustainability of the efficacy observed in the double-blinded period 
(DBP). 
4.2.2.2 Starting Stimulation Protocols for This Trial 
The stimulation protocol of TPS in this trial will start at 0.25 mJ/mm2 as defined in the CE 
mark approval. 
4.2.2.3 Maximum Dose/Exposure for This Trial 
The stimulation will be always below the threshold that defines high intensity TPS (0.5 
mJ/mm2) and below the threshold defined in the CE mark (0.25 mJ/mm2). 
4.2.3 
Rationale for Endpoints 
4.2.3.1 
Efficacy Endpoints 
Primary endpoints:  
Stage 1. Changes in the motor cortex excitability determined by TMS: neuronal hyper-
excitability has been described in neurodegenerative diseases including ALS. The 
hyperexcitability is consider a consequence of the pathogenic process that contributes to 
neurodegeneration. For this reason, restoring neuronal excitability to normal limits is 
considered as a therapeutic target 
Stage 2. Change from baseline to month 6 in the ALS functional rating scale-revised (ALSFRS-
R) total score.: Changes in the ALSFRS-R is accepted primary endpoint by regulatory 
authorities (EMA and FDA) for defining therapeutic efficacy in this condition. 

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Secondary endpoints:  
Secondary stage 1:  
1. Change in the motor cortex excitability from baseline to week 4: to assess changes in 
excitability in a shorter period of time (4 weeks) 
2. Change plasma NfL levels from baseline to week 4 and 8 
3. Changes in muscle strength, as assessed by MRC sum score and hand-held dynamometry,  
from baseline to week 4 and 8 
 
Exploratory stage 1 
1. Changes in candidate biomarkers SOD1, Ataxin 2, C90rf72, UNC13A, TDP43, stathmin 2, 
NfL and NfH levels in extracellular vesicles of neuronal origin (nEVs) collected from plasma 
from baseline to week 4 and 8: levels of proteins related with ALS pathogenesis in the 
cerebrospinal fluid (CSF) are proposed as biomarkers of the disease. nEVs is a promising 
strategy to identify new biomarkers. Such vesicles can be isolated from plasma (even frozen 
plasma) and reflects the cytoplasm content of the neuronal population 12h in advance25. 
The vesicles content is representative of the cytoplasm and includes proteins, RNAs and 
metabolites. Then, nEVs can be considered as a surrogate approach to a liquid biopsy of the 
brain. As such, several biomarkers have been identified in patients with ALS26, Alzheimer 
disease27, 28, Parkinson disease29, 30, traumatic brain injury or MS31. Here, we propose 
collecting nEVs to conduct a biomarker search study to identify biomarkers associated with 
the TPS therapy in the motor cortex of people with ALS. Using nEVs, we can assess such 
biomarkers from a blood draw sample and reflecting their content in the brain, becoming a 
powerful approach to validate new biomarkers for ALS and response to therapy 
 
Secondary stage 2: 
1. Differences (treated vs sham) and change (from baseline to end of the study (month 6)) in 
the slow vital capacity (SVC)  
2. Differences (treated vs sham) and change (from baseline to end of the study (month 6)) in 
plasma NfL levels or other biomarkers  from exploratory stage 1 if found significant 
3. Differences (treated vs sham) and change (from baseline to end of the study (month 6)) in 
in cortical hyperexcitability (MEP amplitudes, resting motor threshold, ICF and SICI) 
4. Changes in muscle strength, assessed by MRC sum score from baseline to end of the 
study (month 6) 
5. Changes in hand-held dynamometry, from baseline to end of the study (month 6) 
 
Exploratory stage 2 
1. Differences (treated vs sham) and change (from baseline to end of the study (month 6)) in 
biomarker levels in nEVs collected from plasma that were informative in stage 1 from 
baseline to week 4 and 8: same as above 
4.2.3.2 Safety Endpoints 
The safety and tolerability of TPS will be continuously assessed throughout the study via 
Adverse Event reporting, and vital signs will be assessed at every trial visit. The Columbia-

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Suicide Severity Rating Scale (C-SSRS) will be conducted at the baseline and end of the 
treatment to prospectively assess for the emergence of suicidal ideation and behavior.  
4.2.3.3 
Exploratory Endpoints 
4.3 
Benefit/Risk 
Participants in this study are patients with ALS, which due to the seriousness of their 
condition, have agreed to participate. TPS is not invasive, is well tolerated and is a minimal-
risk device. As a result, the risk/benefit should be highly beneficial for the participants. 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 
Diagnosis/Condition for Entry into the Trial 
Male and female subjects aged 21 to 80 years (inclusive) with sporadic ALS will be enrolled 
in this trial. Familial ALS (fALS) accounts for 10% of cases, with sporadic ALS ( sALS) 
accounting for the remaining 90% of cases. Distinction between fALS and sALS will be done 
by family history. 
5.1.2 
Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be between 21 to 80 years of age (inclusive) on the day of signing informed consent.  
2.  Patients with diagnosis of sporadic ALS (definite or clinically probable) as defined by the 
World Federation of Neurology revised El Escorial criteria)5, SVC of 50% or greater of 
estimated measure and presence of cortical hyper-excitability in the motor cortex as 
demonstrated by TMS.  
3. Each subject must sign the informed consent form, in accordance with local 
requirements, after the scope and nature of the investigation have been explained to the 
subject, and before Screening assessments.  
4. Based on the investigator's judgment, the subject should: 
Be able to speak, read, and understand the language of the trial staff and the 
informed consent form; 
Possess the ability to respond verbally to questions, follow instructions, and 
complete study assessments; 
Be able to adhere to the stimulation protocol and visit schedules. 
5. Have results of a physical examination (PE), including neurological exam and vital signs 
not clinically significant. 
6. If female, following actively anti-conceptive measures or not be of childbearing potential 
as indicated by one of the following: 
• Has reached natural menopause, defined as 45 years of age with ≥6 months of 
spontaneous amenorrhea  
• Has had a hysterectomy; 
• Has had bilateral tubal ligation; or 
• Has had a bilateral oophorectomy (with or without a hysterectomy) and greater 
than 6 weeks have passed since the surgery 

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9. Male participants must ensure a condom is used for all sexual intercourse as well as 
following the acceptable methods of contraception listed above for your female partner. 
You must ensure that they are used for the entire duration of the study. You should not 
father a child or donate sperm for this same period. 
5.1.3 
Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Patietns with familial ALS 
2. Has any unstable medical or psychiatric disease other than ET 
3. Patients that are unable to tolerate TMS studies. 
 
Additional exclusion criteria include: 
1.     Has evidence of a clinically relevant neurological disorder at Screening, including but not 
limited to: cerebellar degeneration, hyperthyroidism, multiple sclerosis,  vascular dementia, 
Alzheimer’s disease (AD), frontotemporal dementia, Huntington's disease, progressive 
supranuclear palsy, neurosyphilis, dementia with Lewy bodies, other types of dementia, 
mental retardation, hypoxic cerebral damage, cognitive impairment due to other disorders, 
or history of head trauma with loss of consciousness that either led to persistent cognitive 
deficits or in the opinion of the investigator confounds the diagnosis. 
2.  Is at imminent risk of self-harm, based on clinical interview and responses on the 
Columbia-Suicide Severity Rating Scale (C-SSRS), or of harm to others in the opinion of the 
investigator. Subjects must be excluded if they report suicidal ideation with intent, with or 
without a plan or method (e.g., positive responses to items 4 or 5 in assessment of suicidal 
ideation on the C-SSRS) in the past 2 months or suicidal behavior in the past 6 months. 
3.  Has a history of alcoholism or drug dependency/abuse within the last 5 years of Screening. 
4.  Has a recent history (within the 6 months prior to Screening) of regular consumption (3 or 
more days per week) of more than 3 alcoholic beverages per day  
5.  Has a recent or ongoing, uncontrolled, clinically significant medical condition where 
participation in the trial would pose a significant medical risk to the subject or would 
confound study results within 3 months of Screening, such as: 
● Conditions including but not limited to diabetes, hypertension, Human 
Immunodeficiency Virus (HIV) or other relevant infections, thyroid or endocrine 
disease, Chronic Obstructive Pulmonary Disease (COPD), delirium, congestive heart 
failure, angina, cardiac or gastrointestinal disease, or renal disease requiring dialysis. 
● Major surgery including not limited to abdominal, thoracic, cardiac, or orthopedic 
surgery, or any procedure requiring general anesthesia 
● Subjects with recently controlled or treated medical conditions may be considered for 
re-screening on a case-by-case basis.  
● Has a history of hepatitis or liver disease that, in the opinion of the investigator, has 
been active within the 6 months prior to Visit 1. 
6.  Has a history of malignancy occurring within the 5 years immediately before Screening, 
except for a subject who has been adequately treated for:  
● Basal cell or squamous cell skin cancer; 
● In situ cervical cancer; 
● Localized prostate carcinoma;  

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22 
● Who has undergone potentially curative therapy with no evidence of recurrence for 
≥3 years post-therapy, and who is deemed at low risk for recurrence by her/his 
treating physician.  
7.  Is pregnant, is attempting to become pregnant, or is nursing children. 
8.  Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling, or 
child) who is investigational site directly involved with this trial. 
5.2 
Trial Treatment(s) 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations. 
5.2.1 Therapeutic regimen Selection: TPS stimulation protocols 
20 min stimulation with a maximum of 6,000 pulses and maximum of 0.25 mJ/mm2 per 
session. 6 Sessions in 2 weeks per treatment period followed with a single stimulation 
session every 2 months (2 additional sessions by month 2 and 4). 
5.2.2 Timing of Therapeutic Regimen Administration 
The treatment will be administered in the first 4 weeks after randomization with a duration 
of 2 weeks for the first period. Then, single stimulation sessions will be conducted every 2 
months, which means 2 additional sessions (month 2 and 4). 
5.2.3 
Trial Blinding/Masking 
Patient and physician will be blinded. The sham reproduces the patient experience of the 
TPS treatment (mainly the sound produce by the stimulator). The treating researcher will be 
unaware of the patient allocation. An independent investigator informed of the therapeutic 
arm will prepare the device to administer treating stimulation or sham and will record such 
assignment for each treating visit in a secured file not available for the treating researcher. 
5.3 
Randomization 
Treatment allocation/randomization will occur centrally using an interactive voice response 
system / integrated web response system (IVRS/IWRS). There are 2 treatment arms: active 
TPS and sham.  Subjects will be assigned randomly in a 1:1 ratio to either TPS or sham.  
5.4 
Stratification 
No randomization stratification is considered in this study 
5.5  Concomitant Treatments (Allowed) 
Patients will be allowed to take their therapy prescribed for ALS and any other comorbidity. 
Treatments specifically prohibited in the exclusion criteria are not allowed during the 
ongoing study. If there is a clinical indication for any treatment specifically prohibited during 
the trial, discontinuation from trial therapy may be required.  The investigator should 
discuss any questions regarding this with the Principal Investigator.  The final decision on 
any supportive therapy rests with the investigator and/or the subject's primary physician. 
However, the decision to continue the subject on trial therapy requires the mutual 
agreement of the investigator and the subject. 
5.6 
Rescue Treatments & Supportive Care 
No rescue or supportive treatments are specified to be used in this trial. 
5.7 
Diet/Activity/Other Considerations 

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23 
Not required. 
5.7.1 Diet 
Subjects should maintain their usual diet throughout the duration of the trial. 
5.7.2 
Use of Alcohol, Caffeine, and Tobacco 
The site should advise subjects that alcohol should NOT be consumed during the study. The 
site should advise subjects to limit their alcohol intake as follows: 
Refrain from consuming any alcohol for at least 24 hours prior to the study.  
The site should advise subjects to limit their caffeine consumption as follows: 
Limit their daily caffeine consumption to ≤600 mg caffeine. (See Appendix 12.7 for 
additional guidance on caffeine products and content.). In addition, caffeinated 
products should not be consumed until after completion of all procedures at the 
visit. 
The site should advise subjects to limit their tobacco use as follows:  
Refrain from the equivalent of >15 cigarettes a day during the study, and 
Refrain from smoking during the study 
5.7.3 
Activity 
NA 
5.8 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at 
the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be withdrawn by the investigator if enrollment into the trial is inappropriate, the trial 
plan is violated, or for administrative and/or other safety reasons.  Specific details regarding 
discontinuation or withdrawal procedures are provided in Section 7.1.4 – Other Procedures. 
Table 2 provides reasons why a subject must be discontinued from treatment but may 
continue to be monitored in the trial, as well as reasons why a subject must be discontinued 
from treatment and the trial. 
Table 2 
Discontinuation Scenarios 
Reason for Discontinuation Scenario 
Action 
The subject or legal representative (such as a parent or 
legal guardian) withdraws consent. 
Discontinuation from 
Treatment and Trial 
The subject has a medical condition or personal 
circumstance which, in the opinion of the investigator, 
places the subject at unnecessary risk through 
continued participation in the trial or does not allow 
the subject to adhere to the requirements of the 
protocol. 
Discontinuation from 
Treatment and Trial 
The subject is no longer able to participate in the trial or 
is not compliant with trial-related procedures. 
Discontinuation from 
Treatment and Trial 
The subject takes a prohibited treatment during the 
trial.  
This deviation should be 
documented and consulted 

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24 
regarding the management of 
the subject. 
Subjects who report suicidal ideation with intent, with 
or without a plan or method (i.e., a positive response to 
items 4 or 5 in the assessment of suicidal ideation on 
the C-SSRS) or suicidal behavior may meet 
discontinuation criteria.   
Please refer to Section 
7.1.2.2.11, 7.2.3.2 and the ECI 
guidance document for details. 
Discontinuation from treatment is “permanent.” Once a subject is discontinued, he/she 
shall not be allowed to restart treatment. 
5.9 
Subject Replacement Strategy 
No subject replacement is intended. 
5.10 Beginning and End of the Trial 
The overall trial begins when the first subject signs the informed consent form. The overall 
trial ends when the last subject completes the last study-related phone-call or visit, 
discontinues from the trial, or is lost to follow-up (i.e., the subject is unable to be contacted 
by the investigator). 
5.11 Clinical Criteria for Early Trial Termination 
There are no pre-specified criteria for terminating the trial early. 
 
 

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6.0 TRIAL FLOW CHART 
Table 3 Trial flow chart 
Stage 1 
Visit Number 
1 
2 
3-5 
6 
Visit Title 
Screen 
Baseline 
Stimulation 
End  
Scheduled Week 
0 
1 
2-3 
4 
Scheduling Window  
by Days: 
3 
3 
2 
5 
Administrative  
Procedures 
 
 
 
 
Informed Consent  
X 
 
 
 
Inclusion/Exclusion  
Criteria 
X 
 
 
 
Identification Card 
X 
 
 
 
Medical History 
X 
 
 
 
Prior Medication Review 
X 
 
 
 
Monitor Trial  
Device Compliance 
 
X 
X 
 
Clinical Procedures Assessments 
 
 
 
 
TPS stimulations 
X 
X 
X 
 
Vital Signs 
 
X 
X 
X 
Physical Exam 
 
X 
X 
X 
MRC sum score 
 
X 
X 
X 
Hand-held dynamometry 
 
X 
X 
X 
Brain MRI 
 
X 
 
 
TMS 
 
X 
 
 
Neurological  
examination 
X 
X 
X 
X 
 C-SSRS 
X 
X 
X 
 
ALSFRS-R 
X 
X 
X 
X 
Blood draw 
 
X 
X 
X 
SVC 
 
X 
 
 
 
 
 

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26 
 
Stage 2  
Visit Number 
1 
2 
3-5 
6-7 
8 
9 
10-16 
17-
18 
19 
Visit Title 
Screen 
Rand 
Base 
Stim 
Stim 
FU  
End 
DBP 
Onset 
OLE 
Stim 
3 
Stim 
FU 
End 
OLE 
Scheduled Week 
0 
1 
2-3 
8-16 
16 
16 
16-18 
26-
34 
34 
Scheduling Window  
by Days: 
3 
3 
2 
2 
5 
7 
2 
2 
5 
Administrative  
Procedures 
 
 
 
 
 
 
 
 
 
Informed Consent  
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
Criteria 
X 
 
 
 
 
 
 
 
 
Identification Card 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Prior Medication Review 
X 
 
 
 
 
 
 
 
 
Monitor Trial  
Device Compliance 
 
X 
X 
X 
 
 
X 
X 
 
Clinical Procedures 
Assessments 
 
 
 
 
 
 
 
 
 
TPS stimulations 
X 
X 
X 
X 
 
 
X 
X 
 
Vital Signs 
 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
 
X 
X 
X 
X 
X 
X 
X 
X 
MRC sum score 
 
X 
X 
X 
X 
X 
X 
X 
X 
Hand-held dynamometry 
 
X 
X 
X 
X 
X 
X 
X 
X 
Brain MRI 
X 
 
 
 
 
 
 
 
 
TMS 
X 
X 
X 
X 
X 
 
 
 
 
Neurological  
examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 C-SSRS 
X 
X 
X 
X 
 
 
X 
X 
 
ALSFRS-R 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood draw 
 
X 
X 
X 
X 
 
 
 
 
SVC 
 
X 
 
 
 
X 
 
 
 
Stim: TPS stimulation (6 times in 2 weeks, 20 min each); rand: randomization; Base: 
baseline; DBP: double blind period; OLE: Open Label Extension 
 
 

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27 
 
7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 
7.1.1 
Administrative Procedures 
7.1.1.1 Informed Consent 
The investigator or qualified designee must obtain documented consent from each 
potential subject or each subject’s legally acceptable representative prior to participating in 
a clinical trial. Documented consent from each subject (referred to as subject consent) will 
also be obtained by the investigator or qualified designee. 
7.1.1.1.1 General Informed Consent 
Consent will be documented by the subject’s dated signature on a consent form along with 
the dated signature of the person conducting the consent discussion.  
A copy of the respective signed and dated consent forms (subject consents) will be given to 
the subject and subject before participation in the trial. 
The initial subject informed consent forms, any subsequent revised written informed 
consent forms and any written information provided to the subject will receive the Ethic 
Committee of the Hospital del Mar approval/favorable opinion in advance of use. The 
subjects will be informed in a timely manner if new information becomes available that may 
be relevant to their willingness to continue participation in the trial.  The communication of 
this information will be provided and documented via a revised consent form(s) or 
addendum to the original consent form(s) that captures the subject’s dated signature. 
Relevant clinical or MRI findings will be disclosed to the patient and refer for appropriate 
care. 
Specifics about a trial and the trial population will be added to the consent form template(s) 
at the protocol level.  Informed consent(s) will adhere to the ethics Committee 
requirements, applicable laws and regulations. 
7.1.1.2 
Inclusion/Exclusion Criteria 
If it is determined that the subject does not meet the inclusion/exclusion criteria at visits, 
the subject will be withdrawn from the study.  
7.1.1.3 
Subject Identification Card 
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial. The card will contain trial site (Hospital del Mar) contact information 
(including direct telephone numbers) to be utilized in the event of an emergency.  The 
investigator or qualified designee will provide the subject with a Subject Identification Card 
immediately after the subject provides written informed consent. 
7.1.1.4 Medical History 
A medical history will be obtained by the investigator or qualified designee. 

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7.1.1.5 
Prior and Concomitant Treatments Review 
7.1.1.5.1 Prior Treatments 
The investigator or qualified designee will review any prior therapeutic drug or 
neurostimulation use, in advance to visit 2, and record prior treatment taken by the subject 
within 30 days before starting the trial.  
7.1.1.5.2 Concomitant Treatments 
The investigator or qualified designee will record treatment(s), if any, taken by the subject 
during the trial. Any changes to treatment(s) (i.e., dose, frequency) will also be recorded. If 
the subject reports taking any prohibited treatments during the study, this will be recorded 
as a study deviation. Concomitant treatments will not be changed during the study, without 
first consulting the investigator, except in cases of medical emergencies or other obvious 
exceptions. Please see Section 5.5 for more details. 
7.1.1.6 
Assignment of Screening Number 
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  
Each subject will be assigned only one screening number.  Screening numbers must not be 
re-used for different subjects. 
7.1.1.7 
Assignment of Treatment/Randomization Number 
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number. The treatment/randomization number identifies the subject for all procedures 
occurring after treatment allocation/randomization. Once a treatment/randomization 
number is assigned to a subject, it can never be re-assigned to another subject. 
A single subject cannot be assigned more than 1 treatment/randomization numb 
7.1.1.8 
Trial Compliance (Treatment) 
During stimulation visits, administration of TPS therapy will be witnessed by the investigator 
and/or trial staff. Accounting of trial treatment will be conducted as specified in the Trial 
Flow Chart.  
7.1.1.9 
Interactive Voice Response System/Integrated Web Response System 
The investigator or designee will call/log into IVRS/IWRS as specified in the Trial Flow Chart. 
Upon confirmation of a subject’s eligibility at Visit 2, the investigator or designee will call 
IVRS or log into IWRS to randomize the subject. Subjects who do not meet eligibility criteria 
at Visit 4 will be screen-failed in IVRS/IWRS. For all randomized subjects, the investigator or 
designee will continue to call/log into IVRS/IWRS as per the Trial Flow Chart. For completed 
or discontinued subjects, the investigator or designee will make the final call/web action 
into IVRS/IWRS at their last trial visit. For additional information, please refer to Section 5.3. 
7.1.2 
Clinical Procedures/Assessments 
7.1.2.1 Physical Assessments/Examinations 
7.1.2.1.1 Physical Examination/Neurological Examination (PE/Neuro Exam) 
A complete physical examination (PE), including a neurological exam, will be performed by a 
primary investigator or sub-investigator. This examination will also be performed in the 
event of early discontinuation. The following body systems should be included in these 
exams: 

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29 
● Head, Eyes, Ear, Nose, and Throat 
● Neck 
● Cardiovascular system 
● Respiratory system 
● Abdomen 
● Skin 
● Extremities 
● Neurological system (see Appendix 12.11) 
● Musculoskeletal system 
Examination of the breast, rectum, and urogenital system are at the investigator’s 
discretion (i.e., clinically indicated). If a physical or neurological abnormality is noted post-
treatment, the investigator will indicate whether the result is clinically significant and if it 
constitutes an adverse event. 
7.1.2.1.3 Vital Signs 
Body Temperature:  Body temperature will be measured with an oral or tympanic 
thermometer. The same method (e.g., oral, or tympanic, ºC) should be used for all 
measurements for each individual subject and should be the same for all subjects 
throughout the trial. 
Heart Rate (HR), Blood Pressure (BP) and Respiratory Rate (RR):  Subjects should be resting 
for at least 10 minutes prior to having vital sign measurements obtained. The same 
position should be used for all measurements for each individual subject and should be the 
same for all subjects throughout the trial. The correct size of the blood pressure cuff and 
the correct positioning on the subject’s arm is essential to increase the accuracy of blood 
pressure measurements. The same method (e.g., manual, or automated) should be used for 
all measurements for each individual subject and should be the same for all subjects 
throughout the study. 
7.1.2.1.4 Body Height/Weight 
Height (cm/in) and body weight (kg/lbs.) will be collected and recorded. Measurements 
should be recorded to the nearest centimeter/inch and kilogram/pound. Body weight data 
will be collected without shoes and with heavy clothing (such as coats) removed. Body 
weight should be performed on the same scale for the same individual throughout the 
study. 
7.1.2.2 Neurological and Cognitive exam 
At baseline and by end of the visit 2 (stimulation) a neurological exam (as defined in section 
12.6) will be administered for identifying CNS related adverse events.  
7.1.2.2.2 The ALSFRS-R 
The ALS Functional Rating Scale in its revised version (ALSFRS-R)32 is a disease-specific 
severity score that reflects motor impairment and functional deterioration in people with 
amyotrophic lateral sclerosis (ALS). It has been widely applied in both clinical practice and 
ALS research. The scale is disease-specific and encompasses 12 prompts-referred to as 
items-grouped into four domains to assess bulbar symptoms, limb and trunk functionality, 
respiratory symptoms, and the need for percutaneous endoscopic gastrostomy, non-
invasive ventilation, or tracheostomy with invasive ventilation. The precursor scale was 

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30 
initially developed as an outcome measure for clinical trials, but over time its revised 
version became commonly used in both ALS research and clinical practice 
7.1.2.2.2.1. MRC sum score  
The muscle strength of the limbs will be scored using the Medical Research Council (MRC) 
sum score, an established multifactorial scoring system with a total score between 0 and 
6033. The MRC sum score evaluates global muscle strength by combining the scores of six 
muscles (shoulder abductors, elbow flexors, wrist extensors, hip flexors, knee extensors, 
and ankle dorsiflexors) that are evaluated bilaterally.  
7.1.2.2.2.2 Dynamometry  
Hand-held dynamometry megascore (average of z-scores across 16 muscle groups in the 
arms and legs, with higher values indicating greater strength) will be obtained as described 
in34.  
7.1.2.2.3 TMS: motor threshold and excitability assessment 
Studies using transcranial magnetic stimulation (TMS) have established cortical motoneuron 
hyperexcitability, heralded by decreased short-interval intracortical inhibition (SICI), as an 
early feature of sporadic and familial ALS35. Greater cortical excitability is prognostic of 
disease progression. Motor cortex excitability has been used previously as a relevant 
endpoint in clinical trials in patients with ALS.36 Paired-pulse transcranial magnetic 
stimulation (ppTMS) will be conducted in both motor cortex at each side to record: 1) 
motor evoked potential (MEP) amplitudes; 2) resting motor threshold; 3) intra-cortical 
facilitation (ICF); and 4) short intracortical inhibition (SICI)37. The primary criteria for 
defining changes in motor excitability related with the therapy is SICI36. MEP amplitude was 
measured at increasing stimulator strengths (eg, 120%, 140%, and 150% of RMT) 
7.1.2.2.4 SVC 
The slow vital capacity (SVC) is the volume of air expired through an unforced maneuver 
measured by spirometry. SVC of 50% or greater of estimated measure is required to 
participate in the study. 
7.1.2.2.5. The Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidal ideation and behavior will be prospectively assessed during this study using the 
Columbia Suicide Severity Rating Scale (C-SSRS). The C-SSRS will be administered by trained 
raters at specified time points, as indicated in the Trial Flow Chart, as well as at unscheduled 
visits as clinically indicated. Site staff will review the contents of the C-SSRS for 
completeness. Note that the C-SSRS assessment is not considered complete until all 
available sources of information have been considered (e.g., subject input may be 
necessary). 
The C-SSRS is not explicit about whether the subject specifically has ideation at the time of 
screening. If a subject reports a prior history of ideation/behavior, the assessor will also 
inquire and document if this is also present at the time of the screening visit. 
Subjects who at any time during this trial report suicidal ideation or behavior that is 
considered to be an adverse event, either between visits or during visit interviews, must be 
assessed by the Investigator. Subjects who report suicidal ideation with intent, with or 
without a plan or method (i.e., a positive response to items 4 or 5 in the assessment of 
suicidal ideation on the C-SSRS) or suicidal behavior must be evaluated that day by a 

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31 
psychiatrist or other trained mental health professional who is a licensed psychologist, 
social worker, or mental health nurse practitioner (or comparable professional qualification 
in countries outside the United States). Only subjects whose suicidal ideation is passive, 
who expressly deny any intent to act, and who, after evaluation, are not judged to be at 
serious risk for self-harm during the trial may continue in the study; others must be 
discontinued from trial participation and receive appropriate clinical follow-up care to 
ensure their safety. In addition, any reports of 1) suicidal behavior; 2) suicidal ideation with 
intent, with or without a plan or method; or 3) suicidal ideation considered to be a clinically 
significant change, including all cases of suicidal ideation that are treatment- emergent (i.e., 
start or worsen after trial treatment is initiated) must be recorded as an Event of Clinical 
Interest (See Section 7.2.3.2). Sites will designate which health care professionals are to be 
responsible for acute care on-site and to specify referral center(s) to be used for further 
evaluation. The C-SSRS will be completed in paper form, and will be scored by the qualified 
trained rater, via a subject interview. 
7.1.3 
Laboratory Procedures/Assessments 
7.1.3.1. Neurofilaments light (NfL) levels in plasma 
Plasma NfLs has been validated as outcomes for ALS trials, based on tofersen approval by 
FDA34. At the designed visits, blood will be collected, plasma will be extracted and frozen 
until its use. Plasma NfL will be measured by Simoa at baseline, after each stimulation 
session and by end of the DBP and end of the OLE. 
7.1.3.2. Biomarkers in nEVs 
Extracellular vesicles of neuronal origin (nEVs) is a promising strategy to identify new 
biomarkers. Such vesicles can be isolated from plasma (even frozen plasma) and reflects the 
cytoplasm content of the neuronal population 12h in advance. The vesicles content is 
representative of the cytoplasm and includes proteins, RNAs and metabolites. Then, nEVs 
can be considered as a surrogate approach to a liquid biopsy of the brain. As such, several 
biomarkers have been identified in patients with ALS26, Alzheimer disease27, 28, Parkinson 
disease29, 30, traumatic brain injury or MS31. Here, we propose collecting nEVs to conduct a 
biomarker search study to identify biomarkers associated with the TPS therapy in the motor 
cortex of people with ALS. 
Multiple protein related with the pathogenesis of ALS or CNS damage (SOD1, Ataxin 2, 
C90rf72, UNC13A, TDP43, stathmin 2, NfL and NfH levels) has been proposed as biomarkers 
of ALS39. However, their levels required a lumbar tap, reducing their feasibility. The use of 
extracellular vesicles of neuronal origin will allow to determine such proteins reflecting the 
neurons cytoplasmatic content 12h before26. 20 ml of blood will be collected at the 
designated visits (5 visits = 100 ml in total) and plasma and serum will be collected and 
stored at -80C until analysis (no DNA will be collected). Protein levels will be measured by 
SIMOA, MSD or WES at Villoslada’s lab. 
7.1.4 
Other Procedures 
7.1.4.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws from participation in the trial during visit 2 (before 
completing the three planned stimulations), all applicable activities scheduled for the end of 
visit 2, as outlined in Section 6.0 Trial Flow Chart, will be performed at the time of 

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32 
discontinuation.  Any adverse events which are present at the time of 
discontinuation/withdrawal will be followed in accordance with the safety requirements 
outlined in Section 7.2 - Assessing and Recording Adverse Events 
7.1.4.2 
Blinding/Unblinding 
When the investigator or sub-investigator needs to identify the treatment arm used by a 
subject in case of emergency e.g., the occurrence of serious adverse experiences, he/she 
will contact the emergency unblinding call center by telephone and make a request for 
emergency unblinding.  As requested by the investigator or sub-investigator the emergency 
unblinding call center will provide the information to him/her promptly and report 
unblinding.  The emergency unblinding call center will make a record promptly however, 
the investigator or sub-investigator must enter the intensity of the adverse experiences 
observed, their relation to study arm, the reason thereof, etc., in the medical chart etc., 
before unblinding is performed. Additionally, the investigator must go into the IVRS system 
and perform the unblind in the IVRS system to update arm disposition.  If the emergency 
unblinding call center is not available for a given site in this trial, IVRS/IWRS should be used 
for emergency unblinding in the event that this is required for subject safety. 
If unblinding has occurred, the circumstances around the unblinding (e.g., date and reason) 
must be documented promptly, and principal investigator notified as soon as possible.  Only 
the principal investigator or delegate and the respective subject’s code should be 
unblinded.  Trial site personnel directly associated with the conduct of the trial should not 
be unblinded. 
7.1.4.3 Domiciling 
NA 
7.1.4.4 
Calibration of Critical Equipment 
TPS device is calibrated as follows: the electromagnetic stimulator is calibrated by the 
vendor (Storz medical) every 2 million pulses. The distillated water of the stimulator is 
replaced every 6 months. The systems have no other calibration or maintenance 
requirements. 
7.1.5 
Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.5.1 
Visits 
Each visit should be performed as noted in the Trial Flow Chart. For visits that require 
additional explanations, please see those specific visits below. 
7.1.5.1.1 Visit 1: Screening, brain MRI, TMS  and SVC 
At Visit 1, subjects who provide informed consent will undergo a series of diagnostic and 
safety assessments to determine if they are eligible for the trial. A designated subject must 
also consent to participate and will be asked to complete certain assessments throughout 
the trial. Subjects planning to undergo elective procedures during the study (known prior to 
trial start) should not proceed until such procedures have been completed. 

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33 
At the screening visit, medical history, use of drugs, alcohol, caffeine, smoking will be 
recorded. In addition urine test and the Columbia-Suicide Severity Rating Scale (C-SSRS) will 
be administered. The SVC will be collected by spirometry. 
If the subject fulfills the inclusion criteria and signs the informed consent, a brain MRI and a 
TMS study will be scheduled in the following 2-7 days (always before Visit 2). Once obtained 
the brain MRI, it will be uploaded to the TPS device for neuronavigation purposes. TMS will 
be conducted for defining presence of hyper-excitability.  
7.1.5.1.2 Visit 2: baseline 
Patients will be randomized to either treatment or sham stimulation and assigned a code 
(except for patient sin stage 1, which are not randomized, and all receive active 
stimulation). Before starting stimulation, the researcher will conduct a vital signs, physical 
exam and neurological examination. Urine (50 ml) and blood (20 ml) will be collected and 
stored. Then, the patient will be subjected to the first TPS stimulations (a 20 min 
stimulations).  
7.1.5.1.3 Visit 3-5, 6-12, 15-21 and 22-28: stimulation visits 
At each visit the patient will be reassessed for vital signs, physical exam and neurological 
exam. After the completion of each 6-session period, the C-SSRS will be administered. Blood 
and urine will be collected the last day of stimulation for each 6-session period. TMS and 
ALSFRS-R will be assessed the last day of stimulation for each 6-session period. 
7.1.5.1.2 Visit 13, 14 and 29: end of stage 1, end of DBP, onset and end of OLE of stage 2 
During such visits, vital signs, physical exam, and neurological exam and ALSFRS-R will be 
conducted. 
7.2 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical investigation 
subject administered a medical device treatment and which does not necessarily have to 
have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol 
specified procedure, whether considered related to the medicinal product or protocol 
specified procedure. Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the product, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time. 
Product includes any device, diagnostic agent, pharmaceutical product, biological product, 
or protocol-specified procedure, whether investigational (including sham or active 
comparator treatment) or marketed, manufactured by, licensed by, provided by, or 
distributed by the vendor for human use. 
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
inadequate therapeutic regimen (whether accidental or intentional), from abuse and from 
withdrawal. 

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34 
Electronic reporting procedures can be found in the electronic data capture (EDC) entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent). 
7.2.1 Definition of an Over-treatment for this Protocol and Reporting of Over-treatment  
In this trial, an over-treatment is any therapeutic regimen of higher intensity or of longer 
duration than the specified therapeutic regimen to be administered in a calendar day 
(accidental or intentional). If an adverse event(s) is associated with (“results from”) the 
over-treatment, the adverse event(s) is reported as a serious adverse event, even if no 
other seriousness criteria are met. If the therapeutic regimen meeting the protocol 
definition of over-treatment is taken without any associated clinical symptoms or abnormal 
laboratory results, the over-treatment is reported as a non-serious Event of Clinical Interest 
(ECI), using the terminology “accidental or intentional over-treatment without adverse 
effect.” 
All reports of over-treatment with and without an adverse event must be reported by the 
investigator within 24 hours either by electronic media or paper. Electronic reporting 
procedures can be found in the electronic data capturing (EDC) entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent). 
7.2.2 Reporting of Pregnancy and Lactation 
Female participants may screen for this study if: 
• 
They are surgically sterile [have had a hysterectomy (uterus removed), bilateral 
oophorectomy (ovaries removed), or tubal ligation at least 6 months prior] 
• 
They are of post-menopausal age and have not had a menstrual period for 12 
months 
• 
They have a vasectomized partner (performed at least 6 months prior) who has 
been documented to no longer produce sperm 
• 
They are using a highly effective method of contraception to avoid pregnancy 
throughout the study and for 30 days after you complete this study. 
Examples of acceptable forms of highly effective contraception include: 
1. 
Established use of oral, injected or implanted hormonal methods of contraception 
plus use of a condom for your male partner. 
2. 
Placement of an intrauterine device (IUD) or intrauterine system (IUS) plus use of a 
condom for your male partner. 
3. 
True abstinence: When this is in line with your preferred and usual lifestyle 
NOTE: Periodic abstinence (e.g., calendar, ovulation, symptothermal, post ovulation 
methods), condoms alone or double barrier are not acceptable methods of contraception. 
Male participants must ensure a condom is used for all sexual intercourse as well as 
following the acceptable methods of contraception listed above for your female partner 
and ensuring that they are used for the entire duration of the study, and for at least 90 days 
after you complete this study.  
Although pregnancy and lactation are not considered adverse events, it is the responsibility 
of investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial. 

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35 
7.2.3 
Immediate Reporting of Adverse Events  
7.2.3.1 
Serious Adverse Events 
A serious adverse event is any adverse event occurring at any therapeutic regimen or during 
any use of the product that: 
● Results in death; 
● Is life threatening; 
● Results in persistent or significant disability/incapacity; 
● Results in or prolongs an existing inpatient hospitalization;  
● Is a congenital anomaly/birth defect;  
● Is another important medical event. 
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable in the same timeframe as SAEs to 
meet certain local requirements. Therefore, these events are considered serious for 
collection purposes. 
● Is a cancer; 
● Is associated with an overdose. 
Refer to Table 6 for additional details regarding each of the above criteria. 
For the time period beginning when the consent form is signed until treatment, any serious 
adverse event, or follow up to a serious adverse event, including death due to any cause, 
that occurs to any subject must be reported within 24 hours for weekly days or 72 days over 
the weekend if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, sham treatment or a procedure. The 24 hours for the site starts when 
the site becomes aware of the SAE. SAEs not reported will be considered a major protocol 
deviation.  
For the time beginning at treatment allocation through 14 days following cessation of 
treatment, any serious adverse event, or follow up to a serious adverse event, including 
death due to any cause, whether or not related to the product, must be reported within 24 
hours either by electronic media or paper. Electronic reporting procedures can be found in 
the EDC data entry guidelines. Paper reporting procedures can be found in the Investigator 
Trial File Binder (or equivalent). 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the product that is brought to the attention of the investigator at 
any time outside of the time specified in the previous paragraph also must be reported 
immediately. 
All subjects with serious adverse events must be followed up for outcome. 
7.2.3.2. Events of Clinical Interest (during the stimulation visit 2 (in the 1h after each 
stimulation) 
1. Agitation – daytime or nighttime 
2. Confusion or cognitive impairment - daytime or nighttime 

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36 
Regarding items #1 and 2 above, agitation, confusion or cognitive impairment should be 
considered an ECI if in the investigator’s opinion an acute worsening from baseline has 
occurred, or there is an unusual or atypical presentation of symptoms for a given subject.  
7.2.3.3 
Protocol-Specific Exceptions to Serious Adverse Event Reporting 
7.2.4 
Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 4. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 4 for instructions in evaluating adverse events. 

 
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Table 4 
Evaluating Adverse Events 
Maximum 
Intensity 
Mild 
awareness of sign or symptom, but easily tolerated (for pediatric trials, awareness of symptom, but 
easily tolerated) 
Moderate 
discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like 
something is wrong) 
Severe 
incapacitating with inability to work or do usual activity (extremely distressed or unable to do usual 
activities) 
Seriousness A serious adverse event (SAE) is any adverse event occurring at any Therapeutic regimen or during any use of  
product that: 
†Results in death; or 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event 
as it occurred [Note: This does not include an adverse event that, had it occurred in a more severe form, might have 
caused death.]; or 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal 
life functions); or 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, 
regardless of length of stay, even if the hospitalization is a precautionary measure for continued observation.   
(Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not worsened is not a 
serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Hospital 
del Mar neurosciences product and is documented in the patient’s medical history.); or 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis); or 
Is a cancer (although not serious per ICH definition, is reportable within 24 hours to meet certain local 
requirements); or 
Is associated with an over-treatment (whether accidental or intentional).  Any adverse event associated with an 
over-treatment is considered a serious adverse event for collection purposes. An over-treatment that is not 

 
Page 38 of 61 
 
associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 
24 hours. 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization 
may be considered a serious adverse event when, based upon appropriate medical judgment, the event may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event.  If less than 1 day, indicate the appropriate length of time and 
units 
Action 
Taken  
Did the adverse event cause the product to be discontinued? 
Relationship 
to  
Product 
Did the product cause the adverse event?   The determination of the likelihood that the product caused the 
adverse event will be provided by an investigator who is a qualified physician.  The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a 
medically qualified assessment of causality was done.  This initialed document must be retained for the required 
regulatory time frame.  The criteria below are intended as reference guidelines to assist the investigator in 
assessing the likelihood of a relationship between the test drug and the adverse event based upon the available 
information 
The following components are to be used to assess the relationship between the product and the AE; the greater 
the correlation with the components and their respective elements (in number and/or intensity), the more likely 
the p product caused the adverse event: 
Exposure 
Is there evidence that the subject was actually exposed to the product such as:  reliable history, 
acceptable compliance assessment (pill count, diary, etc.), expected pharmacological effect, or 
measurement of drug/metabolite in bodily specimen? 
Time Course Did  the  AE  follow in  a reasonable temporal  sequence from administration of the  product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with 
investigational medicinal products)? 
Likely Cause Is the AE not reasonably explained by another etiology such as underlying disease, other 
drug(s)/vaccine(s), or other host or environmental factors 
 

 
Page 39 of 61 
 
Relationship 
to the 
Product 
(continued)  
The following components are to be used to assess the relationship between the product and the AE 
(continued) 
Dechallenge Was the  
 product discontinued or dose/exposure/frequency reduced? 
      If yes, did the AE resolve or improve? 
           If yes, this is a positive dechallenge.  If not, this is a negative dechallenge. 
(Note:  This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the 
AE resolved/improved despite continuation of the product; (3) the trial is a single-Therapeutic 
regimen drug trial); or (4)  
product(s) is/are only used one time.) 
Rechallenge Was the subject re-exposed to the  product in this trial? 
      If yes, did the AE recur or worsen? 
          If yes, this is a positive rechallenge.  If not, this is a negative rechallenge. 
(Note:  This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, 
or (2) the trial is a single-Therapeutic regimen drug trial); or (3)  
product(s) is/are used only one time.) 
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH 
MAY HAVE BEEN CAUSED BY THE PRODUCT, OR IF RE-EXPOSURE TO THE PRODUCT POSES 
ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE SUBJECT THEN THE RECHALLENGE MUST BE 
APPROVED IN ADVANCE BY THE CLINICAL DIRECTOR AND THE INSTITUTIONAL REVIEW 
BOARD/INDEPENDENT ETHICS COMMITTEE. 
 
Consistency 
with Trial  
Treatment  
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the  
product or drug class pharmacology or toxicology? 
The assessment of the relationship will be reported on the case report forms /worksheets by an investigator who is a qualified 
physician according to his/her best clinical judgment, including consideration of the above elements. 
Record one of the 
following: 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of 
a  

 
Page 40 of 61 
 
product relationship). 
Yes, there is a reasonable 
possibility of  
 product relationship. 
There is evidence of exposure to the  
 product.  The temporal sequence of the AE onset relative to the administration of the  
 product is reasonable.  The AE is more likely explained by the  
 product than by another cause.  
No, there is not a 
reasonable possibility of  
 product relationship 
Subject did not receive the  
 product OR temporal sequence of the AE onset relative to administration of the  
 product is not reasonable OR the AE is more likely explained by another cause than the  
 product.  (Also entered for a subject with over-treatment without an associated AE.) 
 

  
 
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7.2.5 Investigator Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to the Ethical Committee of Hospital del Mar and 
investigators in accordance with all applicable global laws and regulations, i.e., per ICH 
Topic E6 (R1) Guidelines for Good Clinical Practice. 
8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Statistical Analysis Plan Summary 
Considering this is the first study in a very small population for assessing the safety and 
tolerability and getting insights on the efficacy, results will be provided only as a descriptive 
statistical analysis 
 
Table 5 Statistical analysis plan 
Study Design Overview 
Modulation of the motor pathway by Transcranial Pulse 
Stimulation in people with ALS: a pilot randomized trial 
Treatment Assignment 
Active stimulation: 36,000 pulses in 2 weeks distributed in 6 
sessions 
Sham: stimulations using a sound blocker (membrane filled with 
air) 
Analysis Populations 
Intention to treat  
Per Protocol 
Primary Endpoint(s) 
Stage 1. Change in the motor cortex excitability threshold from 
baseline to week 8.  
Stage 2. Change from baseline to month 6 in the ALS functional 
rating scale-revised (ALSFRS-R) total score. 
Key Secondary 
Endpoints 
Secondary stage 1:  
1. Change in the motor cortex excitability (paired-pulse 
transcranial magnetic stimulation (ppTMS): motor evoked 
potential (MEP) amplitudes, resting motor threshold, intra-
cortical facilitation (ICF) and short intracortical inhibition (SICI)), 
from baseline to week 4 
2. Change plasma NfL levels from baseline to week 4 and 8 
3. Changes in muscle strength, assessed by MRC sum score from 
baseline to week 4 and 8 
4. Changes in hand-held dynamometry from baseline to week 4 
and 8Secondary stage 2: 
1. Differences (treated vs sham) and change (from baseline to 
end of the study (month 6)) in the slow vital capacity (SVC)  
2. Differences (treated vs sham) and change (from baseline to 
end of the study (month 6)) in plasma NfL levels or other 
biomarkers  from exploratory stage 1 if found significant 

   
 
 
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3. Differences (treated vs sham) and change (from baseline to 
end of the study (month 6)) in in cortical hyperexcitability (MEP 
amplitudes, resting motor threshold, ICF and SICI) 
4. Changes in muscle strength, assessed by MRC sum score from 
baseline to end of the study (month 6) 
5. Changes in hand-held dynamometry, from baseline to end of 
the study (month 6) 
Exploratory endpoints 
Exploratory stage 1 
1. Changes in SOD1, Ataxin 2, C90rf72, UNC13A, TDP43, NfL and 
NfH levels in extracellular vesicles of neuronal origin (nEVs) 
collected from plasma from baseline to week 4 and 8 
Exploratory stage 2 
1. Differences (treated vs sham) and change (from baseline to 
end of the study (month 6)) in biomarker levels in nEVs collected 
from plasma that were informative in stage 1 from baseline to 
week 4 and 8 
Statistical Methods for 
Key Efficacy Analyses 
 Changes on ALSFRS-R, motor threshold, biomarker levels before 
and after stimulation will be assessed with ANCOVA test. 
Statistical Methods for 
Key Safety Analyses 
Descriptive statistics 
Interim Analyses 
No interim analysis for efficacy or safety is planned for this study. 
Multiplicity 
Not planned 
Sample Size and Power  Considering that this is a pilot study, and no previous data is 
available for this intervention, a convenience sample size of 10 
subjects for and 40 subjects for stage 2 has been defined. Using 
the results from the CENTAUR trial1 in patients with ALS, a 
sample size of 6 patients per arm provided a 90% to detect 
differences by week 24 with alpha 0.05. 
8.2 Responsibility for Analyses 
The statistical analysis of the data obtained from this study will be the responsibility of the 
Principal Investigator.  
8.3 
Hypotheses 
Objectives and hypotheses of the study are stated in Section 3. 
8.4 
Analysis Endpoints 
Key efficacy and safety endpoints that will be evaluated for within- and/or between-TPS 
protocols are listed below, followed by the descriptions of the derivations of selected 
endpoints.  

  
 
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8.4.1. Efficacy Endpoints 
Rationale for the key efficacy endpoints is given in Section 4.2.3.1 and an initial description 
of the efficacy measures is included in Section 7.1.2.2. In general, if a baseline value exists 
for a particular efficacy measure, then the change from baseline in that value will be 
evaluated.  
Primary Endpoint 
Stage 1. Change in the motor cortex excitability threshold from baseline to week 8.  
Stage 2. Change from baseline to month 6 in the ALS functional rating scale-revised (ALSFRS-
R) total score. 
Secondary Endpoint 
Secondary stage 1:  
1. Change in the motor cortex excitability (paired-pulse transcranial magnetic stimulation 
(ppTMS): motor evoked potential (MEP) amplitudes, resting motor threshold, intra-cortical 
facilitation (ICF) and short intracortical inhibition (SICI)), from baseline to week 4 
2. Change plasma NfL levels from baseline to week 4 and 8 
3. Changes in muscle strength, assessed by MRC sum score from baseline to week 4 and 8 
4. Changes in hand-held dynamometry from baseline to week 4 and 8Secondary stage 2: 
1. Differences (treated vs sham) and change (from baseline to end of the study (month 6)) in 
the slow vital capacity (SVC)  
2. Differences (treated vs sham) and change (from baseline to end of the study (month 6)) in 
plasma NfL levels or other biomarkers  from exploratory stage 1 if found significant 
3. Differences (treated vs sham) and change (from baseline to end of the study (month 6)) in 
in cortical hyperexcitability (MEP amplitudes, resting motor threshold, ICF and SICI) 
4. Changes in muscle strength, assessed by MRC sum score from baseline to end of the 
study (month 6) 
5. Changes in hand-held dynamometry, from baseline to end of the study (month 6) 
 
8.4.2 
Safety Endpoints 
Presence of serious adverse events (together with items of special attention) 
An initial description of the safety measures is included in Sections 7.1.2.1, 7.1.2.2.10 and 
7.1.3. Safety and tolerability will be assessed by statistical and clinical review of the 
following data collected throughout the study:  adverse experiences (AEs), and treatment-
emergent suicidality. The Columbia-Suicide Severity Rating Scale (C-SSRS) will be used to 
ascertain and document the occurrence of suicidal events (i.e., ideation and behavior) 
systematically and prospectively. Responses on the C-SSRS are classified according to 11 
pre-specified categories as described in Appendix 12.14. 
The primary time for safety analyses is Visit 2; Safety endpoints are classified into 2 tiers 
(see Statistical Methods for Key Safety Analyses in Section 8.1 for Tier definitions). 
Tier 1 Safety Endpoints include (the proportion of subjects with): 
1. Any AE 
2. Any Serious AE 
3. Any treatment-Related AE 

   
 
 
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4. Any Serious and treatment-Related AE  
5. Discontinuation due to AE 
Tier 2 Safety Endpoints include: 
1. Specific AEs, SOC AEs or PDLCs which have incidence in all 3 subjects.  
8.5 
Analysis Populations 
8.5.1 
Safety Analysis Population 
The safety population will be used for the analysis of safety data in this study. The safety 
population consists of all subjects who received at least 1 stimulation protocol of trial 
treatment. Subjects will be included in the treatment group corresponding to the trial 
treatment they received for the analysis of safety data using the safety population. Subjects 
who take incorrect trial treatment for the entire treatment period will be included in the 
treatment group corresponding to the trial treatment received.  
At least 1 vital sign measurement obtained after at least 1 stimulation protocol of trial 
treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required. 
8.6 
Statistical Methods 
Safety and tolerability will be assessed by statistical and clinical review of the following data 
collected throughout the study: adverse experiences (AEs), and treatment-emergent 
suicidality derived from the C-SSRS. Safety will be evaluated with doses combined; selected 
safety analyses will be performed for doses separately. 
The analysis of safety results will follow a tiered approach (Table 6). The tiers differ with 
respect to the analyses that will be performed. Safety parameters or adverse experiences of 
special interest that are identified a priori constitute “Tier 1” safety endpoints that will be 
subject to inferential testing for statistical significance with p-values and 95% confidence 
intervals provided for between-group comparisons. Other safety parameters will be 
considered as Tier 2 or Tier 3. Tier 2 parameters will be assessed via point estimates with 
95% confidence intervals provided for between-group comparisons.  
Membership in Tier 1 requires that at least 4 subjects in any treatment group exhibit the 
event; all other adverse experiences and predefined limits of change will belong to Tier 2. 
Summary statistics for baseline, on-treatment, and change from baseline values will be 
provided by the treatment group in table format.    
See Table 6 for a classification of safety endpoints as Tier 1, or 2 and the corresponding 
analysis strategy for each endpoint. 
 
Table 6 
Analysis Strategy for Safety Parameters 
Safety 
Tier 
Safety Endpoint† 
p-Value§ 
95% CI for 
Treatment  
Comparison§ 
Descriptive 
Statistics 
Tier 1 
Any AE 
 
X 
X 

  
 
Page 45 of 61 
 
 
Any Serious AE 
 
X 
X 
 
Any Drug-Related AE 
 
X 
X 
 
Any Serious and Drug-Related AE 
Discontinuation due to AE 
 
X 
X 
X 
X 
 
Specific AEs, SOCs, or PDLCs (incidence 
≥4 subjects in 1 of the treatment groups) 
 
X 
X 
Tier 2 
Specific AEs, SOCs or PDLCs ‡ (incidence 
<4 subjects in all the treatment groups) 
 
 
X 
 
Change from Baseline Results (ECGs,  
Vital Signs) 
 
 
X 
2 Adverse Event (AE) references refer to both Clinical and Laboratory AEs. 
3 Includes only those endpoints not pre-specified as Tier 1 or not already pre-
specified as Tier-2 endpoint 
4 P-value and CI for safety endpoints based upon Miettinen & Nurminen 
method 
Note: SOC=System Organ Class; PDLC=Pre-Defined Limit of Change; X = 
results will be provided. 
 
 
8.6.3 
Summaries of Baseline Characteristics, Demographics, and Other Analyses 
8.6.3.1 
Demographic and Baseline Characteristics 
Demographic variables (e.g., age, gender, race), baseline characteristics, primary and 
secondary diagnoses, and prior and concomitant therapies will be summarized by 
treatment either by descriptive statistics or categorical tables. 
8.7 
Interim Analysis 
No interim analyses for efficacy or safety are planned for this study  
8.8 
Multiplicity 
Not planned. 
8.9 
Sample Size and Power Calculations 
Sample size 
This study will recruit 10 patients for stage 1 (open label) and 40 patients for stage 2 
(randomized DBP).  Using the results from the CENTAUR trial1 in patients with ALS, a sample 
size of 6 patients per arm provided a 90% to detect differences by week 24 with alpha 0.05. 
Power for the primary hypothesis 
Considering that this is a pilot study, and no previous data is available for this intervention, a 
convenience sample size of 10 subjects for stage 1 and 40 for stage 2 has been defined. 
Using the results from the CENTAUR trial1 in patients with ALS, a sample size of 6 patients 
per arm provided a 90% to detect differences by week 24 with alpha 0.05. 

   
 
 
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8.10 Subgroup Analyses  
NA 
8.11 Compliance (Treatment Adherence) 
Summary statistics will be provided on percent compliance by treatment for all subjects 
included. 
8.12 Extent of Exposure 
The total number of days each subject received a particular total daily stimulation protocol 
will be identified and then summarized (as subject counts and percentages)  
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
No drugs are being tested in this study 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Confidentiality 
10.1.1 Confidentiality of Data 
By signing this protocol, the investigator affirms that information furnished to the 
investigator will be maintained in confidence, and such information will be divulged to the 
institutional review board, ethics review committee (IRB/ERC) or similar or expert 
committee, affiliated institution, and employees, only under an appropriate understanding 
of confidentiality with such board or committee, affiliated institution, and employees.  Data 
generated by this trial will be considered confidential by the investigator, except to the 
extent that it is included in a publication as provided in the Publications section of this 
protocol. 
10.1.2 Confidentiality of Subject Records 
By signing this protocol, the investigator agrees that the Ethical Committee, or regulatory 
authority representatives may consult and/or copy trial documents to verify 
worksheet/case report form data.  By signing the consent form, the subject agrees to this 
process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission. 
By signing this protocol, the investigator agrees to treat all subject data used and disclosed 
in connection with this trial in accordance with all applicable privacy laws, rules, and 
regulations. 
10.1.3 Confidentiality of Investigator Information 
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all sub-investigators and trial site 
personnel, may be used and disclosed for trial management purposes, as part of a 
regulatory submissions, and as required by law. This information may include: 
1. name, address, telephone number and e-mail address; 
2. hospital or clinic address and telephone number; 
3. curriculum vitae or other summary of qualifications and credentials; and 
4. other professional documentation. 

  
 
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Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators. By signing this protocol, the investigator expressly consents to these uses and 
disclosures. 
10.1.4 Confidentiality of Ethics Committee Information 
The principal investigator is required to record the name and address of the Ethics 
Committee that reviews and approves this trial. 
10.2 Compliance with Financial Disclosure Requirements 
The investigator/subinvestigator(s) agree to provide his/her financial interests to allow for 
the submission of complete and accurate certification and disclosure statements. The 
investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form.  
10.3 Compliance with Law, Audit and Debarment 
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of 
Good Clinical Practice (e.g., International Conference on Harmonization (ICH) of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: all 
applicable federal, state, and local laws, rules and regulations relating to the conduct of the 
clinical trial. 
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations, is provided in Section 12.1 Hospital del Mar 
Neurosciences Code of Conduct for Clinical Trials. 
The investigator also agrees to allow monitoring, audits, Ethics Committee review and 
regulatory authority inspection of trial-related documents and procedures and provide for 
direct access to all trial-related source data and documents. 
The investigator agrees not to seek reimbursement from subjects, their insurance providers 
or from government programs for procedures included as part of the trial reimbursed to the 
investigator. 
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state, and local 
laws, rules, and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
regulatory agencies. 
Trial documentation will be promptly and fully disclosed by the investigator upon request 
and shall be made available at the trial site upon request for inspection, copying, review 
and audit at reasonable times from any regulatory authorities.  The investigator agrees to 
promptly take any reasonable steps that are requested because of an audit to cure 
deficiencies in the trial documentation and worksheets/case report forms. 
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  
This documentation includes, but is not limited to, the protocol, worksheets/case report 
forms, advertising for subject participation, adverse event reports, subject source data, 

   
 
 
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correspondence with regulatory authorities, consent forms, investigator’s curricula vitae, 
monitor visit logs, laboratory reference ranges, laboratory certification or quality control 
procedures and laboratory director curriculum vitae. By signing this protocol, the 
investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol 
database lock. All trial documents shall be made available if required by relevant regulatory 
authorities. The investigator must consult with and obtain written approval prior to 
destroying trial and/or subject files.   
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed. 
10.4 Compliance with Trial Registration and Results Posting Requirements 
The principal investigator of the trial is solely responsible for determining whether the trial 
and its results are subject to the requirements for submission to EUDRA  
(http://eudragmdp.ema.europa.eu) or ClinicalTrials.org (http://www.clinicaltrials.gov) 
or other local registries. Hospital del Mar researchers will review this protocol and submit 
the information necessary to fulfill these requirements. Information posted will allow 
subjects to identify potentially appropriate trials for their disease conditions and pursue 
participation by calling a central contact number for further information on appropriate trial 
locations and trial site contact information.    
By signing this protocol, the investigator acknowledges that the statutory obligations under 
EMA clinical trials directive or other locally mandated registries are that of the investigators 
and agrees not to submit any information about this trial or its results to those registries. 
10.5 Quality Management System 
By signing this protocol, the principal investigator agrees to be responsible for 
implementing and maintaining a quality management system with written development 
procedures and functional area standard operating procedures (SOPs) to ensure that trials 
are conducted and data are generated, documented, and reported in compliance with the 
protocol, accepted standards of Good Clinical Practice, and all applicable federal, state, and 
local laws, rules and regulations relating to the conduct of the clinical trial. 
10.6 Data Management 
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data. By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature. By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate. Detailed information regarding Data Management procedures for this 
protocol will be provided separately. 
10.7 Publications 

  
 
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This trial may be intended for publication, even if terminated prematurely. Publication may 
include any or all the following: posting of a synopsis online, abstract and/or presentation at 
a scientific conference, or publication of a full manuscript.  The principal investigator will 
work with the authors to submit a manuscript describing trial results within 12 months after 
the last data become available, which may take up to several months after the last subject 
visit in some cases such as vaccine trials. Hospital del Mar researchers will post a synopsis of 
trial results for approved products on EUDRA or Clinicaltrials.gov by 12 months after the last 
subject's last visit for the primary outcome, 12 months after the decision to discontinue 
development, or product marketing (dispensed, administered, delivered, or promoted), 
whichever is later. 
These timelines may be extended for products that are not yet marketed, if additional time 
is needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality 
agreement. When a manuscript is submitted to a biomedical journal, the policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript. If the manuscript is subsequently accepted for publication, the researchers 
will allow the journal, if it so desires, to post on its website the key sections of the protocol 
that are relevant to evaluating the trial, specifically those sections describing the trial 
objectives and hypotheses, the subject inclusion and exclusion criteria, the trial design and 
procedures, the efficacy and safety measures, the statistical analysis plan, and any 
amendments relating to those sections.  
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or 
revising it critically for important intellectual content; and 3) final approval of the version to 
be published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be considered to determine authorship if contributions have also been 
made to all three of the preceding authorship criteria. Although publication planning may 
begin before conducting the trial, final decisions on authorship and the order of authors’ 
names will be made based on participation and actual contributions to the trial and writing, 
as discussed above. The first author is responsible for defending the integrity of the data, 
method(s) of data analysis and the scientific content of the manuscript. 
 
 

   
 
 
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11. LIST OF REFERENCES 
1. 
Paganoni S, Macklin EA, Hendrix S, et al. Trial of Sodium Phenylbutyrate-
Taurursodiol for Amyotrophic Lateral Sclerosis. N Engl J Med 2020;383:919-930. 
2. 
Voroslakos M, Takeuchi Y, Brinyiczki K, et al. Direct effects of transcranial electric 
stimulation on brain circuits in rats and humans. Nat Commun 2018;9:483. 
3. 
Kim HC, Lee W, Kunes J, et al. Transcranial focused ultrasound modulates cortical 
and thalamic motor activity in awake sheep. Sci Rep 2021;11:19274. 
4. 
Feldman EL, Goutman SA, Petri S, et al. Amyotrophic lateral sclerosis. Lancet 
2022;400:1363-1380. 
5. 
Brooks BR, Miller RG, Swash M, Munsat TL, World Federation of Neurology 
Research Group on Motor Neuron D. El Escorial revisited: revised criteria for the diagnosis of 
amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 
2000;1:293-299. 
6. 
de Carvalho M, Dengler R, Eisen A, et al. Electrodiagnostic criteria for diagnosis of 
ALS. Clin Neurophysiol 2008;119:497-503. 
7. 
Shefner JM, Al-Chalabi A, Baker MR, et al. A proposal for new diagnostic criteria for 
ALS. Clin Neurophysiol 2020;131:1975-1978. 
8. 
Goutman SA, Hardiman O, Al-Chalabi A, et al. Recent advances in the diagnosis and 
prognosis of amyotrophic lateral sclerosis. Lancet Neurol 2022;21:480-493. 
9. 
van Eijk RPA, van Den Berg LH. In pursuit of the normal progressor: the holy grail for 
ALS clinical trial design? Amyotroph Lateral Scler Frontotemporal Degener 2020;21:1-2. 
10. 
Westeneng HJ, Debray TPA, Visser AE, et al. Prognosis for patients with amyotrophic 
lateral sclerosis: development and validation of a personalised prediction model. Lancet Neurol 
2018;17:423-433. 
11. 
Taylor JP, Brown RH, Jr., Cleveland DW. Decoding ALS: from genes to mechanism. 
Nature 2016;539:197-206. 
12. 
Mejzini R, Flynn LL, Pitout IL, Fletcher S, Wilton SD, Akkari PA. ALS Genetics, 
Mechanisms, and Therapeutics: Where Are We Now? Front Neurosci 2019;13:1310. 
13. 
Beisteiner R, Matt E, Fan C, et al. Transcranial Pulse Stimulation with Ultrasound in 
Alzheimer's Disease-A New Navigated Focal Brain Therapy. Adv Sci (Weinh) 
2020;7:1902583. 
14. 
Yuan Y, Chen Y, Li X. Theoretical Analysis of Transcranial Magneto-Acoustical 
Stimulation with Hodgkin-Huxley Neuron Model. Front Comput Neurosci 2016;10:35. 
15. 
Guo T, Li H, Lv Y, et al. Pulsed Transcranial Ultrasound Stimulation Immediately 
After The Ischemic Brain Injury is Neuroprotective. IEEE Trans Biomed Eng 2015;62:2352-
2357. 
16. 
Pouget P, Frey S, Ahnine H, et al. Neuronavigated Repetitive Transcranial Ultrasound 
Stimulation Induces Long-Lasting and Reversible Effects on Oculomotor Performance in Non-
human Primates. Frontiers in physiology 2020;11:1042. 
17. 
Alon G, Yungher DA, Shulman LM, Rogers MW. Safety and immediate effect of 
noninvasive transcranial pulsed current stimulation on gait and balance in Parkinson disease. 
Neurorehabil Neural Repair 2012;26:1089-1095. 
18. 
Chen SF, Su WS, Wu CH, Lan TH, Yang FY. Transcranial Ultrasound Stimulation 
Improves Long-Term Functional Outcomes and Protects Against Brain Damage in Traumatic 
Brain Injury. Mol Neurobiol 2018;55:7079-7089. 

  
 
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19. 
Chen X, You J, Ma H, Zhou M, Huang C. Transcranial pulse stimulation in Alzheimer's 
disease. CNS Neurosci Ther 2023;30. 
20. 
Cheung T, Li TMH, Lam JYT, et al. Effects of transcranial pulse stimulation on autism 
spectrum disorder: a double-blind, randomized, sham-controlled trial. Brain Commun 
2023;5:fcad226. 
21. 
Cont C, Stute N, Galli A, et al. Retrospective real-world pilot data on transcranial pulse 
stimulation in mild to severe Alzheimer's patients. Front Neurol 2022;13:948204. 
22. 
Fregni F, Pascual-Leone A. Transcranial magnetic stimulation for the treatment of 
depression in neurologic disorders. Curr Psychiatry Rep 2005;7:381-390. 
23. 
Morberg BM, Malling AS, Jensen BR, Gredal O, Bech P, Wermuth L. Effects of 
transcranial pulsed electromagnetic field stimulation on quality of life in Parkinson's disease. 
Eur J Neurol 2018;25:963-e974. 
24. 
Matt E, Kaindl L, Tenk S, et al. First evidence of long-term effects of transcranial pulse 
stimulation (TPS) on the human brain. J Transl Med 2022;20:26. 
25. 
Kapogiannis D. Exosome Biomarkers Revolutionize Preclinical Diagnosis of 
Neurodegenerative Diseases and Assessment of Treatment Responses in Clinical Trials. Adv 
Exp Med Biol 2020;1195:149. 
26. 
Barbo M, Ravnik-Glavac M. Extracellular Vesicles as Potential Biomarkers in 
Amyotrophic Lateral Sclerosis. Genes (Basel) 2023;14. 
27. 
Mustapic M, Tran J, Craft S, Kapogiannis D. Extracellular Vesicle Biomarkers Track 
Cognitive Changes Following Intranasal Insulin in Alzheimer's Disease. J Alzheimers Dis 
2019;69:489-498. 
28. 
Kapogiannis D, Mustapic M, Shardell MD, et al. Association of Extracellular Vesicle 
Biomarkers With Alzheimer Disease in the Baltimore Longitudinal Study of Aging. JAMA 
neurology 2019;76:1340-1351. 
29. 
Athauda D, Gulyani S, Karnati HK, et al. Utility of Neuronal-Derived Exosomes to 
Examine Molecular Mechanisms That Affect Motor Function in Patients With Parkinson 
Disease: A Secondary Analysis of the Exenatide-PD Trial. JAMA neurology 2019;76:420-
429. 
30. 
Blommer J, Pitcher T, Mustapic M, et al. Extracellular vesicle biomarkers for cognitive 
impairment in Parkinson's disease. Brain 2023;146:195-208. 
31. 
Bhargava P, Nogueras-Ortiz C, Kim S, Delgado-Peraza F, Calabresi PA, Kapogiannis 
D. Synaptic and complement markers in extracellular vesicles in multiple sclerosis. Mult Scler 
2021;27:509-518. 
32. 
Cedarbaum JM, Stambler N, Malta E, et al. The ALSFRS-R: a revised ALS functional 
rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group 
(Phase III). J Neurol Sci 1999;169:13-21. 
33. 
Kleyweg RP, van der Meche FG, Schmitz PI. Interobserver agreement in the 
assessment of muscle strength and functional abilities in Guillain-Barre syndrome. Muscle 
Nerve 1991;14:1103-1109. 
34. 
Miller TM, Cudkowicz ME, Genge A, et al. Trial of Antisense Oligonucleotide 
Tofersen for SOD1 ALS. N Engl J Med 2022;387:1099-1110. 
35. 
Menon P, Geevasinga N, Yiannikas C, Howells J, Kiernan MC, Vucic S. Sensitivity 
and specificity of threshold tracking transcranial magnetic stimulation for diagnosis of 
amyotrophic lateral sclerosis: a prospective study. Lancet Neurol 2015;14:478-484. 

   
 
 
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36. 
Wainger BJ, Macklin EA, Vucic S, et al. Effect of Ezogabine on Cortical and Spinal 
Motor Neuron Excitability in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial. 
JAMA neurology 2021;78:186-196. 
37. 
Di Lazzaro V, Rothwell J, Capogna M. Noninvasive Stimulation of the Human Brain: 
Activation of Multiple Cortical Circuits. The Neuroscientist : a review journal bringing 
neurobiology, neurology and psychiatry 2018;24:246-260. 
38. 
Shepheard SR, Wuu J, Cardoso M, et al. Urinary p75(ECD): A prognostic, disease 
progression, and pharmacodynamic biomarker in ALS. Neurology 2017;88:1137-1143. 
39. 
McMackin R, Bede P, Ingre C, Malaspina A, Hardiman O. Biomarkers in amyotrophic 
lateral sclerosis: current status and future prospects. Nat Rev Neurol 2023. 
 
 
 

  
 
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12. APPENDICES 
 
12.1. List of Abbreviations and Definition of Terms 
 
AE 
Adverse Experience 
ASaT 
All Subjects as Treated 
βhCG 
Beta-Human Chorionic Gonadotropin 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CI 
Confidence Interval 
CNS 
Central Nervous System 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Scale 
DEGs 
Data Entry Guidelines 
ALS 
Amyotrophic Lateral Sclerosis 
ECI 
Events of Clinical Interest 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FSH 
Follicle-stimulating Hormone 
TPS 
Transcranial Pulse Stimulation 
GCP 
Good Clinical Practice 
HR 
Heart Rate 
 
IA 
Interim Analysis 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Review Committee 
IRB 
Institutional Review Board 
kg 
Kilogram 
NCS 
Not Clinically Significant 
PDLC 
Pre-Defined Limit of Change. 
PE 
Physical Examination 

   
 
 
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SAC 
Scientific Advisory Committee 
SAE 
Serious Adverse Experience 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SES 
Standardized Effect Size 
SOC 
System Organ Class 
 
SOP 
Standard Operating Procedure 
SAP 
Statistical Analysis Plan 
ULN 
Upper Limit of Normal 

  
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12.2. ALS Diagnosis criteria5 
The diagnosis of ALS requires: (A) the presence of: 
(A: 1) evidence of lower motor neuron (LMN) degeneration by clinical, electrophysiological 
or neuropathologic examination, 
(A:2 )evidence of upper motoneuron (UMN) degeneration by clinical examination, and 
(A:3)progressive spread of symptoms or signs within a region or to other regions, as 
determined by history or examination,together with: 
(B) the absence of 
(B:1) electrophysiological or pathological evidence of other disease processes that might 
explain the signs of LMN and/or UMN degeneration, and 
(B:2) neuroimaging evidence of other disease processes that might explain the observed 
clinical and electrophysiological signs. 
 
 

CONFIDENTIAL 
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12.3 
General Neurological Exam 
The General Neurological Examination will be performed at the timepoint(s) specified in the 
protocol flow chart. 
Note to the investigator: If at any time abnormalities are observed in the General 
Neurological Exam, the Investigator should do additional examinations as needed based 
on his or her medical judgment. 
The General Neurological Examination includes all of the modules listed below, with the 
exception of Module 1, and is intended to be a general screening examination and 
sufficient for this study and subject population. 
MODULE 2 – CRANIAL NERVE ASSESSMENT 
A. II – Visual Fields and acuity 
B. II, III – Pupil Size and Reactivity 
C. III, IV, VI – Extraocular Movements (range of motion, smooth pursuit, saccades, 
nystagmus) 
1. Observe for nystagmus during eye movements, increased nystagmus at the end of 
gaze or other oculomotor changes (mild nystagmus at extremes of gaze is normal). 
Note direction of nystagmus 
D. V – Facial Sensation, Jaw Strength 
E. VII – Muscles of Facial Expression (wrinkle brow, squeeze eyes shut, smile) 
F. VIII – Auditory Acuity (assessed using a bed-side screening test eg by rubbing fingers on 
each side of subject’s head or by whispering numbers) 
G. IX – Gag reflex 
H. X – Swallow  
I. XI – Shoulder shrug 
J. Tongue Protrusion (midline) 
Score: left and right (except for G, H, J) 
Grade: NORMAL or IMPAIRED and describe abnormality 
MODULE 3 - MOTOR SYSTEM 
A. Muscle Tone 
1. Ask the volunteer to relax. 
2. Flex and extend the volunteer’s elbows and knees (bilaterally). 
3. There is a small, continuous resistance to passive movement. 
4. Observe for involuntary movements (eg, tremor, tics, fasciculations). Observe for 
resistance to passive movement; observe for decreased (flaccid) or increased 
(rigid/spastic) tone. 
Score:  left and right 
Grade: NORMAL, INCREASED or DECREASED 
B. Muscle Strength 

  
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1. Ask the subject to stand up from sitting without using hands Grade: NORMAL, 
IMPAIRED and describe abnormality 
2. Test proximal limb strength by having the volunteer flex and extend the knees and 
elbows against your resistance. 
Test bilaterally and compare 1 side to the other. 
Score:  left and right 
Grade: 5/5: normal; 4/5: movement against resistance impaired; 3/5: movement 
against gravity but not against resistance; 2/5: visible movement but not against 
gravity; 1/5: visible contraction; 0/5: no visible activity 
3. Test distal limb strength by having the volunteer conduct dorsiflexion and plantar 
flexion of the volunteer’s feet; finger abduction and handgrip strength against your 
resistance. 
Test bilaterally and compare 1 side to the other. 
Score:  left and right 
Grade: 5/5: normal; 4/5: movement against resistance impaired; 3/5: movement 
against gravity but not against resistance; 2/5: visible movement but not against 
gravity; 1/5: visible contraction; 0/5: no visible activity 
C. Pronator Drift 
1. Ask the volunteer to hold both arms straight forward with, palms up and eyes closed 
for ~10-15 seconds as tolerated; watch for how well the arm position is maintained. 
2. Instruct the volunteer to keep both arms still while you tap them briskly downward. 
The volunteer should normally be able to maintain extension and supination. 
Inability to maintain extension and supination (and drift into pronation) indicates an 
upper motor neuron deficit. 
Score:  left and right 
Grade: NORMAL or IMPAIRED and describe abnormality 
MODULE 4 - REFLEXES 
A. Biceps 
B. Knee 
Note: Other deep tendon reflexes may be tested at Investigator's discretion (eg elbow, wrist 
or Achilles tendon) 
Score: left and right 
Grade: NORMAL, INCREASED, DECREASED or ABSENT 
C. Babinski 
Score: left and right 
Grade: NORMAL or ABNORMAL 
MODULE 5 - COORDINATION AND GAIT 
A. Rapid, Rhythmic Alternating Movements 

CONFIDENTIAL 
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1. Testing each hand separately, ask the volunteer to tap the distal thumb with the tip 
of each finger, in sequence, as fast as possible.  
Score: left and right 
Grade: NORMAL or IMPAIRED 
Reminder: If the rapid alternate movements are disturbed, the subject will be 
asked to strike his hand on the thigh, raise the hand, turn it over and 
then strike the back of the hand down on the same place.  (This test is 
impaired in cerebellar disease, extra pyramidal disease and upper MN 
weakness.) 
B. Point-to-Point Movements 
1. Ask the volunteer to touch your index finger and their nose alternately several 
times. Move your finger about as the volunteer performs this task. 
Score: left and right 
Grade: NORMAL or IMPAIRED 
Reminder: If the point-to-point testing is disturbed, the subject will be asked to 
place 1 heel on the opposite knee and then run it down the shin to the 
big toe. Repeat this for both sides. (Impaired tests indicate cerebellar 
disease.) 
C. Romberg 
1. Ask the volunteer to stand with both feet together and eyes closed for 20 to 30 
seconds without support. 
2. Be prepared to catch the volunteer if they are unstable. 
Grade: NORMAL or IMPAIRED 
D. Gait 
1. Ask the volunteer to walk across the room, turn and come back (assess posture, 
balance, swinging of arms and movement of the legs). 
Grade: NORMAL or IMPAIRED and describe abnormality 
2. Ask the volunteer to walk heel-to-toe in a straight line (tandem gait). 
Grade: NORMAL or IMPAIRED and describe abnormality 
MODULE 6 - SENSORY 
A. Light touch sense:  cotton wisp on skin of forearms and legs, bilaterally. 
B. Pin prick: safety pin touched lightly to skin of forearms and legs, bilaterally. 
C. Temperature: warm or cool object touched to skin of forearms and legs, bilaterally. 
D. Vibration:  tuning fork vibration detection in hands, feet bilaterally. E. Position sense:  
perception of thumb and toe movement, bilaterally. 
F. Stereognosis: (identify common objects placed in hand, eg, coin, key). 
Score: left and right 
Grade: NORMAL OR IMPAIRED and describe abnormality (for each A to F) 

  
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12.3 Predefined Limits of Change Criteria  
Predefined Limits of Change Criteria for Vital Signs, Weight, and Temperature 
Measurement 
Criteria 
Systolic blood   
pressure 
≥180 mm Hg and ≥20 mm Hg increase from 
baseline 
 < 90 mm Hg and > 20 mm Hg decrease from 
baseline 
Diastolic blood   
pressure 
≥105 mm Hg and ≥15 mm Hg increase from 
baseline 
 < 50 mm Hg and > 15 mm Hg decrease from 
baseline 
Pulse 
≥120 bpm and ≥15 bpm increase from baseline 
 < 50 bpm and > 15 bpm decrease from baseline 
Orthostatic blood 
pressure 
>20 mm Hg systolic sitting to standing after 
treatment  
(but not in baseline) 
Weight 
≥7 % increase from baseline 
≥7 % decrease from baseline 
Temperature 
≥101°F and ≥2°F increase from baseline (≥38.3°C 
and ≥1°C increase from baseline) 
 
Predefined Limits of Change Criteria for ECGs 
Measurement 
Criteria 
QTc Interval† 
Prolongation compared to baseline ≥30 to ≤60 
msec 
Prolongation compared to baseline >60 msec 
Value ≥500 msec‡ 
2 Correction based on Bazett’s formula.  
3 The QTc Interval value must also represent a worsening compared 
to baseline to meet the definition. 
 
 

CONFIDENTIAL 
Page 60 of 61 
 
12.3 Mapping Between the 11 Categories of Suicidal Ideation and Behavior, the CSSRS, 
and CDR for Programming Standard Tables 
Mapping Between the 11 Categories of Suicidal Ideation and Behavior and the C-
SSRS 
Category 
C-SSRS Question (from eCRF)† 
Suicidal ideation 
 
Passive 
1. Wish to be dead 
Active - nonspecific (no method, 
intent, or plan) 
2. Non-specific active suicidal 
thoughts 
Active - method, but no intent or 
plan 
3. Active suicidal ideation with any 
methods (not plan) without 
intent to act 
Active - intent, with or without a 
method, but no plan 
4. Active suicidal ideation with 
some intent to act, without 
specific plan 
Active - method, intent, and plan 
5. Active suicidal ideation with 
specific plan and intent 
Suicidal behavior 
 
Preparatory actions toward 
imminent suicidal behaviors 
Preparatory acts or behavior 
Aborted attempt 
Aborted attempt 
Interrupted attempt 
Interrupted attempt 
Suicide attempt 
Actual attempt 
Completed suicide 
Completed suicide 
Self-injurious  
behavior,  
no  
suicidal intent 
Has subject engaged in non-suicidal 
self-injurious behavior? 
†Data are "yes" or "no"  
 
 
 
 
 
 

  
Page 61 of 61 
 
13.0 SIGNATURES 
13.2 Investigator 
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data 
in accordance with the protocol and, in particular, I agree to report any serious adverse 
events as defined in Section 7.0 – Assessing and Recording Adverse Events.  I also agree to 
handle all clinical supplies and collect and handle all clinical specimens in accordance with 
the protocol.  I understand that information that identifies me will be used and disclosed as 
described in the protocol, and that such information may be transferred to countries that 
do not have laws protecting such information.  Since the information in this protocol and 
the referenced Investigator’s Brochure is confidential, I understand that its disclosure to any 
third parties, other than those involved in approval, supervision, or conduct of the trial is 
prohibited.  I will ensure that the necessary precautions are taken to protect such 
information from loss, inadvertent disclosure, or access by third parties. 
TYPED NAME 
 
TITLE 
 
SIGNATURE 
 
DATE SIGNED