An Exploratory Study to Investigate the Use of Biotelemetry to Identify Markers of Disease Progression in Subjects With Amyotrophic Lateral Sclerosis
Phase: NA
Conditions: Amyotrophic Lateral Sclerosis
Sponsor: GlaxoSmithKline

2014N211002_02 
CONFIDENTIAL 
1 
 
 
The GlaxoSmithKline group of companies 
201283 
 
TITLE PAGE 
Division: Worldwide Development 
Information Type: Protocol Amendment 
 
Title: 
An Exploratory Study to Investigate the Use of Biotelemetry to 
Identify Markers of Disease Progression in Subjects with 
Amyotrophic Lateral Sclerosis 
 
Compound Number: Non-compound specific 
 
Development Phase: 
NA 
 
Effective Date: 
21-SEP-2015 
 
Protocol Amendment Number: 02 
 
Author (s): 
 
Revision Chronology 
 
GlaxoSmithKline 
Document Number 
Date 
Version 
2014N211002_00 
2014-DEC-12 
Original 
2014N211002_01 
2015-APR-09 
Amendment No. 1 
The purpose of this amendment is to: 1) clarify bullet 5 in Exclusion Criterion #3; 2) add 
a requirement to enter into the eCRF, concomitant medications and non-drug therapies 
used to treat AEs\SAEs as defined in the protocol; 3) add hyperreflexia to the 
neurological examinations; 4) and to make other minor clarifications to the text. 
2014N211002_02 
2015-SEP-21 
Amendment No. 2 
The purpose of this amendment is to: 1) modify the age requirement from 50 to 75 years 
to 18 to 80 years (Inclusion Criterion #1); 2) modify the time frame in Inclusion Criterion 
#3 from 12 months to 18 months between symptom onset and ALS diagnosis (and amend 
the description of the population accordingly); 3) clarify bullet 4 in Exclusion Criterion 
#3, 4) clarify that muscle atrophy is one of the limb symptoms to be included as part of 
the neurological examination, , 5) to make other minor clarifications to the text. 
 
Copyright 2015 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited. 
PPD 

2 
 
2014N211002_02 
CONFIDENTIAL 
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SPONSOR SIGNATORY 
 
 
 
 
Marina Zvartau-Hind MD, PhD 
Date 
VP Head of Clinical Development 
R&D Neurosciences Therapy  Area Unit 
PPD 

2014N211002_02 
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MEDICAL MONITOR/SPONSOR INFORMATION PAGE 
Medical Monitor/SAE Contact Information: 
 
Role 
Name 
Day Time Phone 
Number and 
email address 
After-hours 
Phone/Cell/ 
Pager 
Number 
Fax 
Number 
Site Address 
Medical 
PPD 
PPD 
PPD 
PPD 
GlaxoSmithKline 
Monitor 
MD, 
Research and 
PhD 
Development 
Limited 
Iron Bridge Road 
Stockley Park 
West,  Uxbridge, 
Middlesex, UB11 
1BU, UK 
SAE 
contact 
information 
Case 
Management 
Group, GCSP 
PPD 
PPD 
 
Sponsor Legal Registered Address: 
 
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
 
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application. 
 
Regulatory Agency Identifying Number(s): None 

2014N211002_02 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
For protocol number 201283 
 
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment. 
 
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study. 
 
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
 
Investigator Name: 
Investigator Address: 
Investigator Phone Number: 
Investigator Signature 
Date 

2014N211002_02 
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TABLE OF CONTENTS 
 
PAGE 
 
1. 
PROTOCOL SYNOPSIS FOR STUDY 201283 ........................................................ 7 
2. 
INTRODUCTION .................................................................................................... 10 
2.1. 
Background and Study Rationale ................................................................ 10 
3. 
OBJECTIVE(S) AND ENDPOINT(S) ...................................................................... 11 
4. 
STUDY DESIGN .................................................................................................... 12 
4.1. 
Overall Design ............................................................................................ 12 
4.2. 
Type and Number of Subjects ..................................................................... 14 
4.3. 
Design Justification ..................................................................................... 14 
4.3.1. 
General Design ............................................................................ 14 
4.3.2. 
Population .................................................................................... 14 
4.3.3. 
Choice of Endpoints ..................................................................... 14 
4.3.3.1. 
Movement/physical activity ......................................... 14 
4.3.3.2. 
Heart Rate Variability (HRV) ....................................... 15 
4.3.3.3. 
Speech ....................................................................... 15 
4.3.3.4. 
ALSFRS-R and FVC ................................................... 15 
4.3.4. 
Choice of Devices ........................................................................ 16 
4.3.4.1. 
Medical Devices: Accelerometer and Heartbeat 
Sensing Electrode ...................................................... 16 
4.3.4.2. 
Data Transmission Device: LifeInsight Hub ................ 17 
4.4. 
Benefit:Risk Assessment ............................................................................ 18 
4.4.1. 
Risk Assessment ......................................................................... 18 
4.4.2. 
Benefit Assessment ..................................................................... 19 
4.4.3. 
Overall Benefit: Risk Conclusion .................................................. 19 
5. 
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............. 20 
5.1. 
Inclusion Criteria ......................................................................................... 20 
5.2. 
Exclusion Criteria ........................................................................................ 21 
5.3. 
Screening Failures ...................................................................................... 21 
5.4. 
Withdrawal Criteria...................................................................................... 22 
5.5. 
Subject and Study Completion .................................................................... 23 
5.6. 
Treatment after the End of the Study .......................................................... 23 
5.7. 
Concomitant Medications and Non-Drug Therapies .................................... 23 
5.7.1. 
Permitted Medications and Non-Drug Therapies .......................... 23 
5.7.2. 
Prohibited Medications and Non-Drug Therapies ......................... 23 
6. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 23 
6.1. 
Screening and Critical Baseline Assessments ............................................ 24 
6.2. 
Exploratory Measures and Assessments .................................................... 24 
6.2.1. 
Reference Tasks .......................................................................... 25 
6.2.2. 
Movement/Physical Activity .......................................................... 25 
6.2.3. 
Heart Rate Variability (HRV) ........................................................ 26 
6.2.4. 
Quantitative Measure of Speech .................................................. 26 
6.3. 
Gold Standard Measures of Function .......................................................... 27 
6.3.1. 
ALS Functional Rating Scale-Revised (ALSFRS-R) ..................... 27 
6.3.2. 
Forced Vital Capacity (FVC) ........................................................ 27 

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6.4. 
Safety ......................................................................................................... 27 
6.4.1. 
Adverse Events (AE) and Serious Adverse Events (SAEs) .......... 28 
6.4.1.1. 
Time period and Frequency for collecting AE 
and SAE information ................................................... 28 
6.4.1.2. 
Method of Detecting AEs and SAEs ........................... 28 
6.4.1.3. 
Follow-up of AEs and SAEs ........................................ 28 
6.4.1.4. 
Regulatory Reporting Requirements for SAEs ............ 28 
6.4.2. 
Device Incidents/Complaints ........................................................ 29 
6.5. 
Time and Events Tables ............................................................................. 30 
7. 
DATA MANAGEMENT ........................................................................................... 32 
8. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES ................................. 32 
8.1. 
Hypotheses ................................................................................................. 32 
8.2. 
Sample Size Considerations ....................................................................... 32 
8.2.1. 
Sample Size Assumptions ........................................................... 32 
8.2.2. 
Sample Size Sensitivity ................................................................ 33 
8.2.3. 
Sample Size Re-estimation or Adjustment ................................... 34 
8.3. 
Data Analysis Considerations ..................................................................... 34 
8.3.1. 
Analysis Populations .................................................................... 34 
8.3.2. 
Interim Analysis ........................................................................... 34 
8.4. 
Key Elements of Analysis Plan.................................................................... 34 
8.4.1. 
Exploratory Analyses ................................................................... 34 
8.4.2. 
Other Analyses ............................................................................ 36 
8.4.3. 
Safety Analyses ........................................................................... 36 
9. 
STUDY GOVERNANCE CONSIDERATIONS ........................................................ 36 
9.1. 
Posting of Information on Publicly Available Clinical Trial Registers ............ 36 
9.2. 
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................ 36 
9.3. 
Quality Control (Study Monitoring) .............................................................. 37 
9.4. 
Quality Assurance ....................................................................................... 37 
9.5. 
Study and Site Closure ............................................................................... 38 
9.6. 
Records Retention ...................................................................................... 38 
9.7. 
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication ................. 39 
10. REFERENCES ....................................................................................................... 40 
11. APPENDICES ........................................................................................................ 43 
11.1. Appendix 1 – Abbreviations and Trademarks .............................................. 43 
11.2. Appendix 2: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events ............................................... 44 
11.2.1. 
Definition of Adverse Events ........................................................ 44 
11.2.2. 
Definition of Serious Adverse Events ........................................... 44 
11.2.3. 
Recording of AEs and SAEs ........................................................ 45 
11.2.4. 
Evaluating AEs and SAEs ............................................................ 46 
11.2.5. 
Reporting of SAEs to GSK ........................................................... 47 
11.3. Appendix 3: ALS Functional Rating Scale - Revised (ALSFRS-R) .............. 48 
11.4. Appendix 4: Country Specific Requirements ............................................... 51 
11.5. Appendix 5: Protocol Changes .................................................................... 52 

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1. 
PROTOCOL SYNOPSIS FOR STUDY 201283 
Rationale 
This study is being conducted as the first step for developing new meaningful measure(s) 
which might prove to be more effective than existing measures for monitoring clinical 
function and disease course in amyotrophic lateral sclerosis (ALS). The objective of this 
study is to test novel measures of movement/physical activity, heart rate and speech and 
explore how they measure disease progression by evaluating their relationship to gold 
standard measures of function. The ultimate aim of this research is to identify and 
develop sensitive, real-time measures of ALS disease progression which might have 
utility as clinically meaningful endpoints in future ALS studies. 
 
Objective(s)/Endpoint(s) 
 
Objectives 
Endpoints 
Exploratory 
Explore the application of actigraphy: 
• 
For measuring movement/physical 
activity in ALS subjects 
• 
As a marker of ALS disease progression 
• 
Change over time in measurements of 
movement/physical activity by 
accelerometer. 
• 
Relationship between the ALS 
Functional Rating Scale - Revised 
(ALSFRS-R) and accelerometer 
measures of movement/activity. 
• 
Validate the movement/physical activity 
algorithms against in-clinic reference 
tasks of movement to ensure the 
algorithms are correctly capturing the 
defined activity. 
Explore the application of continuous remote- 
monitoring of heart rate measures: 
• 
For measuring autonomic nervous 
system function in ALS subjects 
• 
As a marker of ALS disease progression 
• 
Change over time in heart rate variability 
(HRV) as measured by a heartbeat 
sensing electrode. 
• 
Relationship between the ALSFRS and 
biotelemetry measures of HRV. 
Explore the application of digital, quantitative 
speech testing: 
• 
For measuring speech quality in ALS 
subjects 
• 
As a marker of ALS disease progression. 
• 
Change over time in digital speech 
measures of vowel, running speech and 
word measurements as captured by a 
high fidelity, acoustic sound capture 
interface. 
• 
Relationship between the ALSFRS and 
digital measures of speech. 
• 
Relationship between Forced Vital 
Capacity (FVC) and digital measures of 
speech. 

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Objectives 
Endpoints 
Explore the impact of the accelerometer and 
electrode devices on everyday life in subjects 
with ALS 
Subject/caregiver feedback. 
Explore the feasibility of biotelemetry 
transmission of movement/physical activity 
and HRV data. 
Assessed by successful data transmission 
from the telecommunications hub (LifeInsight) 
to the central secure server at McLaren 
Applied Technologies (MAT). 
Safety 
Monitor safety and tolerability. 
Type and incidence of adverse events (AEs) 
secondary to the devices used in this study or 
due to study procedures. 
Overall Design 
Study 201283 is an exploratory, non-controlled, non-drug study in ALS patients. The 
study consists of two phases: 
 
1. A variable length Pilot Phase to test and confirm the algorithms are capturing 
movement/physical activity, ensure the data transfer device is working correctly, and 
understand the reliability and ease of use/acceptance of the accelerometer and 
electrode. Subjects will attend at least 1 clinic visit to perform a series of set 
reference tasks while wearing the accelerometer and electrode. Subjects will also 
continuously wear the accelerometer and electrode in their routine home-life setting 
for approximately 3 days after the clinic visit (i.e., home monitoring). Repeat clinic 
visits and home monitoring might be necessary if data indicate the algorithms or 
equipment are not performing as expected. It is estimated that 5 subjects will 
participate in this Pilot Phase; however, the number may be less or more depending 
on the data generated. Subjects in the Pilot Phase will continue in the study and 
participate in the Core Study Phase. 
 
2. A 48 week Core Study Phase to evaluate how measures of movement/physical 
activity, speech and HRV relate to ALS disease progression. During this phase, 
subjects will attend 5 clinic visits to perform gold standard measures of function and 
perform a series of set reference tasks while wearing the accelerometer and electrode. 
Subjects will also continuously wear the accelerometer and electrode in their routine 
home-life setting for approximately 3 days after the clinic visits (i.e., home 
monitoring). In between clinic visits, subjects will attach the accelerometer and 
electrode and wear it for approximately 3 days in their home. A telephone contact 
with the subject will be made by the site at the end of each 3-day home monitoring 
period. 
Data will be reviewed in-stream by GlaxoSmithKline (GSK) and McLaren Applied 
Technologies (MAT) throughout the Pilot and Core Study Phases to understand the utility 
of the measures and algorithms, the functionality of the data transmission process, and  
the durability and ease of use/acceptance of the selected accelerometer and electrode. 
Generated data may result in modifications to the study, such as: changes to the 
devices/equipment; repositioning of the accelerometer/electrode; modification to the 

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algorithms, the supportive data collection plan or the data transmission process; dropping 
measures/tests which are not achievable.  The output is therefore not prescriptive. 
Progression from the Pilot Phase to the Core Study Phase will be based on thorough 
review of the generated data. The Core Study Phase will only progress once the data 
from the Pilot Phase is fully interrogated. 
 
Type and Number of Subjects 
Male and female subjects 18 to 80 years of age with ALS will be enrolled into the study. 
Treatment of enrolled subjects will be consistent with local standard of clinical care for 
ALS patients. A maximum of 25 subjects will be enrolled such that approximately 20 
subjects complete the study with 48 weeks of data. 
 
Analysis 
The study is designed to explore if there is a relationship between change from baseline 
in the physical activity/movement, heart rate and speech endpoints and change from 
baseline in the gold standard measures of function (ALSFRS-R and FVC). The analyses 
are all exploratory. Correlation between change from baseline in the movement/physical 
activity, heart rate and speech measures and change from baseline in the ALSFRS-R or 
FVC (as appropriate) will be explored. Depending on the strength of correlation between 
the endpoints further analyses may be performed. 

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2. 
INTRODUCTION 
2.1. 
Background and Study Rationale 
Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease that affects 
motor neurons and is characterized by progressive weakness leading to impaired speech, 
swallowing, mobility and respiration. The average survival time for ALS is 2-3 years 
from symptom onset [Talbot, 2009]. Riluzole is the only licensed medicine which affects 
the ALS disease course and it has only a modest effect on survival. Thus, there remains a 
significant unmet medical need in ALS for therapies to slow progression of functional 
decline and improve survival. 
 
Numerous therapies and experimental agents have been tested in ALS and have failed, 
suggesting a potential need to improve measures of disease progression and overall study 
design. Existing measures have limitations in terms of sensitivity hence requiring long 
trials with large sample sizes.  The gold standard measure of function, the ALS 
Functional Rating Scale - Revised (ALSFRS-R), relies on subject perception of their 
function versus direct assessment of function. Testing burden in trials is heavy and 
involves a number of assessments for overall function, respiratory function, and muscle 
strength; this can be tiring for subjects particularly as the disease progresses leading to 
subject drop out and missing data such that ability to draw conclusions from the data is 
impacted. 
 
Measures which could more objectively and sensitively detect a clinically meaningful 
change in function and disease progression might enable smaller trials, thus reducing the 
need for such large trials in this rare population. An endpoint which could assess 
clinically meaningful functional change in a more ‘holistic’ manner might reduce the 
need for multiple tests thus alleviating patient burden and missing data. Real-time 
measurement of function might allow for quicker interrogation of data and shorter trials 
thus delivering medicines in this life threatening disease faster. 
 
This study is being conducted as the first step for developing new meaningful measure(s) 
which might prove to be more effective than existing measures for monitoring clinical 
function and disease course in ALS. The objective of this study is to test novel measures 
of movement/physical activity, heart rate and speech and explore how they measure 
disease progression by evaluating their relationship to gold standard measures of 
function. The ultimate aim of this research is to identify and develop sensitive, real-time 
measures of ALS disease progression which might have utility as clinically meaningful 
endpoints in future ALS studies. 

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3. 
OBJECTIVE(S) AND ENDPOINT(S) 
 
Objectives 
Endpoints 
Exploratory 
Explore the application of actigraphy: 
• 
For measuring movement/physical 
activity in ALS subjects 
• 
As a marker of ALS disease progression 
• 
Change over time in measurements of 
movement/physical activity by 
accelerometer. Measurements may 
include but not be limited to: total time 
spent walking, time spent sitting, time 
spent standing, time spent active, time 
spent sedentary, average duration of 
walking periods, number of continuous 
walking periods >5mins, time spent 
walking on stairs, Total Activity Score 
(amount and intensity of movement), 
Sleep Fragmentation Index. 
• 
Relationship between the ALSFRS and 
accelerometer measures of 
movement/activity. 
• 
Validate the movement/physical activity 
algorithms against in-clinic reference 
tasks of movement to ensure the 
algorithms are correctly capturing the 
defined activity. Reference tasks may 
include but are not limited to: sitting, 
standing, sit to stand, stand to sit, 
walking, climbing stairs, lying, stand to 
lying, lying to stand and dexterity. 
Explore the application of continuous remote- 
monitoring of heart rate measures: 
• 
For measuring autonomic nervous 
system function in ALS subjects 
• 
As a marker of ALS disease progression 
• 
Change over time in heart rate variability 
(HRV) as measured by a heartbeat 
sensing electrode. Measurements may 
include but not be limited to: HRV 
standard deviation over 5mins, HRV low 
frequency/high frequency (LF/HR) 
variation over 5mins, Sleep 
Fragmentation Index. 
• 
Relationship between the ALSFRS and 
biotelemetry measures of HRV. 
Explore the application of digital, quantitative 
speech testing: 
• 
For measuring speech quality in ALS 
subjects 
• 
As a marker of ALS disease progression. 
• 
Change over time in digital speech 
measures of vowel, running speech and 
word measurements as captured by a 
high fidelity, acoustic sound capture 
interface.  Measurements may include 
but not be limited to: central tendency of 
fundamental frequency, jitter, shimmer, 

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Objectives 
Endpoints 
maximum gap between words, speaking 
rate, average phoneme rate, and 
maximum phonation time. 
• 
Relationship between the ALSFRS and 
digital measures of speech. 
• 
Relationship between Forced Vital 
Capacity (FVC) and digital measures of 
speech. 
Explore the impact of the accelerometer and 
electrode devices on everyday life in subjects 
with ALS 
Subject/caregiver feedback. Feedback may 
include but not be limited to: comfort of the 
devices, ease of applying the devices, and 
ease of data transmission process. 
Explore the feasibility of biotelemetry 
transmission of movement/physical activity 
and HRV data. 
Assessed by successful data transmission 
from the telecommunications hub (LifeInsight) 
to the central secure server at McLaren 
Applied Technologies (MAT). 
Safety 
Monitor safety and tolerability. 
• 
Type and incidence of adverse events 
(AEs) secondary to the devices used in 
this study. 
• 
Type and incidence of AEs due to study 
procedures. 
 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
Study 201283 is an exploratory, non-controlled, non-drug study in ALS patients. The 
study consists of two phases: 
 
1. A variable length Pilot Phase to test and confirm the algorithms are capturing 
movement/physical activity, ensure the data transfer device is working correctly, and 
understand the reliability and ease of use/acceptance of the accelerometer and 
electrode.  Subjects will attend at least 1 clinic visit to perform a series of set 
reference tasks while wearing the accelerometer and electrode. Subjects will also 
continuously wear the accelerometer and electrode in their routine home-life setting 
for approximately 3 days after the clinic visit (i.e., home monitoring). Repeat clinic 
visits and home monitoring might be necessary if data indicate the algorithms or 
equipment are not performing as expected. See Figure 1.  It is estimated that 5 
subjects will participate in this Pilot Phase; however, the number may be less or more 
depending on the data generated.  Subjects in the Pilot Phase will continue in the 
study and participate in the Core Study Phase. 

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2. A 48 week Core Study Phase to evaluate how measures of movement/physical 
activity, speech and HRV relate to ALS disease progression. During this phase, 
subjects will attend 5 clinic visits to perform gold standard measures of function and 
perform a series of set reference tasks while wearing the accelerometer and electrode. 
Subjects will also continuously wear the accelerometer and electrode in their routine 
home-life setting for approximately 3 days after the clinic visits (i.e., home 
monitoring). In between clinic visits, subjects will attach the accelerometer and 
electrode and wear it for approximately 3 days in their home. A telephone contact 
with the subject will be made by the site at the end of each 3-day home monitoring 
period.  See Figure 1. 
 
 
Figure 1 
Study Schematic 
 
Data will be reviewed in-stream by GlaxoSmithkline (GSK) and McLaren Applied 
Technologies (MAT) throughout the Pilot and Core Study Phases to understand the utility 
of the measures and algorithms, the functionality of the data transmission process, and  
the durability and ease of use/acceptance of the selected accelerometer and electrode. 
Generated data may result in modifications to the study, such as: changes to the 
devices/equipment; repositioning of the accelerometer/electrode; modification to the 
algorithms, the supportive data collection plan or the data transmission process; dropping 
measures/tests which are not achievable.  The output is therefore not prescriptive. 
Progression from the Pilot Phase to the Core Study Phase will be based on thorough 
review of the generated data. The Core Study Phase will only progress once the data 
from the Pilot Phase is fully interrogated. 

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4.2. 
Type and Number of Subjects 
Male and female subjects 18 to 80 years of age with ALS will be enrolled into the study. 
Treatment of enrolled subjects will be consistent with local standard of clinical care for 
ALS patients. A maximum of 25 subjects will be enrolled such that approximately 20 
subjects complete the study with 48 weeks of data. 
 
4.3. 
Design Justification 
4.3.1. 
General Design 
 
Application of actigraphy measures of movement/physical activity, measures of heart rate 
and quantitative measures of speech for real-time measurement of function and disease 
progression in ALS is highly novel; therefore, a stepwise approach to the study design 
has been undertaken.  The study consists of two phases, a variable length Pilot Phase and 
a 48 week Core Study Phase. A two phase approach is being utilized to allow for 
refinement of the algorithms, equipment and data transmission processes during the Pilot 
Phase and enable adaptation of components which may not be fit for purpose or working 
well before embarking on the Core Study Phase where measures of movement, heart rate 
and speech will be evaluated as possible measures of disease progression. In such an 
exploratory setting, the two part design helps mitigate taking forward equipment, 
algorithms, data capture methods and data transmission processes that may require 
adaptation and lessens the risk that major changes will be needed during the Core Study 
Phase. 
 
4.3.2. 
Population 
 
The chosen population for study is a subset of the overall ALS population and consists of 
ALS subjects that have mild to moderate disease and have a relatively high level of 
clinical function at baseline. The selected population is expected to experience a 
functional decline during the 48 week study period of approximately 1 ALSFRS-R point 
/month (See Section 8.2.1). This level of decline represents typical natural history of the 
disease and is thought to be sufficient to start to understand the relationship between gold 
standard measures of clinical function and the novel measures of movement/physical 
activity, speech and HRV. 
 
4.3.3. 
Choice of Endpoints 
 
4.3.3.1. 
Movement/physical activity 
 
ALS results in progressive wasting and paralysis of voluntary muscles leading to an 
inability to move one’s arms, legs and body [Talbot, 2009; Kiernan, 2011]. A 
measurement of movement/physical activity could be a meaningful endpoint for 
monitoring ALS disease progression. 
 
Daily activity and walking can be measured over time using motion-sensing devices, 
such as accelerometers, which measure positional change and motion. Walking 
behaviour, sedentary behaviour, and postural transitions as measured by an accelerometer 
have been shown to provide a composite picture of daily activity in healthy elderly 

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subjects [Lord, 2011]. To date, accelerometer data have not been reported for ALS 
patients; however, accelerometers have been shown to have utility across other 
neurological conditions with mobility problems.  Post stroke actigraphy has been shown 
to be a useful tool to measure recovery of function [Reiterer, 2008], monitor general 
patterns and amount of activity [Craig, 2012; Gebruers, 2010; Lindemann, 2012], and has 
been shown to correlate with clinical scales [Gebruers, 2010]. In Parkinson’s Disease, 
actigraphy has been shown to effectively monitor ambulatory activity [Lord, 2013] and 
activity data has been shown to correlate with clinical scales [Pan, 2013]. Wireless 
accelerometer applications have also successfully quantified and monitored hand tremor 
in Parkinson’s disease [LeMoyne, 2010; LeMoyne, 2013]. 
 
4.3.3.2. 
Heart Rate Variability (HRV) 
 
Autonomic function is known to be impaired in ALS [Pavlovic, 2010; Merico, 2011; 
Pinto, 2012]. HRV is a measure of autonomic function and analysis of HRV may prove 
useful in early detection of autonomic nervous system abnormalities, including 
sympathetic hyperactivity and sympathovagal imbalance [Shimizu, 2013]. In particular, 
increase in low frequency/high frequency (LF/HF) ratio has been reported to be linked 
with the imbalance of sympathovagal function [Pisano, 1995], while decreased LF and 
HF bands with reduced baroreflex sensitivity and diminished cardiorespiratory transfer 
has been reported during normal breathing in ALS [Linden, 1998]. Additionally, reduced 
HRV has been identified as a potential mortality risk factor in ALS [Pinto, 2012]. 
Therefore, continuous real-time measurement of HRV could be a meaningful endpoint in 
ALS. 
 
4.3.3.3. 
Speech 
 
Speech is produced as a result of muscle and respiratory function [Green, 2013], which 
are both affected in ALS.  ALS results in progressive bulbar motor deterioration leading 
to impaired speech and swallowing and complications from these bulbar symptoms can 
significantly impact survival [Green, 2013]. Pseudobulbar manifestations may also 
contribute to speech impairment. Speech measurement is part of the assessment of bulbar 
function in ALS; however, many of the available tests do not provide meaningful 
information on disease progression [Green, 2013]; therefore, an easy to use, quantitative 
measure of speech might be a meaningful endpoint for monitoring ASL disease 
progression. 
 
4.3.3.4. 
ALSFRS-R and FVC 
 
ALSFRS-R is a gold standard measure of functional decline in ALS and is routinely used 
to monitor disease progression and evaluate treatment effects in clinical trials and in 
clinical practice [Brinkmann, 1997; Cudkowicz, 2004; Cedarbaum, 1999]. In order for 
any new outcome measure to be clinically meaningful and relevant to physicians and 
regulators, it will need to correlate to the ALSFRS-R. 
 
FVC is considered a gold standard measure of respiratory function in ALS and is 
routinely used to monitor disease progression and evaluate treatment effects in clinical 
trials [Brinkmann, 1997; Cudkowicz, 2004].  FVC, as a measure of lung capacity, may 

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help explain the physical effects of air flow over the glottis and the impact of reduced 
respiratory function on phonation and speech. 
 
4.3.4. 
Choice of Devices 
 
4.3.4.1. 
Medical Devices: Accelerometer and Heartbeat Sensing Electrode 
 
The selected accelerometer is the commercially available eMotion Faros 180° ECG 
Sensor manufactured by Mega. The selected heartbeat sensing electrode is the 
commercially available Fast Fix electrode patch manufactured by Mega. Both devices 
are CE-marked under the Medical Device Directive 93/42/EEC. 
 
The Faros sensor is a wearable, externally applied, accelerometer and electrocardiograph 
recorder and transmitter that is intended for health monitoring and scientific research in 
both clinical and non-clinical settings; it does not have any analysis or diagnostic 
capability [Mega Electronics Ltd, 2014].  The Faros sensor measures physical activity 
and has the capacity to record heart rate variability. Physical activity is captured via the 
3-axis accelerometer within the Faros sensor. Heart rate is captured via electrodes in the 
Fast Fix electrode patch and transmitted to the Faros sensor via a Universal Serial Bus 
(USB) connection. The Fast Fix electrode patch also has adhesive strips which secure the 
Faros sensor and Fast Fix electrodes together. See Figure 2. The physical activity and 
heart rate data are transmitted from the Faros sensor to the data transmission system via 
secure Bluetooth wireless signal. 
 
Figure 2 
Mega Faros Sensor 
 
The advantages for using the Faros sensor and Fast Fix electrode patch are: 
 
• 
Ability to collect both physical activity data and heart rate data. 
• 
Ability to buffer and store a subject’s data for the duration of the study which 
prevents data loss. 
• 
Ability to transmit the physical activity and heart rate data via Bluetooth which 
prevents having to manually download data and allows for in-stream data 
transmission and review of data by GSK and MAT which facilitates in-stream 
decision making and informed adaptations. 

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4.3.4.2. 
Data Transmission Device: LifeInsight Hub 
 
The LifeInsight hub was developed by MAT as a platform to enable easy, real-time 
transmission of data for research purposes (see Figure 3). The hub is CE-marked under 
the Radio and Telecommunications Terminal Equipment Directive 1999/5/EC. 
 
Figure 3 
LifeInsight Hub 
 
The hub receives data from the accelerometer via secure Bluetooth wireless signal every 
2mins. The hub then automatically uploads the data in real-time (every 10 minutes) to 
secure servers at MAT via a secure connection on the 3G mobile phone network.  The 
hub also has sufficient memory to retain a copy of all data generated for a subject at a site 
for the duration of the trial. This system of biotelemetry data transmission has several 
advantages, specifically the hub: 
 
• 
Enables real-time monitoring of data at GSK/MAT which facilitates in-stream 
decision making and informed adaptations for the study. 
• 
Ensures data is transmitted in-stream to MAT which minimizes the impact of lost 
hubs or accelerometers. 
• 
Ensures a copy of the data is securely retained so that data will not irrevocably be 
lost during the transmission/upload process. 
• 
Prevents having to download data from the accelerometer and upload the data to the 
secure server via a manual process. 
• 
Avoids issues associated with installing software on local computers in 
hospitals/clinics. 
• 
Avoids issues with local firewalls for data transmission/upload to secure servers. 

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4.4. 
Benefit:Risk Assessment 
The following section outlines the risk assessment and mitigation strategy for this 
protocol as well as the potential benefit to subjects. 
 
4.4.1. 
Risk Assessment 
 
Potential Risk of Clinical 
Significance 
Management/Mitigation 
Trial Risks 
Subjects may consider the nature 
and extent of the assessments to 
be a burden and prohibitive for 
enrolment or continuation in the 
study. 
The protocol has been designed to follow the standard in-clinic 
visit schedule for ALS treatment and monitoring and the 
selected measures of function are familiar to ALS patients and 
are part of routine disease monitoring. In-stream feedback will 
be obtained on the ease of use/acceptance of the devices. 
Every attempt will be made to incorporate the feedback to 
reduce subject/caregiver burden. 
There is negligible risk for 
pregnant females and women of 
childbearing potential (WCBP) to 
wear or handle the devices in this 
study. 
The nature and intensity of the wireless signals used to 
transmit the data are equivalent to a mobile phone or less. 
Medical Device Risks 
The medical-grade 
hypoallergenic adhesive used to 
attach the devices might result in 
a local skin allergic reaction such 
as: irritation, inflammation or 
itching. 
Subjects with a known hypersensitivity to adhesives are 
excluded from the study. Subjects are informed of this 
potential risk in the Informed Consent Form (ICF). Subjects 
are instructed to remove the devices if a reaction occurs and 
contact the site for further instructions. Adverse events (AEs) 
and serious adverse events (SAEs) considered attributable to 
the medical devices will be reported.  Subjects are provided 
with instructions on proper use of the device. 
Because the sensor uses 
Bluetooth wireless signal to 
transmit data, there is a risk of 
electromagnetic interference with 
other medical devices. 
Subjects with an active implantable cardiac medical device 
(e.g. pacemaker or implantable cardioverter-defibrillator) are 
excluded from the study. Subjects at high risk for requiring 
external defibrillation are excluded from the study. Subjects 
are advised to notify the site prior to any medical or surgical 
procedure.  Subjects are provided with instructions on proper 
use of the device. 
Dismantling or submerging the 
sensor in water might result in 
electrical shock 
The sensor does not have any electrical stimulation 
capabilities and has not been shown to cause electrical shock 
in case of accidental water contact in healthy volunteers. 
Subjects are provided with instructions on proper handling of 
the device. AEs and SAEs considered attributable to the 
medical devices will be reported. 
Extreme humidity or temperature 
might result in device 
malfunction. 
Subjects are provided with instructions on proper care of the 
device. 

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Potential Risk of Clinical 
Significance 
Management/Mitigation 
Data Transmission Device Risks 
Non-secure data transfer could 
result in disclosure of unintended 
personally identifiable information 
(PII). 
The data transmitted through the hub does not contain PII. 
Subject information and data security will be handled 
according to GSK Standard Operating Procedures and 
policies. 
The data transfer process from 
sensor to hub and hub to MAT 
might result in missing data or 
inaccurate data. 
The Bluetooth pairing between the sensor and the hub is 
locked to prevent unintended pairing to other Bluetooth- 
enabling devices. Each subject is assigned a specific sensor 
and hub; the data from the subject will be identified by the 
combination of the unique serial numbers on the sensor and 
hub. The hub has memory capacity to store data for the 
duration of the trial.  The hub automatically uploads data to 
MAT in stream. 
Dismantling or submerging the 
hub in water might result in 
electrical shock. 
Subjects are provided with instructions on proper care of the 
hub. AEs and SAEs considered attributable to the data 
transmission device (hub) will be reported. 
 
 
4.4.2. 
Benefit Assessment 
 
Subjects will not have direct clinical benefit from participating in this study.  Subjects 
will continue their usual standard of care as prescribed by their healthcare provider and 
will continue to follow up with their regular physician for their ALS healthcare during the 
study. Subject participation will contribute to the overall knowledge of disease 
progression measurement in ALS, which may have utility in future clinical 
investigations. 
 
4.4.3. 
Overall Benefit: Risk Conclusion 
 
The available data package for the devices used in this study establishes reasonable 
assurance the devices are safe for their intended use in the trial when utilized in 
accordance with instructions for use. The risks to subject safety have been mitigated and 
controlled based on subject eligibility criteria, subject instructions, device labelling, and 
testing certifications of the CE-marked devices supplied in the study. The overall risk to 
subjects is therefore considered to be minimal. While there is no individual subject 
benefit, the development of potentially better and more effective measures for monitoring 
disease progression might provide benefit for future ALS clinical trials, and may advance 
understanding of ALS and development of future treatments. 

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5. 
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA 
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential. 
 
5.1. 
Inclusion Criteria 
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply: 
 
AGE 
1. Between 18 and 80 years of age, inclusive, at the time of signing the informed 
consent. 
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY 
2. Diagnosed with ALS by a neurologist with expertise in ALS. For subjects with 
bulbar onset there must be objective limb involvement of at least one limb. 
3. Diagnosed with ALS within 18 months of symptom onset. 
4. Subjects must be ambulatory (i.e., must not be confined to a wheelchair). 
SEX 
5.  Male and female subjects. 
INFORMED CONSENT 
6. Capable of giving signed (or verbal consent or assent where applicable) informed 
consent as described in Section 9.2 which includes compliance with the requirements 
and restrictions listed in the consent form and in this protocol. 
OTHER 
7. Capable and willing to comply with the requirements of the protocol (either by 
themselves or with assistance). 

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5.2. 
Exclusion Criteria 
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply: 
 
CONCURRENT CONDITIONS/MEDICAL HISTORY 
1. Neurological (other than the subject’s ALS) or non-neurological co-morbidities (e.g. 
joint disease, respiratory disease) which limit mobility. 
2. Clinically significant cognitive impairment in the opinion of the investigator. 
3. Regionally restricted forms of ALS, or other atypical variants: 
• 
Isolated corticobulbar pattern of ALS with normal ambulation 
• 
Flail arm syndrome 
• 
Primary lateral sclerosis 
• 
Signs of chronic partial denervation restricted to a single limb 
• 
ALS parkinsonism dementia complex 
4. Subjects requiring mechanical ventilation (non-invasive ventilation for sleep apnoea 
is allowed). 
5. Historical or current evidence of clinically significant uncontrolled disease which, in 
the opinion of the investigator, would put the safety of the subject at risk through 
participation or impact the study assessments or endpoints. 
OTHER CRITERIA 
6. Presence of an active implantable cardiac medical device (e.g., pacemaker or 
implantable cardioverter-defibrillator) or at a high risk for needing external 
defibrillation. 
7. History of skin hypersensitivity to adhesives. 
8. Current participation in a clinical trial which in the opinion of the investigator and 
GSK medical monitor might impact the objectives of this study. 
 
5.3. 
Screening Failures 
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently enrolled. Subjects who do not meet all inclusion criteria or meet 
any of the exclusion criteria will not be eligible for enrolment. 
 
A subject will be assigned a subject number when the informed consent form (ICF) is 
signed. Any subject assigned a subject number but not enrolled in the study will be 
considered a screen failure. 

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In order to ensure transparent reporting of screen failure subjects, meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements, and respond to 
queries from Regulatory authorities, a minimal set of screen failure information is 
required and will be reported in the electronic case report form (eCRF) including: 
Demography, Screen Failure details, Protocol Deviations, Eligibility Criteria, and any 
SAEs as defined in Section 6.4.1. 
 
5.4. 
Withdrawal Criteria 
A subject may withdraw from the study at any time at his/her own request and for any 
reason, or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural, or administrative reasons. Reasons for premature discontinuation from the 
study will be recorded in the eCRF. Premature discontinuation from the study may result 
under the following circumstances: 
 
• 
AE or SAE related to study procedures or the devices used in the study (AE/SAE 
section of eCRF must be completed) 
• 
Protocol deviation 
• 
Non-compliance with study procedures 
• 
Subject lost to follow-up 
• 
Subject withdraws consent 
• 
Investigator discretion 
• 
Sponsor terminates study 
If a subject is prematurely discontinued from participation in the study for any reason, the 
investigator will make every attempt to perform an Early Withdrawal Visit (EWD). The 
EWD visit may be conducted as an in-clinic visit or by telephone. At a minimum if the 
EWD visit is conducted, AE/SAE data will be collected; other assessments may or may 
not be performed at the discretion of the investigator and consent of the subject. Upon 
discontinuation from the study, the subject will need to return the study devices. 
 
If a subject’s ALS progresses such that he/she is no longer able to attend the clinic for the 
scheduled visits, the subject may still continue in the study and continue with the home 
monitoring assessments.  For subjects who miss a clinic visit or do not complete the 
home monitoring assessments, the following actions should be taken: 
 
• 
The site must attempt to contact the subject and re-schedule as soon as possible. 
• 
The site must counsel the subject on the importance of maintaining the assigned 
Time and Events schedule and ascertain whether the subject wishes to and/or should 
continue in the study. 
• 
In cases where the subject is deemed ‘lost to follow up’, the investigator or designee 
must make every effort to regain contact with the subject (where possible, 3 
telephone calls and if necessary a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the subject’s medical record. 

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• 
Should the subject continue to be unreachable, only then will he/she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
5.5. 
Subject and Study Completion 
A completed subject is one who has completed the study through the Week 48 visit. The 
end of the study is defined as the last subject’s last visit. 
 
5.6. 
Treatment after the End of the Study 
As this study does not involve treatment, subjects will not receive any post-study 
treatment from GSK after completion of the study. The investigator is responsible for 
ensuring consideration has been given to the post-study care of the subject’s medical 
condition. 
 
5.7. 
Concomitant Medications and Non-Drug Therapies 
5.7.1. 
Permitted Medications and Non-Drug Therapies 
 
Medications and non-drug therapies that are prescribed as part of the subject’s ALS 
standard of care or for a concomitant medical condition are permitted and should be 
documented in the source documents. Any medication and non-drug therapy taken by the 
subject during the study from time of enrolment until their last visit in the study which, in 
the opinion of the investigator, might positively or negatively impact the 
movement/physical activity, heart rate or quantitative speech measurements will be 
recorded in the eCRF. In addition, any medication or non-drug therapy taken by the 
subject to treat AEs and SAEs which, in the opinion of the investigator, are related to a 
protocol-mandated procedure or one of the devices used in the study will be recorded in 
the eCRF. Medication name, dose, unit, frequency, route, indication, and dates of 
administration will be recorded in the eCRF. 
 
5.7.2. 
Prohibited Medications and Non-Drug Therapies 
 
There are no prohibited medications or non-drug therapies in this study. Enrolment into 
an investigational drug trial may however be prohibited if, in the opinion of the 
investigator and GSK medical monitor, the investigational drug might impact the 
objectives of this study. 
 
6. 
STUDY ASSESSMENTS AND PROCEDURES 
This section lists the procedures and parameters of each planned study assessment. 
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct. 
 
The timing of each visit and assessment in the Pilot Phase is listed in the Time and 
Events Table, Section 6.5, Table 1. Any repeat visits in this phase will be scheduled as 
needed. 

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The timing of each visit and assessment in the Core Study Phase is listed in the Time and 
Events Table, Section 6.5, Table 2.  In this phase, all subject visits are scheduled relative 
to Baseline/Study Day 1. Should a visit be missed, visit dates should not be re-calculated 
from the date of the previous visit but should remain relative to Baseline/Study Day 1. 
 
Visit windows have been identified and are specified in the Time and Events Tables, 
Section 6.5. 
 
Supplementary study conduct information is provided in the Study Reference Manual 
(SRM). The SRM will provide site personnel with administrative and detailed 
information to complete the assessments. 
 
6.1. 
Screening and Critical Baseline Assessments 
The following assessments/data capture will be performed and the results recorded in the 
eCRF. 
 
• 
Medical history. These data will be assessed in relationship to the 
inclusion/exclusion criteria listed in Section 5 and will help document other 
concurrent conditions which might impact the exploratory measures conducted in 
this study. 
• 
ALS history, including type of ALS, muscle weakness onset date, ALS diagnosis 
date and ALS phenotype at onset. These data are important to help characterize the 
population enrolled in the study. 
• 
Smoking history and current smoking status. These data are important to help 
interpret the quantitative speech measurement data. 
• 
Demographic parameters of: year of birth, sex, race, and ethnicity. These data help 
define the population enrolled as well as help interpret the quantitative speech 
measurement data. 
• A neurological examination will be performed according to local site protocol by 
medically qualified personnel.  Functional regions involved (bulbar, cervical, 
thoracic, lumbosacral) limb symptoms (weakness, muscle atrophy, spasticity, 
hyperreflexia, and fasciculations); and presence or absence of bulbar and 
pseudobulbar symptoms will be recorded. These data are important for understanding 
the neurological phenotype of the ALS subjects being enrolled into the study. A brief 
neurological examination (presence or absence of weakness, hyperreflexia, and 
spasticity in each arm and leg, and presence or absence of bulbar and pseudobulbar 
symptoms) will be performed at the Pilot Screening Visit. 
• 
Gold standard measures of function, specifically ALSFRS-R and FVC. 
• 
Exploratory measures of movement/physical activity, HRV and speech. 
6.2. 
Exploratory Measures and Assessments 
Any trained staff at the study site can perform the exploratory measures and assessments. 
Appropriate training will be provided by GSK and MAT before the start of the study. 

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6.2.1. 
Reference Tasks 
 
At present, the algorithms which will be used to process the movement/physical activity 
data are exploratory and non-validated. To help understand how the algorithms are 
performing in the ALS population as well as over time as the disease progresses, a series 
of reference tasks will be performed at each clinic visit in both the Pilot and Core Study 
Phases (See the Time and Events Tables, Section 6.5).  These reference tasks will serve 
as a ‘blueprint’ for specific movements which the Faros sensor will measure. The data 
generated from these tasks will help understand if the algorithms are correctly measuring 
the specific activities and enable refinement and adaptation of the algorithms as required. 
 
It is possible that during the course of the trial some of the reference tasks may no longer 
be necessary and dropped from the list as they are no longer informing algorithm 
development and refinement; therefore, the list is not fixed. Additionally, during the 
course of a subject’s participation in the study, if a subject is unable to perform one of the 
reference tasks due to disease progression it may be omitted. The reference tasks may 
include the following movements/activities: 
 
• 
Sitting 
• 
Standing 
• 
Lying down 
• 
Walking 
• 
Climbing stairs 
• 
Transitions, such as: sit to stand, stand to sit, stand to lying, lying to stand 
• 
Nine-hole peg test as a measure of arm dexterity 
A detailed protocol on how to perform each reference task and how to manage the order 
of the tasks should a subject not be able to complete all of them will be provided in the 
SRM. 
 
The data generated from the reference tasks will be utilized by MAT to confirm the 
performance of the algorithm and will not be transmitted to GSK for analysis. The 
following supportive data (brief neurological exam) will be captured in the eCRF: 
presence or absence of weakness, hyperreflexia, and spasticity in each arm and leg, 
whether the reference task was attempted, whether the reference task was completed 
according to the prescribed protocol, and use of walking aids. 
 
6.2.2. 
Movement/Physical Activity 
 
Movement/physical activity data will be collected by the Faros sensor throughout the 
study as described in the Time and Events Tables, Section 6.5. At each clinic visit in the 
Pilot and Core Study Phases, the Faros sensor will be placed on the subject just prior to 
the reference tasks and will be worn during completion of the tasks. The sensor will then 
be removed and sent home with the subject.  The morning after the clinic visit, the 
subject will re-attach the sensor and wear it for approximately 3 days (except for the last 
visit where the subject will wear the sensor for 3 days before the visit).  Additionally, in 

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between visits during the Core Study Phase the subject will wear the Faros sensor every 
month for approximately 3 days to enable data collection on a monthly basis over the 48 
week study period. 
 
Each subject will be issued one Faros sensor and ‘LifeInsight Hub’ for use during the 
study. The Faros sensor will be worn on the subject’s chest on the sternum. Once 
attached, the Faros sensor should be worn continuously; however, it will need to be 
removed daily for charging. In the event of any skin discomfort or irritation the subject 
should remove the Faros sensor and contact the investigator for further instructions. 
Subjects will be provided instructions on how to operate and wear the Faros sensor and 
use the hub. 
 
The raw movement and physical activity data will be processed by MAT. At present, the 
algorithms are exploratory. The processed data will be sent to GSK for final statistical 
analysis.  The following supportive data will be captured in the eCRF: serial number of 
the Faros sensor and LifeInsight hub, date/time of sensor placement and removal, number 
of times the sensor fell off, subject activity level while wearing the sensor, subject’s 
determination on ease of sensor set up and use, and subject feedback on whether the 
sensor impacted their activities of daily living or sleep habits. A diary will be provided to 
subjects as a tool to record details about their experience with attaching the sensor, how 
many times it fell off and their activity level while wearing the sensor. 
 
6.2.3. 
Heart Rate Variability (HRV) 
 
HRV data will be measured by the Fast Fix electrode patch throughout the study as 
described in the Time and Events Tables, Section 6.5. The Fast Fix electrode patch is 
worn with the Faros sensor on the subject’s sternum according to the same schedule as 
the Faros sensor (see Section 6.2.2). The Fast Fix electrode patch will be replaced by the 
subject on a daily basis during the 3 day monitoring period. Subjects will be provided 
with a sufficient number of Fast Fix patches to cover each 3 day monitoring period.  In 
the event of any skin discomfort or irritation the subject should remove the Fast Fix 
electrode patch and contact the investigator for further instructions. Subjects will be 
provided instructions on how to operate and wear the Fast Fix electrode patch. 
 
HRV measures will be generated by MAT. The HRV measures will be sent to GSK for 
final statistical analysis. There are no additional supportive data specifically for the 
electrode patch other than what is already captured in the eCRF for the Faros sensor. 
 
6.2.4. 
Quantitative Measure of Speech 
 
Quantitative speech testing will be performed in the Core Study Phase as described in the 
Time and Events Table, Section 6.5, Table 2. Subjects will follow simple prompts on a 
computer screen instructing them to say a series of vowels, words, and paragraphs which 
will be recorded using a high definition digital microphone and stored securely on a 
laptop.  The speech waveform data will be sent via secure method to MAT for 
processing.  At present, the algorithms are exploratory.  The processed data will be sent 
to GSK for final statistical analysis.  The following supportive data will be recorded in 
the eCRF: serial number of the microphone, converter, and converter case, presence or 

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absence of bulbar and pseudobulbar symptoms, smoking history and current smoking 
status, age, gender and ethnicity. 
 
6.3. 
Gold Standard Measures of Function 
No study specific training or certification will be required for the gold standard measures 
of function. Sites should select appropriate, experienced personnel to perform these 
measures. The selected personnel would be expected to have experience performing 
these measures in the ALS population. In addition, level of experience necessary and 
conduct of the measures will be described in the SRM. 
 
6.3.1. 
ALS Functional Rating Scale-Revised (ALSFRS-R) 
 
The ALSFRS-R [Appendix 3] is a 12 item, validated questionnaire-based rating scale that 
assesses the functioning of ALS subjects across 4 domains: gross motor activity, fine 
motor activity, bulbar, and respiratory function [Cedarbaum, 1999]. The ALSFRS-R is 
recommended as a primary outcome measure for ALS clinical trials [EMA, 2013; De 
Carvalho, 2005; Leigh, 2004] and has been used in a number of recently conducted or 
ongoing studies [Cudkowicz, 2011]. The total ALSFRS-R score ranges from 0-48, with a 
lower score indicative of more severe impairment. Telephone administration of the 
ALSFRS-R has been validated [Kaufmann, 2007]. 
 
The ALSFRS-R will be collected in the Core Study Phase as described in the Time and 
Events Table, Section 6.5, Table 2. Telephone administration of the ALSFRS-R is 
permissible to accommodate the planned home visits as well as the planned in-clinic 
visits should the subject not be well enough to attend. Any site staff experienced and 
competent with the ALSFRS-R may administer the scale. A standardized ALSFRS-R 
scoring sheet will be provided to sites. Individual ALSFRS-R item scores will be 
recorded in the eCRF. 
 
6.3.2. 
Forced Vital Capacity (FVC) 
 
FVC is a measure of respiratory function and is the volume of air that can forcibly be 
blown out after a single, full breath. FVC is a sensitive measure of ALS disease 
progression, is used as a standard test for ALS management, and is recommended as a 
secondary outcome measure in ALS clinical trials [Cudkowicz, 2004; Czaplinski, 2006; 
Clavelou, 2013]. 
 
FVC will be collected in the Core Study Phase as described in the Time and Events 
Table, Section 6.5, Table 2 and will be performed by experienced site personnel 
according to local protocol using a calibrated spirometer. Every effort should be made to 
have the same individual perform the FVC for a given subject throughout the study. For 
each time point, the best FVC result (in liters) will be recorded in the eCRF. 
 
6.4. 
Safety 
Planned time points for all safety assessments are listed in the Time and Events Tables, 
Section 6.5. 

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6.4.1. 
Adverse Events (AE) and Serious Adverse Events (SAEs) 
 
Only those AEs and SAEs which, in the opinion of the investigator, are related to a 
protocol-mandated procedure or one of the devices used in the study will be reported. 
The definitions of an AE or SAE can be found in Section 11.2, Appendix 2. The 
investigator and their designees are responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE. 
 
6.4.1.1. 
Time period and Frequency for collecting AE and SAE information 
 
• 
AEs and SAEs as defined above in Section 6.4.1 will be collected from the time a 
subject consents to participate in the study until the subject’s last visit in the study 
(see Section 6.4.1.3), at the time points specified in the Time and Events Tables 
(Section 6.5). 
• 
Medical occurrences that begin after obtaining informed consent but prior to the first 
protocol-mandated procedure may be recorded on the Medical History/Current 
Medical Conditions section of the eCRF. 
• 
All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 2. 
• 
Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to one of the protocol-mandated procedures or devices used 
in the study, the investigator must promptly notify GSK. 
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 2. 
 
6.4.1.2. 
Method of Detecting AEs and SAEs 
 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence. 
 
6.4.1.3. 
Follow-up of AEs and SAEs 
 
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts. All SAEs will be followed until resolution, until the 
condition stabilizes, until the event is otherwise explained, or until the subject is lost to 
follow-up (as defined in Section 5.4). Further information on follow-up procedures is 
given in Appendix 2. 
 
6.4.1.4. 
Regulatory Reporting Requirements for SAEs 
 
Prompt notification by the investigator to GSK of SAEs related to either the protocol- 
mandated procedures or the devices is essential so that legal obligations and ethical 
responsibilities towards the safety of subjects are met. GSK will report all device related 

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AEs and SAEs to the manufacturer for subsequent reporting to Medicines and Healthcare 
Regulatory Agency as appropriate. GSK will comply with country specific regulatory 
requirements relating to safety reporting to the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) and investigators. 
 
6.4.2. 
Device Incidents/Complaints 
 
Should any malfunction or deterioration in the characteristics and/or performance of the 
devices used in this study be reported, GSK will promptly report them to manufacturer. 

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6.5. 
Time and Events Tables 
Table 1 
Time and Events – Pilot Phase 
 
Procedures 
Clinic Visit 
Home 
Monitoring 
(~ 3 days) 
Telephone 
Contacta 
(TC) 
Repeat 
Clinic Visitb 
Home 
Monitoringb 
(~ 3 days) 
Telephone 
Contacta,b 
EWD 
Screening 
Day 0 
Informed consent 
X 
Eligibility criteria 
X 
Demography 
X 
Medical and ALS history 
X 
Brief neurological exam 
X 
X 
AEs/SAEs 
X 
X 
X 
X 
X 
Sensor placement 
X 
X 
X 
X 
Reference tasks 
X 
X 
Subject completes diary 
X 
X 
Site obtains diary information 
X 
X 
X 
Device impact questionnaire 
X 
X 
X 
a. 
Telephone contact to follow the 3-day home monitoring period to ensure the subject has completed the home monitoring period, diary, and to assess AEs, as appropriate. The 
expectation is that this call would occur on the first weekday following the home monitoring period. 
b. 
May be repeated as necessary 

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Table 2 
Time and Events – Core Study Phase 
 
Study Day/Weeka 
Screen/Baseline 
Day 1/Week 0 
Weeks 
0, 4, 8 
Week 
12 
Weeks 
12, 16, 20 
Week 24 
Weeks 
24, 28, 32 
Week 36 
Weeks  
36, 40, 44, 48c 
Week 48 or 
EWD 
Clinic 
Visit 1b 
Home 
Monitoring 
(~3 days) 
Clinic 
Visit 2 
Home 
Monitoring 
(~3 days) 
Clinic Visit 
3 
Home 
Monitoring 
(~3 days) 
Clinic 
Visit 4 
Home 
Monitoring 
(~3 days) 
Clinic Visit 5 
Procedures 
Informed consent 
Xb 
Eligibility criteria 
Xb 
Demography 
Xb 
Medical and ALS history 
Xb 
Neurological exam 
X 
Smoking details 
X 
X 
X 
X 
X 
Brief neurological exam 
X 
X 
X 
X 
AEs/SAEsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medicationse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ALSFRS-Re 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVC 
X 
X 
X 
X 
X 
Speech assessment 
X 
X 
X 
X 
X 
Sensor placement 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Reference tasks 
X 
X 
X 
X 
X 
Device impact questionnaire 
X 
X 
X 
X 
Subject completes diary 
X 
X 
X 
X 
Site obtains diary informationf 
X 
X 
X 
X 
X 
X 
X 
X 
Follow-up Telephone Contactg 
X 
X 
X 
X 
a. 
Clinic visits and home monitoring periods should be conducted within  7 days of the scheduled visit/home period and should be scheduled according to the Baseline Visit. 
b. 
Subjects transitioning from the Pilot Phase do not need to perform these procedures. 
c. 
The Week 48 home monitoring period will occur the three days prior to the Week 48 in-clinic visit (Visit 5). 
d. 
Assessed in clinic at Weeks 0, 12, 24, 36, and 48 and by telephone at Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44. 
e. 
Assessed in clinic at Weeks 0, 12, 24, 36, and 48 and by telephone at Weeks 4, 8, 16, 20, 28, 32, 40, and 44. 
f. 
Diary information should be obtained by telephone at Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44. 
g. 
Telephone contact to follow each 3-day home monitoring period. The expectation is that this call would occur on the first weekday following the home monitoring period. 

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7. 
DATA MANAGEMENT 
• 
For this study subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee, and combined with data provided from other 
sources in a validated data system. 
• 
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., 
removing errors and inconsistencies in the data. 
• 
Adverse events and concomitant medications terms will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) and an internal validated medication 
dictionary, GSKDrug. 
• 
CRFs (including queries and audit trails) will be retained by GSK, and copies will be 
sent to the investigator to maintain as the investigator copy. Subject initials will not 
be collected or transmitted to GSK according to GSK policy. 
• 
No data from this study will be used to inform clinical decision making for a 
subject’s treatment or management. 
8. 
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES 
8.1. 
Hypotheses 
The study is designed to explore if there is a relationship between change from baseline 
in the physical activity/movement, heart rate and speech endpoints and change from 
baseline in the gold standard measures of function (ALSFRS-R and FVC). 
 
8.2. 
Sample Size Considerations 
8.2.1. 
Sample Size Assumptions 
 
The study is intended to explore a number of physical activity/movement, heart rate and 
speech endpoints, but for the purposes of the sample size justification we will explore the 
relationship between the ALSFRS-R and one of the physical activity/movement 
endpoints, the total activity score. 
 
With 20 subjects, we have an 80% chance of detecting a within subject correlation of 
greater than or equal to 0.6 (considered a moderate to strong correlation), if the true 
correlation is 0.7. The sample size is estimated based on statistical simulations conducted 
taking into account a number of assumptions outlined below regarding the two endpoints. 
The within subject correlation is calculated using the method suggested by Bland, 1995 
 
Assumptions about the rate of decline in ALSFRS-R over time are estimated from a 
meta-analysis, performed by GSK, of nine similar ALSFRS-R trials from the literature. 
The limited biotelemetry data from stroke patients in the MAG104615 study has been 
used for the assumptions for the biotelemetry data. As this data was limited and in a 
different patient population, sensitivity to these assumptions are explored in Section 

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8.2.2. Total activity score is used as an example of one of the movement endpoints 
captured by the device. 
 
In detail, the assumptions used in these simulations include: 
 
• 
Both the ALSFRS-R and total activity score have a linear decline over time. 
• 
The ALSFRS-R declines at a rate of 0.943 points per month. The variance of the 
rate of decline is assumed to be 0.771, and the within subject variance is assumed to 
be 4. 
• 
The total activity score declines at a rate of 10 points per month. The variance of the 
rate of decline is assumed to be 0.6, and the within subject variance is assumed to be 
10. 
• 
The correlation between the two endpoints is assumed to take an auto-regressive 
structure, where within a subject at the same time point the two endpoints have a 
correlation of ρ while when the visits are i time points apart the correlation is 
assumed to be decreased to ρi+1. 
• 
The correlation is assumed to be ρ=0.7. 
8.2.2. 
Sample Size Sensitivity 
 
Sample size sensitivity in Table 3 shows the probability of detecting a moderate to strong 
within subject correlation between the two endpoints, defined as a correlation greater 
than or equal to 0.6, for various scenarios regarding the strength of the true correlation 
and the variance of the decline for the total activity score. All the other sample size 
assumptions listed in Section 8.2.1 remain unchanged. As the variance of the slope is the 
main component in the total variance, exploration into changing the within subject 
variance had little impact on the probability of detecting a strong correlation and so the 
results are not presented here. 
 
The probabilities are based on a simulation study carried out in R 2.15.2 with 10,000 
simulated datasets per scenario. 

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Table 3 
Probability of detecting a moderate to strong within subject 
correlation between the change from baseline in total activity score 
and the change from baseline in ALSFRS-R (N=20 subjects) 
 
Correlation Variance of decline Probability of strong correlation (%) 
0.8 
0.6 
83 
0.7 
0.6 
80 
0.6 
0.6 
80 
0.8 
0.7 
83 
0.7 
0.7 
80 
0.6 
0.7 
79 
0.8 
0.8 
83 
0.7 
0.8 
80 
0.6 
0.8 
79 
 
8.2.3. 
Sample Size Re-estimation or Adjustment 
 
There is no sample size re-estimation planned for this study. 
 
8.3. 
Data Analysis Considerations 
8.3.1. 
Analysis Populations 
 
Two populations are defined for this study: 
 
• 
Enrolled population: This will consist of all subjects who have signed consent and 
are not a screen failure. 
• 
Full Analysis Set (FAS): This will consist of all subjects with at least one post 
baseline measure for the ALSFRS-R and at least one physical activity/movement 
measure. 
8.3.2. 
Interim Analysis 
 
No formal interim analyses will be performed. Review of in stream data will be carried 
out to understand the utility of the measures and algorithms, the functionality of the data 
transmission process, and the durability and ease of use/acceptance of the selected 
accelerometer and electrode. Generated data may result in modifications to the study, 
such as: changes to the devices/equipment; repositioning of the accelerometer/electrode; 
modification to the algorithms, the supportive data collection plan or the data 
transmission process; dropping measures/tests which are not achievable. 
 
8.4. 
Key Elements of Analysis Plan 
8.4.1. 
Exploratory Analyses 
 
As the purpose of the study is to be hypothesis generating, all analyses are considered 
exploratory. 

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A hierarchical approach will be used to focus the analysis on the endpoints where a 
correlation with either the ALSFRS-R or FVC (as applicable) is present. To begin with, 
the within subject correlation between the following endpoints will be explored using the 
analysis method detailed below: 
 
• 
The change from baseline in the movement/physical activity endpoints as measured 
by the accelerometer device and the change from baseline in the ALSFRS-R 
• 
The change from baseline in the heart rate endpoints as measured by the electrode 
device and the change from baseline in the ALSFRS-R 
• 
The change from baseline in the speech endpoints and the change from baseline in 
the ALSFRS-R 
• 
The change from baseline in the speech endpoints and the change from baseline in 
the FVC 
An estimate of the between-subject correlation and the within-subject correlation will be 
obtained using the method described in Roy, (2006).  The between-subject correlation 
will characterize whether subjects with greater decrease in the endpoint also tend to have 
the greater change in ALSFRS-R (or FVC). The within-subject correlation will describe 
whether a decrease in one endpoint within an individual is associated with a decrease in 
the other endpoint. 
 
A mixed effect model with the change from baseline in the movement/physical activity 
endpoints and the change from baseline in the ALSFRS-R score as dependent variables 
will be fitted. An indicator variable to distinguish the two endpoints will be fitted as a 
fixed effect and a random effect. Other explanatory covariates will be fitted as fixed 
effects, as appropriate. 
 
The RANDOM and REPEATED statements will be used to specify the structure of the 
covariance matrix for the two responses. The RANDOM statement will be used to 
specify an unstructured variance-covariance structure for the two responses. The 
REPEATED statement will be used to specify the variance covariance matrix for the 
error terms in the model. The structure of the variance covariance matrix is constructed 
by taking the Kronecker product of an unstructured matrix, which models the covariance 
for the two endpoints, with an unstructured or autoregressive (AR(1)) covariance matrix 
which models the covariance for the 2 repeated measures across visits. 
 
As part of a sensitivity analysis, if the data allows the model to be fitted, a random 
intercept and slope will be specified in the RANDOM statement with an unstructured 
covariance matrix. Comparison between the model without and with the random 
intercept and slope will be assessed using the Bayesian information criteria (BIC). 
 
If the data is not sufficient to allow for convergence of the model, then alternative 
variance covariance matrices may be considered.  If convergence of the model 
parameters still cannot be achieved, the approach by Bland, 1995 will be used to estimate 
the within subject correlation. 

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Based on a predetermined rule that will be detailed in the Reporting Analysis Plan (RAP) 
further investigation of the endpoints may be carried out. This could include, but is not 
limited to: 
 
• 
Summary statistics of the endpoints over time 
• 
Plots of the individual subject change from baseline in the movement/physical 
activity, HRV and speech measures and the change from baseline in ALSFRS-R or 
FVC (as appropriate) 
• 
A mixed model repeated measures (MMRM) analysis to characterize the change 
from baseline in the endpoint over time using an unstructured covariance matrix. If 
due to the limited number of subjects, the parameters of the unstructured covariance 
matrix cannot be estimated then other covariance structures will be considered. 
Covariates for baseline movement/physical activity, visit and a baseline by visit 
interaction will be included in the model. Where appropriate the results of the 
MMRM will be presented graphically. No imputation will be carried out for missing 
data. 
Further details of the analyses will be specified in the RAP. 
 
8.4.2. 
Other Analyses 
 
Feedback from the subjects regarding the use of the sensor and electrode will be collected 
and summary statistics presented as appropriate. 
 
8.4.3. 
Safety Analyses 
 
The proportion of subjects reporting AEs related to a protocol-mandated procedure or the 
devices will be tabulated. A similar table for SAEs related to a protocol-mandated 
procedure or the devices will also be produced. 
 
9. 
STUDY GOVERNANCE CONSIDERATIONS 
9.1. 
Posting of Information on Publicly Available Clinical Trial 
Registers 
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins. 
 
9.2. 
Regulatory and Ethical Considerations, Including the 
Informed Consent Process 
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy. The study will also be conducted in accordance with ICH Good 
Clinical Practice (GCP), all applicable subject privacy requirements, and the guiding 
principles of the current version of the Declaration of Helsinki. This includes, but is not 
limited to, the following: 

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• 
IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable 
• 
Written informed consent must be obtained from each subject prior to participation 
in the study. Depending on the ability of the subject to provide written informed 
consent, it may be necessary for verbal consent or assent to be obtained from the 
subject and written informed consent will then be obtained from the subject’s legally 
acceptable representative, or caregiver on behalf of the subject (as per local 
requirements). 
• 
Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC) 
• 
GSK will provide full details of the above procedures, either verbally, in writing, or 
both. 
9.3. 
Quality Control (Study Monitoring) 
• 
In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements. 
• 
When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the eCRF will 
serve as the source document. 
GSK will monitor the study and site activity to verify that the: 
 
• 
Data are authentic, accurate, and complete. 
• 
Safety and rights of subjects are being protected. 
• 
Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents. 
 
9.4. 
Quality Assurance 
• 
To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and the 
regulatory agencies may conduct a regulatory inspection at any time during or after 
completion of the study. 
• 
In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective 
and/or preventative actions to address any findings/issues identified. 

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9.5. 
Study and Site Closure 
• 
Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard Operating 
Procedures. 
• 
GSK reserves the right to temporarily suspend or prematurely discontinue this study 
at any time for reasons including, but not limited to, safety or ethical issues or severe 
non-compliance. For multicenter studies, this can occur at one or more or at all sites. 
• 
If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable). When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action. 
• 
If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action. 
• 
If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation. 
9.6. 
Records Retention 
• 
Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by 
local regulations to be maintained elsewhere), in a safe and secure location. 
• 
The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review in 
conjunction with assessment of the facility, supporting systems, and relevant site 
staff. 
• 
Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken. 
• 
The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, including 
re-generating a hard copy, if required. Furthermore, the investigator must ensure 
there is an acceptable back-up of these reproductions and that an acceptable quality 
control process exists for making these reproductions. 
• 
GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by any 

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institutional requirements or local laws or regulations, GSK standards/procedures, 
and/or institutional requirements. 
• 
The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of ownership 
of the records in the event the investigator is no longer associated with the site. 
9.7. 
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually- 
agreeable location. 
 
GSK will also provide the investigator with the full summary of the study results. The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate. 
 
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge. 

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10. 
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Brinkmann JR, Andres P, Mendoza M, Sanjak M. Guidelines for the use and 
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Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, Nakanishi A. The 
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Cudkowicz M, Qureshi M, Shefner J. Measures and Markers in Amyotrophic Lateral 
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Cudkowicz M. et al. The effects of dexpramipexol (KNS-760704) in individuals with 
amyotrophic lateral sclerosis. Nature medicine 17 (12), 1652-1656 (2011) 
 
Czaplinski A, Yen AA, Appel SH. Forced vital capacity as an indicator of survival and 
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De Carvalho M, Chio A, Dengler R, Hecht M, Weber M, Swash M. Neurophysiological 
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Kiernan M, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, Burrell JR, Zoing 
MC. Amyotrophic lateral sclerosis.  Lancet. 2011;377;942-955. 
 
Leigh PN et al. Amyotrophic lateral sclerosis: a consensus viewpoint on designing and 
implementing a clinical trial.  ALS and other motor neuron disorders 5, 84-98 (2004). 
 
LeMoyne R, Mastroianni T, Cozza M, Coroian C, Grundfest W. Implementation of an 
iPhone for characterizing Parkinson's disease tremor through a wireless accelerometer 
application, Conf. Proc. IEEE Eng. Med. Biol. Soc. 2010; 2010:4954-8. 
 
LeMoyne R. Wearable and wireless accelerometer systems for monitoring Parkinson’s 
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Lindemann U, Jamour M, Nicolai SE, Benzinger P, Klenk J, Aminian K and Becker C. 
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Linden D, Diehl RR, Berlit P. Reduced baroreflex sensitivity and cardiorespiratory 
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Lord S, Godfrey A, Galna B. Ambulatory activity in incident Parkinson’s: more than 
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amyotrophic lateral sclerosis.  Muscle & Nerve. 2012;46:341–345. 
 
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NONE 
None 
 
11. 
APPENDICES 
11.1. 
Appendix 1 – Abbreviations and Trademarks 
Abbreviations 
 
AE 
Adverse Event 
ALS 
Amyotrophic Lateral Sclerosis 
ALSFRS-R 
Amyotrophic Lateral Sclerosis Functional Rating Scale - 
Revised 
AR 
Autoregressive 
BIC 
Bayesian Information Criteria 
CONSORT 
Consolidated Standards of Reporting Trials 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EWD 
Early Withdrawal Visit 
FAS 
Full Analysis Set 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
GSK 
GlaxoSmithKline 
HF 
High Frequency 
HRV 
Heart Rate Variability 
ICF 
Informed Consent From 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
LF 
Low Frequency 
MAT 
McLaren Applied Technologies 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-Effects Model Repeated-Measure Analysis 
PII 
Personally Identifiable Information 
RAP 
Reporting and Analysis Plan 
SAE 
Serious Adverse Event 
SRM 
Study Reference Manual 
USB 
Universal Serial Bus 
WCBP 
Women of Childbearing Potential 
 
Trademark Information 
 
Trademarks of the GlaxoSmithKline 
group of companies 
Trademarks not owned by the 
GlaxoSmithKline group of companies 

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11.2. 
Appendix 2: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events 
11.2.1. 
Definition of Adverse Events 
 
Adverse Event Definition: 
• 
For this non-drug study, an AE is any untoward medical occurrence in a clinical 
investigation subject which, in the opinion of the investigator, is related to a 
protocol-mandated procedure or one of the devices used by the subject during the 
study. 
11.2.2. 
Definition of Serious Adverse Events 
 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc). 
 
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that: 
a. Results in death 
b. Is life-threatening 
NOTE: 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c. 
Requires hospitalization or prolongation of existing hospitalization 
NOTE: 
• 
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. 
• 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in disability/incapacity 
NOTE: 
• 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 

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• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These should also be considered 
serious. 
• 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
11.2.3. 
Recording of AEs and SAEs 
 
AEs and SAE Recording: 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event. 
• 
The investigator will then record all relevant information regarding an AE/SAE in 
the eCRF 
• 
It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE eCRF page. 
• 
There may be instances when copies of medical records for certain cases are 
requested by GSK. In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission to GSK. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms. 

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11.2.4. 
Evaluating AEs and SAEs 
 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories: 
• 
Mild: An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities. 
• 
Moderate: An event that is sufficiently discomforting to interfere with normal 
everyday activities. 
• 
Severe:  An event that prevents normal everyday activities.  An AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe. 
• 
An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE. 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between the device or study- 
mandated procedure and the occurrence of each AE/SAE. Only those events which 
are considered to be attributable to either one of the devices or a study-mandated 
procedure will be reported in the eCRF. 
• 
A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes such as concomitant therapy, other risk factors, and the temporal 
relationship of the event to the procedure or device placement will be considered and 
investigated. 
• 
The investigator will also consult the Participant Information Leaflet in the 
determination of his/her assessment. 
• 
All AEs/SAEs considered attributable to one of the devices or a protocol-mandated 
procedure must be documented clearly in the medical notes by the investigator. 
• 
If, based on follow up information, the investigator determines an AE/SAE is no 
longer attributable to either one of the devices or a protocol-mandated procedure, the 
event should be removed from the eCRF. The change in causality should be 
documented and retained in the medical notes. 

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Follow-up of AEs and SAEs 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE. 
• 
The investigator is obligated to assist. This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals. 
• 
If a subject dies during participation in the study or during a recognized follow-up 
period as a result of a device or study procedure related event, the investigator will 
provide GSK with a copy of any post-mortem findings, including histopathology. 
• 
New or updated information will be recorded in the originally completed eCRF. 
• 
The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames. 
 
 
11.2.5. 
Reporting of SAEs to GSK 
 
SAE reporting to GSK via electronic data collection tool 
• 
Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool (eCRF). 
• 
If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the SAE coordinator. 
• 
Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available. 
• 
The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72hrs of submission of the 
SAE. 
• 
After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data 
• 
If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the SAE 
coordinator by telephone. 
• 
Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page. 

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11.3. 
Appendix 3: ALS Functional Rating Scale - Revised 
(ALSFRS-R) 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, 
which are protected by third party copyright laws and therefore have been excluded. 

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11.4. 
Appendix 4: Country Specific Requirements 
No country-specific requirements exist. 

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11.5. 
Appendix 5: Protocol Changes 
Amendment #1 09-APR-2015 
 
This amendment applies to all sites in this study. 
 
Summary and Rationale of Amendment Changes 
 
This amendment is being made to: 1) clarify bullet #5 in Exclusion Criterion #3; 2) 
collect medications and non-drug therapies used to treat AEs\SAEs considered to be 
related to study procedures and/or devices in the eCRF; 3) include hyperreflexia on the 
full and brief neurological examinations; and to provide 4) further clarification or 
correction to other wording in the protocol. 
 
List of Specific Changes 
 
New text is identified by bolded wording and replaced/removed text is identified by 
strikethrough text. 
 
Section 5.2, Exclusion Criterion #3 
 
Exclusion criterion #3 was revised to remove an extraneous “or” in the fifth bullet: 
Revised text: 
3. Regionally restricted forms of ALS, or other atypical variants: 
 
• 
Isolated corticobulbar pattern of ALS with normal ambulation 
• 
Flail arm syndrome 
• 
Primary lateral sclerosis 
• 
Signs and chronic partial denervation restricted to a single limb 
• 
ALS or parkinsonism dementia complex 
Section 5.7.1, Permitted Medications and Non-Drug Therapies 
 
The wording has been revised to collect information on medications and non-drug 
therapies used to treat AEs and SAEs related to study procedures or devices in the eCRF. 
The wording has also been revised to reflect the medication data being collected in the 
eCRF (i.e., dose, unit, frequency, and route added). 
 
Revised text: 
 
Medications and non-drug therapies that are prescribed as part of the subject’s ALS 
standard of care or for a concomitant medical condition are permitted and should be 
documented in the source documents. Any medication and non-drug therapy taken by the 
subject during the study from time of enrolment until their last visit in the study which, in 
the opinion of the investigator, might positively or negatively impact the 
movement/physical activity, heart rate or quantitative speech measurements, will be 

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recorded in the eCRF. In addition, any medication or non-drug therapy taken by the 
subject to treat AEs and SAEs which, in the opinion of the investigator, are related 
to a protocol-mandated procedure or one of the devices used in the study will be 
recorded in the eCRF. Medication name, dose, unit, frequency, route, indication, and 
dates of administration will be recorded in the eCRF. 
 
Addition of hyperreflexia to the neurological and brief neurological examinations 
 
The ALS symptom of hyperreflexia has been added to the neurological and brief 
neurological examinations, and wording has been added to differentiate between the 
neurological examination performed at the Core Screen/Baseline visit, and the brief 
neurological examination performed at the Pilot Screening visit and during the Core 
Phase of the study. 
 
Section 6.1: Screening and Critical Baseline Assessments, fifth bullet, clarifications 
to the first and second sentences, and a fourth sentence added 
 
Revised text: 
 
• A brief neurological examination will be performed according to local site protocol 
by medically qualified personnel. Functional regions involved (bulbar, cervical, 
thoracic, lumbosacral) limb symptoms (weakness, atrophy, spasticity, hyperreflexia, 
and fasciculations); and presence or absence of bulbar and pseudobulbar symptoms 
will be recorded. These data are important for understanding the neurological 
phenotype of the ALS subjects being enrolled into the study. A brief neurological 
examination (presence or absence of weakness, hyperreflexia, and spasticity in 
each arm and leg, and presence or absence of bulbar and pseudobulbar 
symptoms) will be performed at the Pilot Screening Visit. 
 
Section 6.2.1:  Reference Tasks, fourth paragraph, second sentence 
Revised text: 
The data generated from the reference tasks will be utilized by MAT to confirm the 
performance of the algorithm and will not be transmitted to GSK for analysis. The 
following supportive data (brief neurological exam) will be captured in the eCRF: 
presence or absence of weakness, hyperreflexia, and spasticity in each arm and leg, 
whether the reference task was attempted, whether the reference task was completed 
according to the prescribed protocol, and use of walking aids. 
 
Study Clarifications/Corrections 
 
These changes are being made to clarify the intent of existing text and/or correct 
erroneous text. 

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Section 6.2.4 Quantitative Measure of Speech, sixth sentence 
 
Revised wording to reflect the actual components more accurately, and to add the 
collection of the serial number for the converter case: 
 
Revised text: 
 
Quantitative speech testing will be performed in the Core Study Phase as described in the 
Time and Events Table, Section 6.5, Table 2. Subjects will follow simple prompts on a 
computer screen instructing them to say a series of vowels, words, and paragraphs which 
will be recorded using a high definition digital microphone and stored securely on a 
laptop.  The speech waveform data will be sent via secure method to MAT for 
processing.  At present, the algorithms are exploratory.  The processed data will be sent 
to GSK for final statistical analysis.  The following supportive data will be recorded in 
the eCRF: serial number of the microphone and, converter, and converter case, presence 
or absence of bulbar and pseudobulbar symptoms, smoking history and current smoking 
status, age, gender and ethnicity. 
 
Section 6.5, Time and Events, Table 1 and Table 2 
 
Renamed “ALS symptom assessment” to “Brief neurological exam” in both Time and 
Event tables. 
 
Original text: 
 
ALS symptom assessment 
New text: 
Brief neurological exam 
 
Section 7, Data management, third bullet 
 
Removed the requirement to code the medical history data, as it was determined that an 
exemption to code the medical history information for this small, twenty-five subject 
study was not necessary, and that the listing of medical history terms would be sufficient 
for review and reporting. 
 
Revised text: 
 
Adverse events, medical history and concomitant medications terms will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA) and an internal validated 
medication dictionary, GSKDrug. 
 
Protocol title 
Remove the RAD prefix from the protocol title as the title should only include the 
numeric component. 

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Original text: 
 
Study RAD201283: An Exploratory Study to Investigate the Use of Biotelemetry to 
Identify Markers of Disease Progression in Subjects with Amyotrophic Lateral Sclerosis 
 
Revised text: 
 
An Exploratory Study to Investigate the Use of Biotelemetry to Identify Markers of 
Disease Progression in Subjects with Amyotrophic Lateral Sclerosis 

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Amendment #2 21-SEP-2015 
 
This amendment applies to all sites in this study. 
 
Summary and Rationale of Amendment Changes 
 
This amendment is being made to: 1) modify the age requirement from 50 to 75 years to 
18 to 80 years (Inclusion Criterion #1); 2) modify the time frame in Inclusion Criterion 
#3 from 12 months to 18 months between symptom onset and ALS diagnosis (and amend 
the description of the population accordingly); 3) clarify bullet 4 in Exclusion Criterion 
#3, 4) clarify that muscle atrophy is one of the limb symptoms to be included as part of 
the neurological examination, 5) to make other minor clarifications to the text. 
 
List of Specific Changes 
 
New text is identified by bolded wording and replaced/removed text is identified by 
strikethrough text. 
 
Modification of the age requirement to 18 to 80 years (Inclusion Criterion #1) 
 
The age range for entry into the study specified in Inclusion Criterion #1 was increased 
from 50 to 75 years to 18 to 80 years. This change, in conjunction with the other 
eligibility criteria of the protocol will ensure that the study population is representative of 
a broader ALS patient population without being restrictive, but at the same time is 
appropriate for the study objectives. . 
 
Section 5.1, Inclusion Criterion #1 
 
Revised text: 
 
1. Between 50 18 and 75 80 years of age, inclusive, at the time of signing the informed 
consent. 
 
Synopsis, Type and Number of Subjects 
 
Revised text: 
 
Male and female subjects 50 18 to 75 80 years of age with ALS will be enrolled into the 
study. Treatment of enrolled subjects will be consistent with local standard of clinical 
care for ALS patients. A maximum of 25 subjects will be enrolled such that 
approximately 20 subjects complete the study with 48 weeks of data. 
 
Section 4.2, Type and Number of Subjects 
 
Revised text: 
 
Male and female subjects 50 18 to 75 80 years of age with ALS will be enrolled into the 
study. Treatment of enrolled subjects will be consistent with local standard of clinical 
care for ALS patients. A maximum of 25 subjects will be enrolled such that 
approximately 20 subjects complete the study with 48 weeks of data 

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Modification of the time frame in Inclusion Criterion #3 to 18 months between symptom 
onset and ALS diagnosis. The time frame between onset of symptoms and diagnosis of 
ALS was increased from 12 months to 18 months. The original timeframe was 
preventing subjects from entering the study who were part of the intended study 
population. 
 
Section 5.1, Inclusion Criterion #3 
 
Revised text: 
 
3. Diagnosed with ALS within 12 18 months of symptom onset. 
 
Section 4.3.2, Population 
 
Revised text: 
 
The chosen population for study is a subset of the overall ALS population and consists of 
ALS subjects that have mild to moderate disease, are early in the disease, and have a 
relatively high level of clinical functioning at baseline. The selected population is 
expected to experience a functional decline during the 48 week study period of 
approximately 1 ALSFRS-R point /month (See Section 8.2.1). This level of decline 
represents typical natural history of the disease and is thought to be sufficient to start 
to understand the relationship between gold standard measures of clinical function and 
the novel measures of movement/physical activity, speech and HRV. 
 
 
Section 5.2, Exclusion Criterion #3 
 
Exclusion criterion #3 was revised to amend the word “and” to “of” in the fourth bullet to 
clarify the text. 
 
Revised text: 
 
3. Regionally restricted forms of ALS, or other atypical variants: 
 
• 
Isolated corticobulbar pattern of ALS with normal ambulation 
• 
Flail arm syndrome 
• 
Primary lateral sclerosis 
• 
Signs and of chronic partial denervation restricted to a single limb 
• 
ALS parkinsonism dementia complex 
 
 
Section 6.1, Screening and Critical Baseline Assessments, fifth bullet 
 
This change is being made to clarify that muscle atrophy is one of the limb symptoms to 
be included as part of the neurological examination. 

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• A neurological examination will be performed according to local site protocol by 
medically qualified personnel.  Functional regions involved (bulbar, cervical, 
thoracic, lumbosacral) limb symptoms (weakness, muscle atrophy, spasticity, 
hyperreflexia, and fasciculations); and presence or absence of bulbar and 
pseudobulbar symptoms will be recorded. These data are important for understanding 
the neurological phenotype of the ALS subjects being enrolled into the study. A brief 
neurological examination (presence or absence of weakness, hyperreflexia, and 
spasticity in each arm and leg, and presence or absence of bulbar and pseudobulbar 
symptoms) will be performed at the Pilot Screening Visit. 
 
 
Study Clarifications 
 
These changes are being made to clarify the existing text. 
 
11.5.2.1 
Heart Rate Variability (HRV) 
 
Autonomic function is known to be impaired in ALS [Pavlovic, 2010; Mega Electronics 
Ltd, 2014; Merico, 2011; Pinto, 2012]. 
 
Section 4.3.3.3, Speech 
 
Revised text: 
 
Speech is produced as a result of muscle and respiratory function [Green, 2013], which 
are both affected in ALS. ALS results in progressive bulbar motor deterioration leading 
to impaired speech and swallowing and complications from these bulbar symptoms can 
significantly impact survival [Green, 2013]. Pseudobulbar manifestations may also 
contribute to speech impairment. Speech measurement is part of the assessment of bulbar 
function in ALS; however, many of the available tests do not provide meaningful 
information on disease progression [Green, 2013]; therefore, an easy to use, quantitative 
measure of speech might be a meaningful endpoint for monitoring ASL disease 
progression. 
 
Section 4.3.3.4, ALSFRS-R and FVC 
 
Revised text: 
 
ALSFRS-R is a gold standard measure of functional decline in ALS and is routinely used 
to monitor disease progression and evaluate treatment effects in clinical trials and in 
clinical practice [Brinkmann, 1997; Cudkowicz, 2004; Cedarbaum, 1999]. In order for 
any new outcome measure to be clinically meaningful and relevant to physicians and 
regulators, it will need to correlate to the ALSFRS-R.