Electronic-health Application To Measure Outcomes REmotely Clinical Trial
Phase: NA
Conditions: Neurodegenerative Disease, Weight Loss, Amyotrophic Lateral Sclerosis, Parkinson's Disease, Huntington's Disease, Cachexia
Sponsor: Massachusetts General Hospital

Protocol: Electronic-health Application To Measure Outcomes REmotely (EAT MORE) Clinical Trial 
Version Date: 03.10.2016 
Clinical Study Protocol Version 3.0 
 
CONFIDENTIAL INFORMATION 
1
Electronic-health Application To Measure Outcomes REmotely (EAT MORE) Clinical Trial 
 
Principal Investigator: 
Anne-Marie A. Wills, MD MPH 
 
 
 
 
Assistant Professor in Neurology 
 
 
 
 
Massachusetts General Hospital 
 
 
 
 
Harvard Medical School 
 
Co-Investigator: 
 
Jane Hubbard, RD 
 
 
 
 
Bionutrition Department 
 
 
 
 
Clinical Research Center 
Massachusetts General Hospital 
 
 
 
 
 
Biostatistician: 
 
Eric Macklin, PhD 
 
 
 
 
Department of Biostatistics 
 
 
 
 
Massachusetts General Hospital 
 
 
 
 
Harvard Medical School 
 
 
 
 
Supported By: 
 
ALS Association 
 
IND Number: 
 
Not Applicable 
 
Protocol Date: 
            March 10, 2016 
 
Protocol Version: 
 
Version 3.0 
 
The information contained herein is confidential and proprietary in nature, and will not be 
disclosed to any third party without written approval of ALSA or its authorized designee.  This 
document may be disclosed to the appropriate institutional review boards or to duly authorized 
representatives of the US Food and Drug Administration or a national regulatory authority under 
the condition that they maintain confidentiality. 

Protocol: Electronic-health Application To Measure Outcomes REmotely (EAT MORE) Clinical Trial 
Version Date: 03.10.2016 
Clinical Study Protocol Version 3.0 
 
CONFIDENTIAL INFORMATION 
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TABLE OF CONTENTS 
INVESTIGATOR’S AGREEMENT 
...………………………………………..………….5 
PRÉCIS ……………………………………...………………………………………………..….6 
LIST OF ABBREVIATIONS……..………...…………………………………………………..9 
SCHEDULE OF ACTIVITIES ……………...……………………………………….……… 10 
1. 
STUDY OBJECTIVES …………………………………………………..………….11 
1.1 
Specific Aims …………………………………………………………………....11 
2. 
BACKGROUND AND SIGNIFICANCE…………………………………………..12 
2.1 
Background and Rationale………………………………………………….12 
2.1.1  Weight loss in Neurodegenerative disease... …….……………………12 
2.1.2 Weight loss in PD.....................…………………………………………12 
2.1.3 Weight loss in HD....................…………………………………………12 
2.1.4 Weight loss in ALS..................…………………………………………12 
2.1.5 Hypercaloric Diets as a Potential ALS therapy………....…...…….…13 
2.1.6     Preclinical Supporting Data ……....…………………………….…….13 
2.1.7 Human Supporting Data …………....…………………………………14 
2.1.8  Significance………..…………………....……………………………….16 
2.2 
Risks and Benefits of the Current Study ………………………………….17 
2.2.2 Risks of Medical Nutrition Therapy..………………………………….17 
2.2.3 Risks of Dual-energy Xray Absorptiometry (DXA) ………………….17 
2.2.4 Potential Benefits …………………………………..…………..……….17 
3. 
STUDY DESIGN ………………………………………..………………………….18 
3.1 
Study Design Overview …………..…………………..……………………18 
3.2 
Setting ……………………………..………..………………………………18 
4. 
Study Population Selection ……………………………..………………………….18 
4.1  
Study Population ………………………………..………………………….18 
4.2 
Subject Inclusion Criteria ..………...…………..………………………….18 
4.3 
Exclusion Criteria …………………..…………..………………………….18 
4.4 
Enrollment Procedures ………..………………..………………………….19 
4.4.1 Informed Consent …………………………...………………………….19 
4.4.2 Randomization Process ..…………………....………………………….19 
5. 
STUDY INTERVENTIONS..…………………………..………………………….19 
5.1.1 In-Person Nutritional Counseling …………………………………….19 
5.1.2 E-Health Nutritional Counseling ….………………………………….20 
5.1.3 Standard Care...............................….………………………………….20 
              5.2 
Compliance with Dietary Recommendations………............……………20 

Protocol: Electronic-health Application To Measure Outcomes REmotely (EAT MORE) Clinical Trial 
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              5.3 
Monitoring of Weight..........................................…………………………21 
5.4 
Concomitant Medications…………...………..………………………….21 
5.4.1 Exclusionary Medications…………………..………………………….21 
6.  
STUDY ACTIVITIES....…………………..……………………………….……22 
6.1 
Study Visits……………….………………………………………………...22 
6.1.1 Screening/Baseline Visit and Informed Consent……….……………..22 
6.1.2 Telephone Visits ……….………………..……….……….……………..22 
6.1.3  Clinic Visits ………………………..……………..……….….…………23 
6.1.4 Treatment Withdrawals and Loss to Follow-up ..…………………….23 
6.1.5 Final Evaluations and Post Intervention Phone Call.…...……………24 
6.1.6 End of Study Phone Call………………..……………....………………24 
6.2   
Definitions of Evaluations and Outcome Measures ....…………………24 
6.2.1 Primary Outcome Measures...................................................................24 
6.2.1.1 Safety and Tolerability........................................................................24 
6.2.1.2 Weight..................................................................................................24 
6.2.2  Secondary Outcome Measures……………………………….......……25 
6.2.3  Tertiary and Exploratory Outcome Measures……………………….25 
6.2.3.1 Survival...............................................................................................25 
6.2.3.2 Time to Percutaneous Endoscopic Gastrostomy.............................25 
6.2.3.3 Exploratory Outcome Measures.......................................................25 
7. 
Adverse Experiences Related to Medical Nutrition Therapy.………....………26 
7.1 
Management of Adverse Experiences……………………………………26 
 
   8.  
Intervention Suspension Related to Nutritional Counseling ..........................28 
9. 
STATISTICAL CONSIDERATIONS..................................................................28 
9.1 
Safety and Tolerability...........................................................................28 
9.2 
Weight and Caloric Intake.....................................................................28 
9.3 
Sample Size Calculation.........................................................................29 
9.4 
Tertiary and Exploratory Outcomes.....................................................29 
9.5 
 Stopping for Safety ................................................................................30 
10. 
Data Collection and Adverse Event Monitoring ................................................31 
10.1 
Records to be Kept and Project Organization 
......................................31 
10.2  Purpose of NeuroBANK™ ..........................................................................31 
10.3 Role of Data Management .................................................................................31 
10.3.1 Data Entry and Checks............................................................................31 
10.3.2 Data Lock Process 
...............................................................................32 
10.3.3 Data Handling and Record Keeping......................................................32 

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10.3.4 Database Security.....................................................................................32 
10.4 
Confidentiality 
.......................................................................................33 
10.4.1  Global Unique Identifier (GUID)...........................................................33 
 
10.4.4 Quality Assurance.....................................................................................33 
10.5 E-Health App Privacy and Security...................................................................33 
10.6 Adverse Experiences Monitoring and Reporting.............................................33 
10.6.1 Evaluating and Recording of Adverse Events...........................................35 
11. 
HUMAN SUBJECTS..............................................................................................37 
11.1 
Institutional Review Board (IRB) Review and Informed Consent..............37 
11.2 
Subject Confidentiality.....................................................................................37 
11.3  Inclusion of Women ........................................................................................37  
11.4 
Inclusion of Minorities......................................................................................37 
11.5 
Study Modification/Discontinuation................................................................38 
12.    PUBLICATION OF RESEARCH FINDINGS..........................................................38 
13.    REFERENCES ..............................................................................................................39 
14.    APPENDICES 
Appendix 1: Nutrition Resource Book 
Appendix 2: Self Weighing Log  
Appendix 3: Informed Consent Form  
Appendix 4: E-Health App Specifications 
Appendix 5: PROMIS SF v1.1 scale 
Appendix 5: ALSFRS-R scale 
Appendix 6: UDysRS 
Appendix 7: UHDRS 
Appendix 8: CNAQ  
Appendix 9: Self-reported screening questionnaire for Neurogenic dysphagia 

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INVESTIGATOR’S AGREEMENT  
 
I have read the attached protocol entitled, “Electronic-health Application To Measure Outcomes 
REmotely (EAT MORE) Clinical Trial,” dated 3/14/2015 version 1.0 and agree to abide by all 
described protocol procedures. 4.  I agree not to make any clinical practice changes that would 
conflict with the goals and implementation of the trial.  I agree to comply with the World 
Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving 
Human Subjects, the International Conference on Harmonisation Tripartite Guidelines on Good 
Clinical Practice, applicable U.S. Food and Drug Administration (FDA) regulations and 
guidelines identified in 21 CFR Parts 11, 50, 56, and 312.7, the applicable provisions of sections 
402(i) and 402(j) of the U.S. Public Health Service Acts (PHS Act) [42 U.S.C. §§ 282 (i) and 
(j)], amended by Title VII of the FDA Amendments Act of 2007 (Public Law No. 110-85, 121 
Stat.904), local Institutional Review Board (IRB) guidelines and policies, and the U.S. Health 
Insurance Portability and Accountability Act (HIPAA). 
 
 
 
 
 
 
 
Principal Investigator Signature:   ____________________________ Date: ______________ 
 
Print Principal Investigator Name: Anne-Marie Wills MD MPH 
 
 
 
 
 
 
 

Protocol: Electronic-health Application To Measure Outcomes REmotely (EAT MORE) Clinical Trial 
Version Date: 03.10.2016 
Clinical Study Protocol Version 3.0 
 
CONFIDENTIAL INFORMATION 
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 PRÉCIS 
 
Title: Electronic-health Application To Measure Outcomes REmotely (EAT MORE) Clinical 
Trial 
 
Study Objectives and Clinical Phase:  
 
This is a phase II feasibility, safety, tolerability and preliminary efficacy study of an e-Health 
application and in-person nutritional counseling to maintain or increase weight in patients with 
ALS and other neurodegenerative diseases.  
 
Objectives and Endpoints 
 
Primary Objectives 
To study the feasibility, safety, tolerability and efficacy to maintain or increase body weight of 
an e-Health application and in-person nutritional counseling compared to standard of care and to 
each other.  
 
Secondary Objectives 
To measure the number of calories required to maintain or increase body weight in patients with 
neurodegenerative diseases. 
 
Tertiary Objectives: To test the effects of an e-Health application compared to in-person 
nutritional counseling on survival, disease progression using the ALSFRS-R, UDysRS, or 
UHDRS, and on quality of life using the PROMIS SF v1.1 scale. 
 
Background and Rationale 
 
 
Progressive weight loss is a common symptom of ALS and other neurodegenerative diseases 
including Huntington’s disease (HD) and Parkinson’s disease (PD) and correlates with disease 
progression and time to death [1-3] [4, 5].  While nutritional interventions have been found to be 
effective in other chronic diseases including cystic fibrosis (reviewed in [6]) and COPD 
(reviewed in [7]), nutritional interventions have not been tested in a systematic way in 
neurodegenerative diseases. 
 
Unintentional weight loss is common in ALS and is believed to be due to a combination of 
reduced caloric intake from dysphagia, anorexia, dependence on caregivers, and increased 
caloric needs due to increased energy expenditure [8, 9].  Kasarskis et al. first recommended 
increasing calorie intake in patients with ALS based on a retrospective review of ALS subjects 
close to the time of death, showing that these subjects consumed only 84% of the recommended 
daily allowance of calories [2, 10].  However the type of caloric intake and exact amount has not 
been adequately studied (reviewed in [11]). In our recently completed study, the Trial of High 
Fat/High Calorie Diet vs. Optimal Nutrition in ALS, funded by the Muscular Dystrophy 
Association[12], we found that participants randomized to excess calories and weight gain using 
a calorie-dense enteral formula had a reduced risk of dying during the study than patients 
randomized to calorie replacement.  Given these promising results, we now wish to test whether 
an e-Health application designed specifically to promote hypernutrition will lead to weight gain, 
prevent weight loss and muscle loss, and improve survival and quality of life.   

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Study Design:  
 
This is a phase II feasibility, safety, tolerability and efficacy study of an e-Health application 
compared to in-person nutritional counseling and standard care. Approximately 150 ALS 
participants and approximately 75-150 PD and HD patients at MGH will be randomized 1:1:1 to 
one of three interventions: medical nutrition therapy using in-person counseling vs. the e-Health 
Application vs. standard care.   
 
Interventions and Duration 
 
Administration of Intervention 
The goal of the two intervention arms (medial nutrition therapy using in-person counseling or 
using the e-Health Application) will be modest weight gain of 0.5-1 kg/month.  Participants in 
the in-person nutritional counseling arm will receive an initial face-to-face nutrition counseling 
session according to a resource book outlining the general nutritional recommendations (see 
Appendix 1), as well as a personalized nutrition plan with daily caloric goals.  They will then 
receive telephone monitoring of weight with additional telephone counseling as needed between 
return clinic visits. Home self-reported weights in both intervention arms will be verified at 
routine clinic visits.  Patients in the in-person counseling arm will also receive in-person 
nutritional counseling at every clinic visit.  
 
Participants in the e-Health arm will receive dietary guidance from the treating RD at the 
baseline visit including instruction in the completion of food records and weight monitoring 
using the e-Health App.  They will be asked to enter their dietary intake and home weights every 
2 weeks. The treating RD will also have access to the e-Health App data and will be able to 
modify the dietary recommendations of the application according to the recorded weights. 
 
The standard care group will receive routine nutritional counseling by a treating physician or 
nurse about the importance of avoiding weight loss at regular clinic visits, as is the standard of 
care in our Neurology clinics.   
 
A research coordinator will collect data on adverse events, disease progression, appetite and 
quality of life measures in all participants, including standard care participants at month 1 by 
telephone and at every clinic visit, approximately every 3 months.  If participants are unable to 
make it to the clinic, the above measures will be collected by telephone interview.  The total 
duration of the interventions will be 6 months. 
 
Recruitment and Randomization 
 
Adult with ALS, PD or HD who come to the MGH Neurology clinics will be asked if they wish 
to participate in the study. Those who agree to participate will be randomized 1:1:1 to each of the 
three treatment arms using a computer generated randomization list generated by the MGH 
Biostatistics Center.   
 
Statistical Methods 
 

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Statistical analyses will be performed by the MGH Biostatistics Center. The primary and 
secondary efficacy outcomes of change in weight and caloric intake will be compared between 
the treatment groups using a shared-baseline linear mixed model for correlated, longitudinal 
assessments of weight with fixed effects of time and the treatment x time interaction and age, 
gender, and baseline dysphagia and their interactions with time included as covariates and 
random participant specific intercepts and slopes. 
 
Safety data will be summarized by treatment group and reported to an independent Medical 
Monitor every 3 months during the study. Total numbers of adverse events will be compared 
between groups using negative binomial regression and the proportion of participants 
experiencing each type of event by Fisher's exact test.  
 
In the tolerability analyses, a subject will be regarded as a treatment success if he/she complies 
with at least 80% of the nutritional counseling sessions, or enters at least 80% of the required 
electronic data.  
 
Sample size calculation: Using the component estimates from weight data collected in the 
clinical trial of Ceftriaxone in ALS [13] the effective standard deviation for rate of change in 
weight assuming weight assessments every 2 weeks, an annual 23% mortality rate, and 20% loss 
to follow-up is 0.98 kg/month. Given a sample size of 150 ALS participants randomized 1:1:1 to 
the two interventions and standard care will provide at least 80% power to detect a true 0.75-
kg/month difference between each intervention arm and the control arm over 24 wks at a two-
tailed p < 0.027 using Dunnett’s method (testing superiority of each intervention over standard 
care). Based on a non-inferiority bound of 0.5 kg/month, the study will have at least 80% power 
to declare the e-Health intervention non-inferior to in-person consultation with an RD based on a 
one-tailed test at p < 0.05 and assuming that the two interventions are in fact equivalent.   

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LIST OF ABBREVIATIONS 
AAN  
 
American Academy of Neurology 
AE 
 
 
Adverse Event/Experience 
ALS 
 
 
Amyotrophic Lateral Sclerosis 
ALSA  
 
ALS Association 
ALSFRS-R 
 
Amyotrophic Lateral Sclerosis Functional Rating Scores – revised 
BMI 
Body Mass Index 
CNAQ 
Council on Nutrition Appetite Questionnaire 
CRF 
 
 
Case report form 
CFR 
 
 
Code of Federal Regulations 
CNS  
 
Central nervous system 
CRC  
 
Clinical Research Center 
DM 
 
 
Data Management 
eCRF  
 
Electronic Case Report Form 
EDC  
 
Electronic data capture 
FDA     
 
Food and Drug Administration 
GCP  
 
Good Clinical Practice 
HD 
Huntington’s Disease 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IRB 
 
 
Institutional Review Board 
MDA  
 
Muscular Dystrophy Association 
MedDRA 
 
Medical Dictionary for Regulatory Activities  
MGH  
 
Massachusetts General Hospital 
MGH-SST 
 
MGH Swallow Screening Tool 
MM 
 
 
Medical Monitor 
MND  
 
Motor neuron disease 
MRC  
 
Medical Research Council 
NCRI  
 
Neurology Clinical Research Institute 
NIH 
 
 
National Institutes of Health 
NINDS 
 
National Institute of Neurological Disorders and Stroke 
NP 
 
 
Nurse Practitioner 
ODBC  
 
Open Database Connectivity  
OHRP  
 
Office for Human Research Protections 
PAV  
 
Permanent assisted ventilation 
PD 
 
 
Parkinson’s Disease 
PDF 
 
 
Portable Document Format 
PI 
 
 
Principal Investigator 
PROMIS SF v1.1 
Patient Reported Outcome Measurement Information System Short Form 
RD 
 
 
Registered Dietitian 
SAE 
 
 
Serious adverse event 
SDF 
 
 
Source Document Form 
SLP 
 
 
Speech Language Pathologist 
UDysRS 
Unified Dyskinesia Rating Scale 
UHDRS 
Unified Huntington’s Disease Rating Scale 
VC 
 
 
Vital capacity 
WHO  
 
World Health Organization 

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Table 1. Schedule of Activities 
Schedule of Activities 
Screening/ 
Baseline 
2 week 
Automatic 
Alerts 
Telephone 
Visits (every 
2-4 weeks) 
In-Person Visits 
(3 and 6 months 
+/- 1 month) 
All Participant Groups including 
Standard Care 
 
 
 
 
Written Informed Consent 
X 
 
 
 
Abbreviated History/Weight history 
X 
 
 
 
MGH Swallow Screening Tool 
X 
 
 
X 
Inclusion/Exclusion review 
X 
 
 
 
Adverse Events  
 
 
X1 
X* 
Vital Signs including Height, 
Weight 
X 
 
 
X 
Clinical Laboratory Assessments 
X2,4 
 
 
X3,4 
Disease-specific rating scales 
(ALSFRS-R, UDysRS, UHDRS) 
X* 
 
 
X* 
PROMIS SF v1.1  
X* 
 
 
X* 
CNAQ 
X* 
 
 
X* 
Dietary Intake using 24 hour recall 
X 
 
 
 
Dietary Intake using 4 day food 
records 
X 
 
 
X 
DXA Scan (optional) 
X 
 
 
X (month 6 only) 
In-Person Nutritional Counseling 
 
 
 
 
Nutritional Counseling per Protocol 
X 
 
X 
X* 
Dietary Intake using 4 day food 
records 
 
 
X (by fax) 
 
Weight 
X 
 
X† 
X 
e-Health Application Arm 
 
 
 
 
4 days of Dietary Intake using the 
e-Health App 
X 
X 
 
 
Weight (2 days)  
X 
X† 
 
X 
1 Adverse events and changes in concomitant medications will be obtained by the research coordinator 
telephone interview in all participants 1 month after the start of the study, including the Standard Care 
arm. Adverse events will also be captured at every telephone contact by the Registered Dietitian in the In-
Person Nutritional Counseling arm.  
2 Screening labs to include basic chemistry, liver function tests,  lipid panel, thyroid stimulating hormone 
(TSH), uric acid, albumin, and exploratory labs including leptin, PYY and ghrelin.  
3 Routine Safety labs to include basic chemistry, liver function tests, lipid panel, albumin and hemoglobin 
A1c. Six month labs will also include exploratory labs (leptin, PYY and ghrelin).  
4 Labs drawn within 4 weeks of visit for clinical or research purposes may be used for the study 
* May be administered or obtained by telephone within 1 week of the scheduled in-person visit if 
participants are unable to come to the clinic or too fatigued to complete during their clinic visit.  If 
participants are unable to come to clinic, a self-reported home weight will be obtained and marked as self-
reported.  
† Participants will weigh themselves at home following specific instructions. 
Abbreviations: ALSFRS-R= Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised; UDysRS= 
Unified Dyskinesia Rating Scale; UHDRS= Unified Huntington’s Disease Rating Scale; PROMIS SF 
v1.1= Patient Reported Outcome Measurement Information System Short Form; CNAQ= Council on 
Nutrition Appetite Questionnaire; 

Protocol: Electronic-health Application To Measure Outcomes REmotely (EAT MORE) Clinical Trial 
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1. STUDY OBJECTIVES 
 
1.1 
Specific Aims 
The overall goal of this study is to discover a simple, effective clinical intervention to increase 
caloric intake in patients with ALS and other neurodegenerative diseases. Our research is based 
upon a convergence of preclinical, epidemiological and clinical data which suggest that 
hypernutrition may lead to greater survival and improved outcomes in ALS. In the High 
Fat/High Calorie versus Optimal Nutrition in ALS clinical trial (funded by the Muscular 
Dystrophy Association), we hypothesized that a dietary intervention to prevent weight loss and 
increase body weight could have a beneficial effect on ALS survival [12]. The results of this 
study showed that participants who were randomized to the high calorie/weight gain arm had a 
reduced risk of serious adverse events and death, as well as a trend towards slower disease 
progression during the study. The generalizability of this study, however, was limited by its 
small sample size and the fact that all participants were receiving enteral nutrition. 
 
Our long term goal is to follow up our clinical trial results with a large efficacy study to test 
whether increasing caloric intake will slow disease progression and lead to greater disease 
survival. Improving nutritional status has been shown to improve outcomes in other chronic 
diseases including cystic fibrosis (reviewed in [6]) and COPD (reviewed in [7]). However the 
efficacy of nutritional counseling has not been tested in ALS patients (reviewed in [14]) or in 
other neurodegenerative diseases. We now intend to test whether an electronic health application 
is effective as in-person nutritional counseling for patients with neurodegenerative diseases. Our 
study will test whether a specially modified electronic-Health (e-Health) application can provide 
effective nutritional counseling, monitor weights and measure key outcomes remotely.  
 
Primary Aims: To study the feasibility, safety, tolerability and efficacy to maintain or increase 
body weight of an e-Health application and in-person nutritional counseling compared to 
standard of care and to each other. 
 
Secondary Aims: To measure the number of calories required to maintain or increase body 
weight in patients with ALS and other neurodegenerative diseases at all stages of each disease. 
 
Tertiary Aims: To test the effects of an e-Health application and in-person nutritional 
counseling compared to standard of care and to each other on survival, disease progression using 
the ALSFRS-R, UDysRS, or UHDRS, and quality of life using the PROMIS SF v1.1 scale. 
 

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2 BACKGROUND AND SIGNIFICANCE 
 
2.1        Background and Rationale 
 
2.1.1 
Weight loss in Neurodegenerative disease 
 
Body mass index (BMI) has been found to be associated with survival in several 
neurodegenerative diseases including ALS[1-3] Huntington’s[4] and Alzheimer’s disease[15] 
suggesting that nutrition may play a role in these diseases.  Loss of body weight and BMI is a 
common symptom of Parkinson’s disease[16-18] and we have recently found that BMI also 
determines survival in PD [5]. While nutritional interventions have been found to be effective in 
other chronic diseases including cystic fibrosis (reviewed in [6]) and COPD (reviewed in [7]), 
nutritional interventions have not been tested in a systematic way in neurodegenerative diseases.  
 
2.1.2 
Weight loss in PD 
 
Weight loss is common in Parkinson’s disease (PD) and is hypothesized to be due to a 
combination of several factors including hyposmia, difficulty self-feeding, dysphagia, intestinal 
hypomotility, depression, anorexia, nausea, and increased energy requirements due to muscular 
rigidity and increased involuntary movements such as dyskinesia and tremors (reviewed in[19]).  
Weight loss may also be related to direct effects of dopaminergic medication on appetite[20].  
While the nutritional requirements for Parkinson’s disease have not been defined, there is one 
case report commenting on the use high-carbohydrate low-protein oral supplements to stabilize 
weight loss in a patient with Parkinson’s disease dyskinesia[21].   
 
2.1.3 
Weight loss in HD 
 
Rapid weight loss is seen in all stages of HD, even before the onset of chorea, and correlates with 
CAG repeat length [22]. In addition to the hyperkinetic movements which lead to increased 
energy expenditure, there is some data to suggest that HD patients have hypothalamic 
dysfunction as well leading to reduced appetite and intake [23].  Baseline BMI is also predictive 
of disease progression in HD [4].  Nutritional counseling is recommended for patients who have 
lost 10% of their body weight in the prior 3-6 months, and for patients with a BMI <20 who have 
lost 5% of their body weight over the last 3-6 months [24].  However the effect of nutritional 
interventions on HD disease progression has not previously been studied.    
 
2.1.4 
Weight loss in ALS 
 
Rapid weight loss is a hallmark of ALS, due to a combination of inadequate caloric intake and a 
hypermetabolic state.  ALS patients have also reported reduced appetite [25].  Patients are often 
instructed to increase their calorie intake; however studies have shown that patients not using 
enteral nutrition consume on average only 84% of their recommended calorie needs.  Weight 
loss correlates with disease progression and time to death [2, 10].  Subjects with abnormally low 
BMI (i.e. malnourished patients) have shorter survival [2, 8-10] and we have published that there 
is a U-shaped survival curve in ALS with the maximum survival at BMI 30-35 (mild obesity by 
WHO standards)[1].  It has been hypothesized that the effect of malnourishment on survival is 

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confounded by disease progression, i.e. that reduced BMI is due to dysphagia, reduced calorie 
intake and loss of muscle mass as the disease progresses.  We have shown that this effect is 
independent of disease severity, as BMI was still a significant predictor of survival even after 
adjusting for ALSFRS-R, bulbar onset, FVC, and time since diagnosis [1].  Interestingly, two 
recent prospective studies have also found a reduction in amyotrophic lateral sclerosis risk in 
patients who are overweight and obese [26, 27].  
 
2.1.5 Hypercaloric Diets as a Potential ALS therapy 
 
Kasarskis et al. first recommended increasing calorie intake in patients with ALS based on a 
retrospective review of ALS subjects close to the time of death, showing that these subjects 
consumed only 84% of the recommended daily allowance of calories [2, 10].  However the type 
of caloric intake and exact amount has not been adequately studied (reviewed in [11]). Nau et al 
recommended that caloric intake should slightly exceed patients’ needs [28].  A recent study 
found that oral supplements containing a modest 35% calories from fat were slightly more 
effective at causing weight gain than supplements containing 0% calories from fat, however 
there was no placebo arm to test the effects of supplementation on survival or disease 
progression [29].  
 
2.1.6 Preclinical Supporting Data  
Hypercaloric diets using calorically-dense diets high in fat calories were shown to lead to 
increased weight and improved survival in the mutant SOD1 mouse model.  Specifically, a high 
fat diet consisting of 38% carbohydrates, 47% fats and 15% protein (by calorie content) 
increased the median survival time of G93A SOD1 mice from 140 to 270 days ([30], Figure 1).  
A high fat diet consisting of 21% butter fat and 0.15% cholesterol (by weight) increased the 
mean survival of G86R SOD1 mice by 20 days in a second study [31].  A ketogenic diet 
consisting of 60% fat, 20% carbohydrate and 20% protein did not result in a significant increase 
in lifespan, however this study only enrolled 11 mice total [32].  Conversely, calorie restriction 
in the mutant SOD1 mouse model significantly reduces survival [33, 34].     

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Based upon the preclinical mouse data and upon the epidemiologic data above, we recently 
completed a small phase II double-blind placebo-controlled clinical trial of a hypercaloric diets 
using enteral nutrition: The High Fat/High Calorie Diet versus Optimal Nutrition in ALS clinical 
trial, funded by the Muscular Dystrophy Association (NCT00983983)[12]. 
 
 2.1.7 Human Supporting Data 
 
 
In brief, in the High Fat/High Calorie Diet versus Optimal Nutrition in ALS clinical trial[12], 24 
ALS receiving percutaneous enteral nutrition were randomized 1:1:1 to 100% of caloric needs 
using Jevity 1.0 (control diet), approximately 125% of caloric needs using Jevity 1.5 (high 
carbohydrate/high calorie diet, HC/HC), or 125% of caloric needs using Oxepa which contains 
55% fat calories (high fat/high calorie diet, HF/HC) (all Abbott Laboratories, Abbott Park, IL) 
and followed for four months.  Total Daily Energy Expenditure was estimated based upon 
Measured Resting Energy Expenditure (MREE) multiplied by their physical activity level, or 
participants' pre-randomization nutrition requirements, whichever was greater.  Participants and 
evaluating investigators were blinded to treatment assignment.  Primary endpoints included 
adverse events (AE) and compliance rates. 
 
Seven participants were randomized to the control diet, 9 to the high carbohydrate/high calorie 
diet, and 8 to the high fat/high calorie arms, although four participants (1, 1, and 2, respectively) 
withdrew after randomization but before starting study diet.  There was no imbalance in 
treatment allocation accross sites, and baseline demographics were similar among the three study 
arms. Control participants were more likely to discontinue the study diet due to adverse events 

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(three Cntl vs. zero HC/HC vs. one HF/HC) and less likely to complete the study on the 
intervention diet (17% vs. 88%, vs. 83%; p=0.03 and 0.08 for the difference in tolerability 
between Cntls and the HC/HC and HF/HC groups, respectively). 
 
Participants on the HC/HC diet experienced fewer adverse events (AEs) and serious adverse 
events (SAEs) compared to control and HF/HC participants (24 AEs and 0 SAEs in HC/HC vs. 
42 AEs and 9 SAEs in controls, vs. 49 AEs and 3 SAEs in the HF/HC arm, Appendix 1). The 
most common AEs were gastrointestinal (50% of HC/HC vs. 100% of Cntl vs. 100% of HF/HC). 
None of the participants in the two hypercaloric arms experienced elevated serum bicarbonate 
(compared to three participants in the control arm), as we had postulated might occur due to 
respiratory weakness. In addition, there were no cardiovascular AEs or SAEs in the hypercaloric 
arms and the HF/HC diet was not associated with increased cholesterol or hs-CRP levels (Table 
3). Finally, there was no evidence that the hypercaloric diets led to diabetes based on fasting 
blood glucose levels and serum insulin levels (Table 3). 
 
Participants randomized to the control arm were essentially weight-stable gaining on average 
0.11 kg/month (95% CI -0.64, 0.86), although there was substantial variation in weight in the 
control arm (see Supplementary Figure 2A). On average, control participants consumed 
1.21±0.26 times their estimated energy requirements, including both prescribed enteral nutrition 
and oral intake. Participants in the HC/HC arm gained on average 0.39 kg/month (95% CI -0.16, 
0.95), consuming 1.54±0.33 times their estimated energy requirements. Participants in the 
HF/HC arm lost 0.46 kg/month (95% CI -1.11, 0.18) despite consuming on average 1.51±0.33 
times their estimated energy requirements.  Based on the eleven participants who underwent 
repeated DXA measurements after four months, participants who gained weight overall during 
the study gained primarily fat mass compared to LBM (2.23 ±2.25 kg vs. 0.17 ±1.29 kg) while 
those with net weight loss lost 1.61 ±0.99 kg LBM while still gaining a small amount of fat mass 
(0.39 ±0.35 kg).  
 
Survival is shown in Figure 2.  Overall, the high-carbohydrate hypercaloric arm experienced no 
deaths during the study while there were 3 deaths in the control arm (logrank p=0.03).  The 
difference between the high-fat/hypercaloric and control arm was not statistically significant.  In 
addition, the ALSFRS-R appeared to decline more slowly in the high calorie arm -1.06 (95% CI 
-1.71, -0.41) points/month vs. -2.17 (95% CI -3.25, -1.1) in the controls (p=0.07, see Table 1). 
There was no difference in the rate of decline in FVC.   

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Figure 2:  Kaplan-Meier curves for survival as defined by time to death or tracheotomy.  
The log-rank test for the difference in survival between the control and high calorie arms 
was significant (p=0.03).  
 
In summary, despite the small size of this study, we believe that these results are promising and 
are consistent with the preclinical and epidemiologic observational data suggesting that 
hypercaloric diets may improve ALS survival.  In addition to the survival data, the ALSFRS-R 
rate of decline, safety, and tolerability data all consistently favored the high calorie arm.  We 
therefore have designed the current study to test the effects of hypercaloric diets at earlier stages 
of ALS, and to explore the effects of hypernutrition in other neurodegenerative diseases with 
unintentional weight loss.   
 
2.1.8     Significance 
 
Unintentional weight loss is a common symptom of all neurodegenerative diseases, and our data 
in ALS suggests that modifying this clinical feature may modify the progression of the 
underlying disease.  Given that there are no effective treatments for ALS, we believe that this 
non-pharmacologic, supportive care intervention may offer a low-risk, cost effective approach to 
improving patient survival as well as quality of life.   
 
There are currently no clinical guidelines on the type and amount of nutritional support needed in 
neurodegenerative diseases such as ALS, PD and HD.  The observational data which we will 
obtain from measuring actual caloric intake and body weights during this study will allow us to 
estimate the nutritional requirements of participants with these diseases.  Finally, this study will 
create a database linking micro and macronutrient intake with disease survival, which may create 
new hypotheses for testing nutritional interventions in the future.   
 
 

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2.2  
Risks and Benefits of the Current Study 
 
2.2.2 Risks of Medical Nutrition Therapy 
 
Weight gain is an anticipated risk and would not be considered an adverse event during the trial.  
In the High Fat/High Calorie vs. Optimal Nutrition in ALS, we had postulated that excess calorie 
intake might result in increased carbon dioxide production and hypercarbia.  However, using 
serum bicarbonate levels as a measure of hypercarbia, 3 participants in the control arm 
experienced hypercarbia vs. 0 participants in the two hypercaloric arms.  We had also 
hypothesized that hypercaloric diets could lead to increased risk of vascular events (myocardial 
infarction, stroke or peripheral vascular disease).  However, in the High Fat/High Calorie study, 
only one participant experienced an elevated troponin level, and this occurred in the control arm 
(Table 3).  Diabetes was a theoretical risk from weight gain, however elevated blood glucose was 
not seen as an adverse event in routine safety labs.  In addition, there was no increase in 
circulating serum insulin levels in the two hypercaloric arms.  
 
2.2.3 Risks of Dual-energy Xray Absorptiometry (DXA) 
 
Radiation  
 
Those participants who consent to the optional DXA portion of the study be exposed to two 
DXA scans, one at the baseline and one at the final visit.  The radiation exposure associated with 
two whole body DXA scans is approximately 0.017 milliSieverts (mSv).  This amount of 
radiation is approximately equal to 2 day’ exposure from natural background sources of radiation 
(cosmic rays and naturally occurring radioactive materials from the earth and the sky) [35].    
This does not pose excessive risk to subjects.  Female participants of child-bearing age will be 
instructed to use highly effective birth control for the duration of the study and will be tested for 
pregnancy using a urine pregnancy test immediately prior to the DXA scan.   
 
2.2.4 Potential Benefits 
 
Participants in this trial will benefit from frequent nutritional counseling, monitoring of weight to 
prevent weight loss, and possibly may gain a psychological benefit from having increased 
supportive care.  Participants randomized to the e-Health arm will also receive an iPad for the 
duration of the study, if they do not already have an iPad or iPhone.  In addition, there is a future 
benefit of furthering research and improving the care of other patients with neurodegenerative 
diseases.  This study will test whether all multidisciplinary Neurology clinics should include a 
registered dietitian on their multidisciplinary staff.   We will also minimize risks by collaborating 
with their existing clinical providers and minimizing travel for participants.  

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3. STUDY DESIGN 
 
3.1 Study Design Overview 
 
This is a phase II feasibility, safety, tolerability and preliminary efficacy study of an e-Health 
application versus in-person nutritional counseling to maintain or increase weight in patients 
with neurodegenerative disease. Approximately 150 ALS participants and approximately 75-150 
PD and HD participants at MGH will be randomized 1:1:1 to one of three interventions: medical 
nutrition therapy using in-person counseling vs. an e-Health application vs. standard care. The 
total duration of the interventions will be 6 months, and participants will be asked to consent for 
long-term follow-up by telephone at the time of the final subject final visit.  We anticipate that 
enrollment of the ALS participants will be completed within 12 months and the overall study 
will be completed within 30 months. The timing of enrollment of HD and PD participants will 
depend on funding and infrastructure.  
 
3.2    Setting 
 
The study will be conducted in the outpatient Neurology Clinics of Massachusetts General 
Hospital, Boston, Massachusetts.  A Registered Dietitian from the MGH Clinical Research 
Bionutrition Center will be the head research RD for this study.   
 
4. Study Population Selection 
 
4.1  
Study Population 
 
Approximately 150 ALS participants and approximately 75-150 PD and HD patients will be 
eligible to participate. Due to the low risk of the intervention, participants will be allowed to 
enroll concurrently in other research studies. There will be no prohibited medications during the 
study, including experimental medications.  The clinical trial will be advertised in the clinic using 
IRB approved pamphlets and posters.   
 
4.2  
Subject Inclusion Criteria 
1. Adults with neurodegenerative diseases such as ALS, PD or HD with or without a history of 
unintentional weight loss.   
2. Male or female subjects aged 18 years or older. 
3. Participants must be capable of providing informed consent and complying with trial 
procedures. 
4. Participants must have an MGH swallowing screening tool score≥5 at the time of the 
screening visit [36] 
5.   Participants or a designated caregiver must be able to obtain weights and communicate to 
their RD 
 
4.3  
Exclusion criteria: 
1. Clinical evidence of unstable medical or psychiatric illness, in the investigator’s judgment, 
which would prevent the participant from completing their assessments. 
2. BMI > 35 combined with a history of cardiovascular disease; or a history of diabetes 
regardless of BMI. 

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4.4 Enrollment Procedures 
 
4.4.1 Informed Consent  
 
The investigator or IRB approved designee will explain the protocol and obtain informed consent 
from all subjects prior to initiation of any research evaluations.  The investigator will determine 
study eligibility as determined by the inclusion and exclusion criteria.  If the study subject 
agrees, provides informed consent, and signs the IRB approved informed consent form, the study 
visits are scheduled.  If the subject is unable to sign the consent, they may provide verbal or 
typed consent and have a witness sign the consent.  One copy of the signed informed consent 
form will be given to the subject, and another copy may be maintained in the subject’s medical 
record.  The informed consent details the potential benefits of participating in the research as 
well as the potential risks of the experimental interventions.  
 
4.4.2 Randomization Process  
 
Randomization of sites will be performed independently by the MGH Biostatistical center using 
a computer-generated system.  Randomization will be stratified by disease group and by the 
presence or absence of weight loss at baseline (i.e., a decline of 5% of body weight from the time 
of first symptoms by self-report). Each participant will receive a unique ID number (see section 
10.4.1) for data entry.  This unique ID will also be used to identify the subject's Source 
Documents, electronic case report forms (eCRFs), and all communications.  The unique ID will 
also be used to link the study data to the e-Health App data by having participants enter their 
unique ID into the e-Health App system when creating their username.  Due to the design of the 
study, participants and evaluators cannot be blinded to treatment assignments. 
 
5. STUDY INTERVENTIONS 
 
5.1.1 In-Person Nutritional Counseling  
 
The head research Registered Dietitian (RD) will provide the clinic RDs with training and 
guidance to ensure uniformity in nutritional counseling.  Clinic RDs will be provided with a 
resource book, patient-oriented educational materials, and access to the head research RD for 
counseling support.  The clinic RDs will then provide each patient randomized to the in-person 
nutritional counseling arm an initial face-to-face nutritional counseling session with written 
instructions outlining their dietary goals.  This will be followed by telephone monitoring of 
weight with additional telephone counseling as needed between return clinic visits.  Participants 
will complete 4-day food records at regular intervals and will fax them to the clinic RD. At every 
clinic visit, patients will receive in-person nutritional counseling and dietary recommendations.   
 
For participants with ALS, we will estimate baseline caloric needs using the ALS Calorie 
Calculator created by Kasarskis et al.[37] . The treating RDs will counsel patients to gain weight 
at approximately 0.5-1 kg/month (an additional 117.5-235 kcal/day) depending on their baseline 
BMI and weight history (See Table 2). Based upon participants’ weight gain or loss during the 
study, the clinic RD will be able to modify their dietary recommendations empirically. These 
prescribed changes will be captured as will the actual intake using 4-day food records. By 

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monitoring weights over time relative to actual intake, the clinic RD will be able to further refine 
their nutritional recommendations for each study participant.   
 
For participants with HD, nutritional support will follow the European Huntington’s Disease 
Network Standards of Care Dietitians Group Dietitians Group recommendations [24]with the 
following additional specifications:  Baseline caloric needs will be calculated using the formula 
for total energy expenditure from Gaba et al[38], which adjusts the Harris-Benedict (HB) 
equation by an activity factor: [1.748 + (0.0071 × BMI)] – (0.0004 × BMI2).  Additional calories 
will be added based upon Table 2, and the clinic RD will be able to adjust the recommended diet 
further based upon observed weight gain or weight loss.  All prescribed dietary recommendations 
and participant intake will be captured electronically.   
 
The nutritional requirements for Parkinson’s disease have not been defined, although one case 
report commented on the use of 1000 calorie high-carbohydrate low-protein oral 
supplements/day to stabilize weight loss in a patient with Parkinson’s disease dyskinesia[21].  
We will therefore start with the HB equation, adjusted for a self-reported activity factor [39] and 
empirically measure the number of calories required to maintain or increase weight during the 
study with the weight goals in Table 2.   
 
Table 2: Weight goals by baseline nutritional status.  
Baseline BMI 
Self-reported weight change since 
diagnosis 
Weight goal during 
study 
Calorie Goals/day 
<25 
Positive or negative 
+1 kg/month 
Deficit +235 Kcal 
25≤30 
<5% of body weight lost 
+0.5 kg/month 
Deficit +117.5 Kcal 
25≤30 
>5% of body weight lost 
+1 kg/month 
Deficit +235 Kcal 
30-35 
<5% of body weight lost 
Weight Stability 
Deficit +0 Kcal 
30-35 
>5% of body weight lost 
+0.5 kg/month 
Deficit +117.5 Kcal 
>35 
Positive or Negative 
Weight Stability 
Deficit + 0 Kcal 
 
5.1.2 E-Health Nutritional Counseling  
 
Participants in the e-Health arm will receive the same nutritional goals as above from the 
research RD using the e-Health application interface.  Each participant will be asked to enter 4 
days of dietary intake and 2 home weights every 2 weeks.  The application will prompt them to 
enter their data automatically, and the research RD will receive notification of any missing data.  
The research RD will have access to the e-Health App data and will be able to modify the dietary 
recommendations made by the application according to the recorded weights using the same 
guideline as in Table 2.  
 
5.1.3 Standard Care  
 
The standard care group will receive routine nutritional counseling by a treating physician or 
nurse about the importance of avoiding weight loss at regular clinic visits, as is the standard of 
care in our Neurology clinics.  All participants will be asked to complete and bring with them 4-
day food records to each clinic visit.  
 
5.2 Compliance with Dietary Recommendations (Adherence Assessment)  
 

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The treating RDs will monitor weight and dietary intake either using paper food diaries every 2-4 
weeks (in-person arm) or using the self-reported dietary intake using the e-Health app to verify 
dietary compliance.  Compliance will be defined as greater than 80% data entry using either the 
paper or electronic food diaries and consuming > 90% of the recommended diet.  
 
5.3 Monitoring of Weight  
 
Weight will be assessed at every clinic visit in all three groups.  Participants in both intervention 
arms will be asked to weigh themselves at home or in a clinic or allied health professional office 
every 2-4 weeks and either enter their weights into the e-Health app or in to their Self-Weighing 
Log.  Participants in the in-person arm will be instructed to report significant weight changes by 
phone to their clinic RD. The clinic RD may modify the dietary recommendations at any time 
based on observed weight loss, adverse events, or at their discretion.  Persistent weight loss 
despite >90% dietary compliance will prompt an increase in target calories by 235 Kcal/day, or 
more if the weight loss is more than 0.5 kg/week.  Changes in the dietary recommendations will 
be recorded in the EDC.  
 
Any weight loss >1.5 kg during the study will prompt an increase in the frequency of telephone 
contact and an appropriate increase in the recommended caloric goals.  In addition, any report of 
weight loss will prompt the treating dietitian to explore (by telephone) whether this is due to 
unwillingness to continue participation in the trial, inability to comply with the prescribed diet 
(due to weakness, dysphagia, or dependence on caregivers), or inadequate caloric 
recommendations.  Reported dysphagia (using the swallow screening questionnaire, Appendix 9) 
will prompt the treating RD to refer the patient for an early in-person evaluation by their medical 
providers.   Participants who lose more than 3 kg despite non-invasive attempts to maintain body 
weight will be referred to a Speech Language Pathologist for evaluation of dysphagia and 
possible consideration of a feeding tube.   
 
All participants who require a feeding tube during the study will be prescribed enteral nutrition 
based upon results of the High Fat/High Calorie diet study. Jevity 1.5 will be prescribed at 1.5 
times their calculated TDEE using the HB equation, adjusted for a self-reported activity factor 
[39].  Given the safety and tolerability results of this study, we do not feel that it is ethical to use 
a control or eucaloric diet in the standard care arm.   
 
5.4  
Concomitant Medications 
 
Throughout the study, investigators may prescribe any other concomitant medications or 
treatments deemed necessary to provide adequate supportive care.  All concomitant medications 
received by a subject will be recorded on the appropriate source documents and in the Electronic 
Data Capture (EDC) System.  
 
5.4.1 Exclusionary Medications   
 
None.  Due to the low risk of the study, investigational medications will also be allowed during 
the trial.  

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6. Study Activities 
 
6.1 Study Visits 
6.1.1 Screening/Baseline Visit and Informed Consent 
 
A schedule of activities for each intervention is provided in Table 1.  At the screening visit, 
subjects will provide informed consent.  Informed consent may be obtained by physicians, 
research nurses or study coordinators with IRB approval to consent participants in the study.  No 
procedures will be done prior to consent.  Participants will be asked basic demographic questions 
and will be asked for contact information for their caregivers.  Participants will provide basic 
information about their diagnosis and disease history, such as date of diagnosis and site of 
symptom onset.  Participants will be screened for dysphagia using the MGH Swallow Screening 
Tool (MGH SST) and must score at least a 5 in order to enroll (in order to ensure that they will 
be able to comply for 6 months with an oral diet).  Participants who score below a 5 on the 
MGH-SST will be referred to a SLP and their treating physician and nurse will be informed.  
Participants who pass the MGH-SST will then be weighed and asked questions about the degree 
of weight loss they may have experienced since before their illness (weight loss may predate 
their diagnosis).    Once all incusion criteria have been met, all participants will be randomized 
into one of the three study arms.   
 
Additional study activities may be completed within 2 weeks of the screening/baseline visit if 
participants are unable to complete the activities at that time.  All participants will complete a 24 
hour recall. Participants in the two intervention arms will then receive written instructions with 
their calculated caloric goals and general dietary recommendations.   Participants in the e-Health 
App arm who do not have access to an iPhone or iPad will be provided an iPad for the duration 
of the study free of cost.  They will then be trained and will enter their randomization codes into 
the application in order to access their caloric goals and recommendations.  The research RD will 
maintain a list linking the identification codes of the participants to their contact information.  
Participants will also have their blood drawn for the research and safety laboratory studies 
incuding a urine pregnancy test for participants who have consented for the optional DXA study. 
Participants who have had safety labs drawn for routine clinical (or research purposes) within 4 
weeks may have their laboratory data used for the study rather than repeating the labs. Finally, 
participants will be given a Self Weighing Log (Appendix 1) and told to weigh themselves at 
least every 2-4 weeks using the log and to contact the site if they lose 3 or more pounds.   
 
Participants who consent to the optional DXA study will be invited to go to the MGH CRC at 
their convenience for the DXA exam.   All women of child-bearing potential will undergo a 
urine pregnancy test immediately prior to the DXA exam.  The timing of this exam can occur 
within 14 days of the baseline visit.  
 
6.1.2 Telephone Visits (Every 2-4 weeks) 
 
 
The Research Coordinator on the study will contact all participants by telephone at month 1 in all 
arms to determine if there have been any adverse events.  The Coordinator will also contact 
participants by telephone who are unable to return to the clinic for their routine clinic visits, in 
order to perform disease-related outcome measures and the quality of life questionnaire.   
 

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After the initial screening/baseline visit, the treating Registered Dietitian will monitor dietary 
intake and weight in the in-person arms every 2-4 weeks as necessary based upon observed 
weight changes.  They will monitor dietary compliance by having participants complete paper 
food records and faxing them along with the Self-Weighing Log for review.  They will then 
contact participants by telephone to query any weight loss or emergence of adverse events.  If the 
treating RD identifies weight loss despite >90% compliance with dietary recommendations, they 
will adjust their dietary recommendations to meet the target weight from Table 2.  They will then 
contact the study participant at least once every 2 weeks until the participant’s weight has 
stabilized or increased.  The frequency and duration of counseling sessions will be documented 
in the EDC.   
 
The RD in the e-Health Application arm will contact participants who report weight loss through 
the App directly, through email, or by telephone if necessary.  The RD will assess whether the 
weight loss is due to an inability to comply with the prescribed diet (due to weakness, dysphagia, 
or dependence on caregivers), versus inadequate caloric recommendations.  Symptoms of 
dysphagia using the self-reported swallow screening questionnaire will prompt the treating RD to 
refer the patient to SLP for an early in-person evaluation. 
 
6.1.3 Clinic Visits (Months 3 and 6) 
 
In order to reduce the burden of research visits and data collection, in-person visits in the e-
Health arm and the standard care arm will coincide as much as possible with patients’ routine 
clinic visits. Participants wil be asked to complete a 4-day food record prior to each in-person 
clinic visit.  At the visit, the Registered Dietitian will meet with participants in the in-person arm 
and will verify compliance with the prescribed diet.  Participants will review the dietary goals 
and recommendations with participants and make adjustments as needed based upon observed 
weight loss.  All participants will be rescreened for dysphagia using the MGH–SST and 
participants with dysphagia will be referred to a SLP before continuing in the study.  If the SLP 
determines that a modification of their current diet is required, those modifications will be 
incorporated into the dietary recommendations.  If the SLP determines that the participant cannot 
swallow safely, their study diet will be temporarily suspended until they can obtain a feeding 
tube.  If they decline the feeding tube, participants will still be asked to complete the final visit 
by telephone and to consent for long term follow-up for survival.  Participants’ blood will also be 
drawn for research and safety laboratory studies.  
 
6.1.4 Treatment Withdrawals and Loss to Follow-up 
 
A subject has the right to refuse counseling sessions and contact from the RD at any time and for 
any reason.  If participants express unwillingness to continue to participate in the trial, 
participants will be asked if they would be willing to be followed for telephone-based 
questionnaires, QOL and survival only, with a final telephone visit at 6 months.  The treating RD 
or research coordinator will document the reasons for discontinuation in the EDC.  Long-term 
follow-up for survival will continue until the end of the study and be included in the intention-to-
treat analysis.  For the primary safety analysis, telephone visits will be used to document adverse 
events, changes in medical history and medications.  All attempts will be made to follow these 
subjects for all outcome measures by telephone if necessary.  The analysis of data from subjects 
who stopped treatment and/or refused study visits is discussed in the data analysis section. 

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6.1.5 Final Evaluations and Post-Intervention Phone Calls 
 
 
The final visit will coincide with the participant’s routine clinic visit approximately 6 months 
after study initiation.  Weight, appetite, QOL and disease-specific questionnaires will be 
measured.  Participants will return the study iPad at this visit and all participant data will be 
deleted from the iPad.  Participants’ blood will be drawn for research and safety laboratory 
studies, including a urine pregnancy test if participants have consented for the optional DXA 
study.   
 
One month after the final clinic visit, the research coordinator will contact all participants by 
telephone to document adverse events.  The research coordinator will also contact subjects 
approximately every 6 months until all participants have finished the study, to document vital 
status and weight, dates of feeding tube placement, tracheotomy or death.   
 
6.1.6 End of Study Phone Call 
 
All participants will be contacted at the time of the last subject last visit in order to obtain vital 
status and dates of feeding tube placement, tracheotomy or death.   
   
6.2   
Definitions of Evaluations and Outcome Measures 
 
6.2.1 Primary Outcome Measures 
 
6.2.1.1 Safety and Tolerability 
 
Safety will be evaluated using reporting of hospitalizations, deaths and other serious adverse 
events, and treatment discontinuations due to adverse events.  Tolerability will be defined as the 
number of participants who do not decline nutritional counseling, i.e. the number of participants 
who complete the 6 months of counseling sessions in the in-person arm, or who enter at least 
80% of the required data in the e-Health application arm.  Tolerability will not be defined based 
on compliance with nutritional recommendations as compliance may be affected by other factors 
such as disease progression.  
 
Adverse Events: 
The research coordinator will collect data by telephone on adverse events after the first month, 
and at each clinic visit in all participants. Adverse events will be recorded using the MedDRA 
coding system. Safety labs including the basic metabolic panel, lipid profile, hemoglobin A1c 
and liver function tests will be performed at the Screening/Baseline and routine clinic visits.   
 
6.2.1.2 Primary Outcome Measure: Weight 
 
The primary outcome of weight will be compared between each intervention arm and the control 
arm using the measured weights from each clinic visit, approximately every 3 months.  
Participants will be weight lightly clothed without shoes or braces.  Participants may use a chair 
scale or wheelchair scale if they are unable to stand. Body mass index will be calculated at the 
initial visit using a baseline height measurement.   

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Weight will also be used to direct therapy.  Participants in the in-person counseling arm will be 
given a Self-Weighing Log to weigh themselves every 2-4 weeks, and to call the center if they 
experience 2 or more pounds of weight loss compared to their baseline weight.  The e-Health 
arm will be prompted automatically by the application to weigh themselves twice every 2 weeks, 
and to enter the data into the application. If there is a greater than 2 pound change from the prior 
weight, the treating RD will be alerted and will be able to contact the participant by telephone or 
by instant messaging through the application to verify the weight change.  They will then be able 
to make dietary adjustments and to monitor weights more frequently in any participant who 
experiences weight loss. Self-reported weights will be verified at routine clinic visits.  Self-
reported weights will also be used to compare the two intervention arms. 
 
6.2.2 Secondary Outcome Measures: 
 
In order to monitor dietary compliance and to collect comprehensive nutritional information, we 
will use 4 day food records in the in-person counseling arm. The e-Health application arm will 
be prompted every 2 weeks to report all dietary intake for 4 days (including 1 weekend day) 
along with their activity level and home weights (measured twice over 2 days). The 4 day food 
records will be analyzed using Nutrition Data System for Research (NDSR) software Version 
2014 by the RD and coordinator, while the e-Health application data will automatically analyze 
the data into total caloric intake, percent protein, fat, and carbohydrate. 
 
6.2.3 Tertiary Outcome Measures: 
 
Tertiary outcome measures will be collected by a research coordinator at every clinic visit, 
approximately every 3 months, including standard care participants. Tertiary outcome measures 
will include change in disease-related questionnaires (ALSFRS-R, UDysRS, UHDRS), quality of 
life using the PROMIS SF v1.1 questionnaire, and the CNAQ appetite questionnaire.  For 
participants who are unable to physically come to the clinic for their clinic visits, the patient-
reported sections of these questionnaires will be administered by telephone.  The study is not 
powered to detect changes in disease progression.   
 
6.2.3.1 Survival: 
 
Survival will be defined as time to death, tracheotomy or the initiation of permanent assisted 
ventilation (PAV).  PAV is defined as noninvasive or invasive ventilation used for more than 22 
hours in a 24-hour period for 14 consecutive days.  Participants will also be asked to consent for 
long-term follow-up at the initial visit and their vital status will be determined every six months 
by telephone until the final participant completes the study, unless they expressly withdraw their 
consent. 
 
6.2.3.2 Time to Percutaneous Endoscopic Gastrostomy (PEG) or Jejunostomy (PEJ) 
Placement: 
 
Date of placement of PEG or PEJ feeding tubes will be captured using the EDC.  Frequency and 
time to placement of feeding tubes will be compared between the different arms.  We 
hypothesize that participants in the two intervention arms will be more willing to undergo 

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feeding tube placement and that there will be less weight loss before feeding tube placement in 
the two intervention arms.   
 
6.2.3.3 Exploratory Outcome Measures: 
 
Exploratory outcome measures include changes in weight, fat mass, and fat free mass using 
DXA scans, lipid levels, serum markers of nutritional status, and the appetite regulatory 
hormones Leptin, Ghrelin and PYY.  Leptin is an important regulator of appetite, food intake, 
and energy expenditure (reviewed in [40]).  Leptin is a peripherally circulating hormone 
produced by adipose tissue which crosses the blood brain barrier and binds to leptin receptors 
primarily in the hypothalamus where it leads to anorexia and weight loss.  In addition to 
regulating appetite, leptin has also been reported to be neuroprotective in ischemic models and 
amyloid toxicity [41-43].  Patients with Alzheimer’s disease have been shown to have lower 
circulating leptin levels than controls, and low premorbid leptin levels are associated with an 
increased risk of cognitive decline and Alzheimer’s disease in two large prospective studies, 
even adjusted for waist-hip ratio and BMI [44, 45].  This is in contrast to the data showing that 
mid-life obesity is a risk factor for Alzheimer’s disease.  Leptin levels have not been measured in 
ALS except in one small study of 21 patients where the results were not compared to controls 
and not adjusted for BMI [46].   
 
                                                                                                                        
7.  Adverse Experiences Related to Medical Nutrition Therapy 
 
 Weight gain 
An increase in weight in either of the intervention arms is expected and would not be considered 
an adverse event.  In the High-Fat/High Calorie versus Optimal Nutrition in ALS clinical trial, 
there were no complications of heart disease, diabetes, or breathing problems in the study arms 
who received hypercaloric diets.  Increase in weight was seen in the high-carbohydrate 
hypercaloric arm and was associated with fewer AE and SAE.  We will therefore tell participants 
that they are expected to gain weight and that we will not consider this an adverse event. 
 
Gastrointestinal Side Effects 
In the High-Fat/High Calorie clinical trial, the following adverse events were observed (Table 3).  
The most common adverse events were gastrointestinal and presumably related to the enteral 
formulae that participants received.  Because the current study is designed primarily for 
participants taking food by mouth, we anticipate a lower frequency of gastrointestinal side 
effects.  However, we anticipate the following common adverse events that may be observed 
with any nutritional intervention: 
 • Abdominal Fullness 
• 
Belching 
• 
Flatulence 
• 
Constipation 
• 
Heartburn 
 
Management of Adverse Experiences 
As above, weight gain would not be considered an adverse event.  Weight loss will be managed 
by increasing the target calorie goal by 235 Kcal/day or more as measured empirically.  
Gastrointestinal side effects will be managed by adding over-the counter simethicone, fiber 

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(psyllium, cellulose, wheat dextrin), or by removing possible culprit foods such as dairy, wheat.  
Gastroesophageal reflux will be managed with over-the counter calcium carbonate, or if 
ineffective, prescription medications at the discretion of the treating physician.  

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Table 3. Adverse Events by 
Body Sytem 
  
 Cntl  
HC/HC 
 HF/HC  
 p values (events) 
 p values (% Pts) 
Type 
N 
Pts 
(%) 
N  
Pts 
(%) 
N 
Pts 
(%) 
Overall HC/HC 
vs. Cntl 
HF/HC 
 vs. Cntl 
Overall HC/HC 
vs. Cntl 
HF/HC 
 vs. Cntl 
Allergy/Immunology 
(Allergic rhinitis) 
AE 
0 
0 (0) 
1 
1 (13) 
0 
0 (0) 
0.81 
0.69 
>0.99 
>0.99  
>0.99 
>0.99 
SAE 
0 
0 (0) 
0 
0 (0) 
0 
0 (0) 
>0.99 
>0.99 
>0.99 
>0.99 
>0.99  
>0.99 
Cardiac (Atrial fibrillation, 
elevated troponin) 
AE  
2 
1 (17) 
0 
0 (0) 
0 
0 (0) 
>0.99 
0.97 
0.97 
0.6 
0.43 
>0.99 
SAE 
0 
0(0) 
0 
0 (0) 
0 
0 (0) 
>0.99 
>0.99 
>0.99 
>0.99  
>0.99  
>0.99 
Constitutional Symptoms 
(Fatigue, weight change) 
AE 
7 
2 (33) 
2 
2 (25) 
5 
2 (33) 
0.41 
0.2 
0.78 
>0.99  
>0.99  
>0.99 
SAE 
0 
0 (0) 
0 
0 (0) 
0 
0 (0) 
>0.99 
>0.99 
>0.99  
>0.99  
>0.99  
>0.99 
Dermatology 
(Abration) 
AE  
0 
0 (0) 
0 
0 (0) 
1 
1 (17) 
0.71 
>0.99 
0.51 
0.6 
>0.99  
>0.99 
SAE 
0 
0 (0) 
0 
0 (0) 
0 
0 (0) 
>0.99 
>0.99 
>0.99  
>0.99  
>0.99  
>0.99 
Gastrointestinal (detached 
feeding tube, bloating, 
dyspepsia, diarrhea) 
AE 
13 
6 
(100) 
8 
4  
(50) 
21 
6 
(100) 
0.04 
0.11 
0.21 
0.02 
0.09 
>0.99 
SAE 
0 
0 (0) 
0 
0 (0) 
0 
0 (0) 
>0.99 
>0.99 
>0.99  
>0.99  
>0.99  
>0.99 
Hematology/Coagulation 
(Thrombocytopenia) 
AE  
1 
1 (17) 
0 
0 (0) 
0 
0 (0) 
>0.99 
0.97 
0.64 
0.6 
0.43 
>0.99 
SAE 
0 
0 (0) 
0 
0 (0) 
0 
0 (0) 
>0.99 
>0.99 
>0.99  
>0.99  
>0.99  
>0.99 
Infection 
(Urinary tract, pneumonia) 
AE 
5 
2 (33) 
3 
3 (38) 
6 
4 (67) 
0.46 
0.41 
0.82 
0.62 
>0.99  
0.57 
SAE 
1 
1 (17) 
0 
0 (0) 
0 
0 (0) 
0.6 
0.43 
>0.99  
0.6 
0.43 
>0.99  
Metabolic/Laboratory 
(Elevated alkaline 
phosphatase, hypokalemia)  
AE  
2 
1 (17) 
0 
0 (0) 
0 
0 (0) 
>0.99 
0.97 
0.97 
0.6 
0.43 
>0.99 
SAE 
0 
0 (0) 
0 
0 (0) 
0 
0 (0) 
>0.99 
>0.99 
>0.99  
>0.99  
>0.99  
>0.99 
Musculoskeletal 
(Falls, weakness) 
AE  
0 
0 (0) 
5 
1 (13) 
4 
2 (33) 
>0.99 
0.97 
0.97 
0.45 
>0.99  
0.45 
SAE 
0 
0 (0) 
0 
0 (0) 
0 
0 (0) 
>0.99 
>0.99 
>0.99  
>0.99  
>0.99  
>0.99 
Neurology/Psychiatry 
(Dizziness, depression) 
AE  
1 
1 (17) 
1 
1 (13) 
1 
1 (17) 
0.97 
0.9 
0.99 
>0.99  
>0.99  
>0.99 
SAE 
0 
0 (0) 
0 
0 (0) 
1 
1 (17) 
0.6 
>0.99 
>0.99  
0.6 
>0.99  
>0.99 
Pain 
(Abdomin, neck, limb) 
AE  
3 
2 (33) 
2 
2 (25) 
4 
3 (50) 
0.58 
0.46 
0.72 
0.84 
>0.99  
>0.99 
SAE 
2 
1 (17) 
0 
0 (0) 
0 
0 (0) 
0.18 
0.18 
0.5 
0.6 
0.43 
>0.99 
Pulmonary/Upper 
Respiratory (Dyspnea, 
hypoxia, aspiration, cough) 
AE 
8 
3 (50) 
1 
1 (13) 
6 
3 (50) 
0.16 
0.075 
0.72 
0.28 
0.24 
>0.99 
SAE 
6 
3 (50) 
0 
0 (0) 
2 
2 (33) 
0.007 
0.006 
0.29 
0.07 
0.06 
>0.99 
Total 
AE  
42 
6 
(100) 
23 
8 
(100) 
48 
6 
(100) 
0.06 
0.06 
0.73 
>0.99  
>0.99  
>0.99 
 
SAE  
9 
4 (67) 
0 
0 (0) 
3 
3 (50) 
<0.001 
<0.001 
0.15 
0.03 
0.015 
>0.99 

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8. Intervention Suspension Related to Nutritional Counseling 
 
While we do not anticipate serious adverse events from medical nutrition therapy, we will 
suspend the nutritional interventions while participants are hospitalized, or if participants 
withdraw consent during the study.  If participants wish to continue in the study after discharge, 
they may resume nutritional counseling with the approval of their treating physician.  If 
participants develop significant dysphagia during the study and are deemed unable to swallow 
safely by a Speech Language Pathologist, even with dietary modifications, the study nutritional 
goals will be suspended until participants are able to obtain a feeding tube.  Participants who 
receive a feeding tube will then receive Jevity 1.5 at 1.5 times their estimated total daily energy 
expenditure, regardless of the study arm to which they have been randomized. 
 
9. STATISTICAL CONSIDERATIONS 
 
Statistical analyses will be performed by Dr. Eric Macklin of the MGH Biostatistics Center, who 
was the statistician on the High Fat/High Calorie vs. Optimal Nutrition in ALS clinical trial. 
Safety and tolerability will be assessed in all randomized participants, analyzed according to the 
treatment they actually received. Efficacy will be estimated from an intent-to-treat (ITT) sample, 
consisting of all randomized participants and analyzed according to their originally assigned 
treatment group regardless of adherence to that treatment. Secondary efficacy analyses will 
consider a per-protocol sample that adhered to their assigned treatment if this would differ from 
the mITT analysis for more than 10% of the sample. ALS, PD, and HD participants will be 
analyzed separated. 
 
9.1  
Safety and Tolerability  
 
All randomized subjects will be considered evaluable for tolerability and safety. Subjects lost to 
follow-up will be considered treatment failures at the time they drop out of the study.  The data 
will be reviewed by the independent Medical Monitor, using the considerations here as 
guidelines.  Their recommendation would then be reviewed by the Principal Investigator. 
 
Safety data will be summarized by disease group and treatment group and reported to the 
independent Medical Monitor every 3 months during the study. Total numbers of adverse events 
will be compared within each disease group and among treatment groups using negative binomial 
regression and the proportion of participants experiencing each type of event by Fisher's exact 
test. Every 3 months the Medical Monitor will review cumulative study reports to determine if 
there has been an excess rate of serious adverse events in any of the arms. At two interim 
analyses, mortality rates will be compared, and one or both intervention arms may be terminated 
for one or more disease groups according to pre-determined stopping rules described below. 
 
In the tolerability analyses, a subject will be regarded as a treatment success if he/she complies 
with at least 80% of the nutritional counseling sessions, or enters at least 80% of the required 
electronic data.   
 
9.2  
Weight and Caloric Intake: 
 

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The primary and secondary efficacy outcomes of change in weight and caloric intake will be 
compared within each disease group and among the treatment groups using a shared-baseline 
linear mixed model for correlated, longitudinal assessments of weight with fixed effects of time 
and the treatment x time interaction and age, gender, and baseline swallowing score and their 
interactions with time included as covariates and random participant specific intercepts and 
slopes. Pairwise comparisons between treatment groups will be analyzed using linear contrasts 
from the full mode, with correction for multiple comparisons vs. standard of care using Dunnett’s 
method. Significant benefit from the eHealth or RD intervention will be declared if less weight is 
lost and the two-tailed p-value for comparison to standard of care is less than 0.027 for each 
intervention separately. 
 
9.3  
Sample size calculation:  
 
 
Using the component estimates from weight data collected in the clinical trial of Ceftriaxone in 
ALS [13] the effective standard deviation for rate of change in weight assuming weight 
assessments every 2 weeks, an annual 23% mortality rate, and 20% loss to follow-up is 0.98 
kg/month. Given a sample size of approximately 150 ALS participants randomized 1:1:1 to the 
two interventions and standard care will provide at least 80% power to detect a true 0.75-
kg/month difference between each intervention arm and the control arm over 24 wks at a two-
tailed p < 0.027 using Dunnett’s method (testing superiority of each intervention over standard 
care). Based on a non-inferiority bound of 0.5 kg/month, the study will have at least 80% power 
to declare the e-Health intervention non-inferior to in-person consultation with an RD based on a 
one-tailed test at p < 0.05 and assuming that the two interventions are in fact equivalent. 
 
Accrual Targets:  We intend to enroll 3-4 ALS subjects per week for the first 12 weeks, after 
which the rate will slow to 2-3 subjects/week, in order to accommodate return schedules and 
telephone visits. It should take approximately 12 months to enroll 150 participants at an average 
rate of 10 subjects per month.  PD and HD subjects will be enrolled separately based upon 
funding and infrastructure availability. 
 
Treatment Discontinuation Rate Targets:  Subjects who discontinue treatment will be 
considered treatment failures in the tolerability analysis.  However if there is an elevated 
discontinuation or study drop-out rate, it will reduce the power to detect a significant treatment 
difference for the primary outcome.  The Steering Committee will analyze enrollment and 
discontinuation rates at pre-specified intervals and if it appears that fewer than 25 subjects per 
arm will complete the 6 month study, they may recommend increasing the enrollment times or 
stopping early for futility.   
 
9.4  
Tertiary and Exploratory Outcomes: 
 
Although the study is not powered to look at the effects of the diet interventions on disease 
progression, we will examine trends in measures of disease progression.  Preliminary analyses of 
survival and disease-specific outcome measures (ALSFRS-R, UDysRS, UHDRS) will use the 
ITT sample.  We will ascertain the final outcome measures of all subjects at the end of the study 
and every subject will be included in the analysis whether or not they elected to stop treatment 
before the end of the study.   
 

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Change in the disease-related outcomes will be compared among the treatment groups using the 
same shared-baseline linear mixed model used to analyze weights. Additional baseline measures 
that might independently predict rate of progression will be considered for inclusion as 
additional covariates based on review of data prior to analysis for treatment differences.  
 
Survival during and after the study intervention will be analyzed using a Cox proportional 
hazards model for treatment assignment, adjusted for age, gender, duration of disease, and 
baseline BMI. Hazard ratios and their 95% confidence intervals will be used to interpret the 
regression results. 
 
The exploratory outcome measures of biomarkers of body composition, lipid metabolism, and 
appetite regulatory hormones will be explored in the ITT and per-protocol samples.  Change over 
time in fat mass, fat-free mass, albumin, pre-albumin, lipid levels, leptin, ghrelin, PYY, will be 
compared among the treatment groups using a shared-baseline linear mixed model with gender, 
treatment and BMI included as covariates.  We hypothesize that weight gain in the intervention 
arms will result in increased lipid levels.  Pairwise comparisons between treatment groups will 
be analyzed using linear contrasts from the full model.  
 
9.5  
Stopping for Safety 
The Principal Investigator is responsible for oversight of the data safety and will work with the 
Medical Monitor and study statistician to monitor the study and evaluate safety on an ongoing 
basis.  Unblinded safety data will be presented to the Medical Monitor every 3 months during the 
study.  Decisions to stop the trial, enrollment of one or more disease groups, or randomization of 
one of the intervention arms early for safety will be made by the Medical Monitor, Principal 
Investigator and study Statistician. There will be a rule for stopping if either nutritional 
counseling intervention appears to increase mortality relative to standard of care, where mortality 
is defined as death or initiation of permanent assisted ventilation. Survival in each counseling 
intervention arm will be compared to the standard of care arm using the logrank test. We will use 
an alpha spending rule to test for increased mortality with a cumulative 1-sided p-value of 0.1 
separately for each disease group. By Dunnett’s test, that equates to cumulative 1-sided p-values 
of 0.0574 for each intervention arm according to the following table: 
 
Analysis  
% of total follow-
up completed 
Z statistic 
Cumulative 
Alpha  
 
P-value to 
stop 
1 (Interim) 
33.3% 
3.09103 
0.000997 
0.000997 
2 (Interim) 
66.7% 
2.06168 
0.019950 
0.019619 
3 (Final) 
100% 
1.63136 
0.057404 
0.051408 
 
Thus, if at the first interim analysis, the p-value for the logrank test comparing the survival 
distributions of one of the interventions versus standard care is less than 0.000997, then this 
intervention arm would be stopped. Each intervention arm may be stopped early independently, 
without affecting continued enrollment and follow-up of participants in the other arms of the 
trial.  The overall probability of stopping at least one arm of the trial early for a given disease 
group when there is in truth no effect on mortality is 10%. The probability of stopping at least 
one arm of the trial early across all three disease groups when there is no effect on mortality in 

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any is 27%. The first interim analysis will occur after one third of total expected follow-up is 
completed.  This may vary depending on accrual rate and total accrual targets for each disease 
group. 
 
10. DATA COLLECTION AND ADVERSE EVENT MONITORING 
 
10.1 
Records to be Kept and Project Organization 
 
The MGH NCRI Data Management group and the Biostatistics Center at the MGH will conduct 
data management, biostatistics, regulatory compliance, adverse event reporting.  For the 
purposes of the study, all clinical data will be captured using the NeuroBANK™ data repository 
platform.  
 
 
10.2  PURPOSE OF NEUROBANK™ 
 
NeuroBANK™ is a collaboration and data repository platform maintained by the Massachusetts 
General Hospital (MGH) Neurological Clinical Research Institute (NCRI).  The system 
conforms to the 21 CFR Part 11 and other guidance documents on computerized systems in 
clinical trials.   This platform facilitates: 
1. Capture of clinical and research data from neurologic patients for individual projects in a 
structured and secure system; 
2. Aggregating and sharing uniform, deidentified and/or anonymized datasets for secondary 
analyses. 
 
10.3 
ROLE OF DATA MANAGEMENT 
 
Data Management (DM) is responsible for the development, execution and supervision of plans, 
policies, programs, and practices that control, protect, deliver, and enhance the value of data and 
information assets. 
 
All data will be managed in compliance with applicable Sponsor and regulatory requirements. 
Site personnel will collect, transcribe, correct, and transmit the data onto source documents, Case 
Report Forms (CRFs), and/or other forms used to report, track and record clinical research data.  
DM is responsible for developing, testing, and managing clinical data management activities. 
 
10.3.1 Data Entry and Checks 
 
Data capture will be entered in a timely manner into the NeuroBANK™ Electronic Data Capture 
(EDC) System.  Data capture is the responsibility of the staff at the site under the supervision of 
the Principal Investigator.  During the study, the Site investigator must maintain complete and 
accurate documentation for the study. 
 
The NeuroBANK™ platform provides password protection.  An edit checking and data 
clarification process will be put in place to ensure accuracy of the data.  Logic and range checks 
as well as more sophisticated rules may be built into the eCRFs to provide immediate error 
checking of the data entered.  The system has the capability to automatically create electronic 

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queries for forms that contain data that are out of range, out of window, missing or not calculated 
correctly.  The sites will only have access to the queries concerning their subjects.   
 
10.3.2 Data Lock Process 
 
The platform will have the ability to lock the project-specific visits to prevent any modification 
of data once the project is closed.  Once this option is activated, every user will have Read-Only 
access to the data.  The database then will be transferred to the Biostatistics Center by unloading 
the relational MS SQL Server database to a SAS format for statistical analysis. 
 
10.3.3 DATA HANDLING AND RECORD KEEPING 
 
The Principal Investigator is responsible to ensure the accuracy, completeness, legibility, and 
timeliness of the data reported.  Data reported in the eCRF derived from source documents 
should be consistent with the source documents and discrepancies should be explained. 
 
10.3.4 Database Security  
 
The MS SQL Server database is located on a secure database server.  This server is located in a 
restricted area of the Partners Healthcare server farm and physical access to it is limited to 
authorized personnel only.  Both database and Web servers are located on the Partners 
Healthcare network behind the firewall.  Access to the data at the clinical site will be restricted 
and monitored through the system's software with its required log-on, security procedures and 
audit trail.  The data will not be altered, browsed, queried, or reported via external software 
applications that do not enter through the protective system software.  There will be a cumulative 
record that indicates, for any point in time, the names of authorized personnel, their titles, and a 
description of their access privileges.  The record will be in the study documentation accessible 
at the site.  Controls will be in place to prevent, detect, and mitigate effects of computer viruses 
on study data and software.  The application utilizes SSL (Secure Sockets Layer) technology and 
128-bit encryption to comply with requirements of 21 CFR Part 11 for Open Systems.  Backups 
of the database will be performed nightly using the services provided by the MGH network.  All 
PC’s run virus protection software full-time and are updated with the latest virus detection 
strings regularly; the Windows NT server does this as well and has the additional security of 
scanning all e-mail for viruses before a user can even access them.  All accounts are password 
protected and passwords must be changed on a regular basis. 
 
 
In addition, the EDC system will have an extra level of password security.  At study initiation, 
the Data Manager will set default passwords for the relevant study personnel at the MGH NCRI 
and at the study site.  When a new user logs in with the assigned username and default password 
for the first time, he or she will be forced to change the password to a unique one (at least six 
characters long), known only to the user.  An ongoing paper log will be kept showing when 
usernames and passwords are set up, for whom, in what user capacity and when usernames are 
disabled.  In case an employee forgets her/his password or a new user is added, they will submit 
a password request form via email to the Data Manager, who will issue a new default password.  
They must then go through the Change Password process.  The passwords will expire every three 
months, when users will be required to go through the Change Password process.  To avoid 
password-based software attacks, the system will lock a user for 1 minute if an incorrect 

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password is provided 3 times in a row.  A user will also be able to change the password at will if 
he or she feels that it may have been compromised. 
 
10.4 
Confidentiality 
 
The NeuroBANK™ software and patient data reside on servers located in the Partners 
Healthcare Systems (Partners) server farm.  Physical and software access to the servers and 
security is provided by the Partners IT department.  Members of the NeuroBANK™ 
management team will do everything, within reason, to keep a participant’s identity protected. 
 
10.4.1 Global Unique Identifier (GUID) 
 
A patient Global Unique Identifier (GUID) will be used as the identifier for individuals 
participating in the study in NeuroBANK™. The GUID is an 11-character string that is 
generated using encryption technology and algorithms licensed by the NCRI from the National 
Institutes of Health (NIH). 
 
The GUID is generated on a secure website that utilizes 128-bit Secure Socket Layer (SSL).  Of 
note, this website is not linked to NeuroBANK™.  The GUID is generated using an irreversible 
encryption algorithm – it accepts twelve identifying data elements, (e.g. last name at birth, first 
name at birth, gender at birth, day, month and year of birth, city and country of birth, etc.), and 
produces a unique random-generated character string, or GUID.  No identifying information is 
stored in the system; it is simply used to generate the GUID.  If the same information is entered 
again, the same GUID will be returned.  
 
The GUID is entered into NeuroBANK™ when the patient is being created in the system. As the 
same patient may participate in multiple studies, NeuroBANK™ will also allow capturing a 
study-specific ID for the patient.  For more information about NeuroBANK™ or the GUID, 
please go to: www.neurobank.org. 
 
10.4.4 Quality Assurance 
 
The Principal investigator will be responsible for ensuring that informed consent is properly 
obtained and that adverse events and protocol violations are reported to the Partners IRB as 
required.    
 
10.4.5 E-Health App Privacy and Security 
 
See Appendix 4 for the specifications related to the e-Health App which will be used for this 
study.   
 
10.5 
Adverse Experiences Monitoring and Reporting  
An adverse event (AE) is any unfavorable and unintended sign (including a clinically significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with a 
study, use of a drug product or device whether or not considered related to the drug product or 
device.   

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The adverse event (AE) definitions and reporting procedures provided in this protocol comply 
with all applicable U.S. FDA and ICH guidelines and regulations. The Principal Investigator will 
carefully monitor each subject throughout the study for possible adverse events.  All AEs will be 
documented on eCRFs designed specifically for this purpose.  It is also important to report all 
AEs, especially those that result in permanent discontinuation of the investigational drug being 
studied, whether serious or non-serious.   
 
Subjects will be monitored for adverse events from the time they sign consent until completion 
of their participation in the study.  For the purposes of this study, symptoms of 
progression/worsening of ALS, PD and HD including ‘normal’ progression, will not be recorded 
as adverse events.   Relationship of adverse experiences to the experimental intervention will be 
assessed at each in-person and telephone study visit by recording all voluntary complaints of 
subjects and by assessment of the medical.  Attention will be directed to clinical adverse 
experiences associated with the prior hypercaloric dietary intervention, as well as any evidence 
of unexpected worsening of the underlying disease.  Laboratory surveillance tests will be 
obtained as outlined above.  
 
A serious adverse event is defined as an adverse event that meets any of the following criteria: 
 
• 
Results in death 
   
• 
Is life threatening: that is, poses an immediate risk of death as the event occurred 
This serious criterion applies if the study subject, in the view of the Site Investigator, is at 
substantial risk of dying from the AE as it occurs.  It does not apply if an AE 
hypothetically might have caused death if it were more severe. 
 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
Hospitalization for an elective procedure (including planned tracheostomy) or a routinely 
scheduled treatment is not an SAE by this criterion because a “procedure” or a 
“treatment” is not an untoward medical occurrence. 
 
• 
Results in persistent or significant disability or incapacity 
This serious criterion applies if the “disability” caused by the reported AE results in a 
substantial disruption of the subjects’ ability to carry out normal life functions. 
 
• 
Results in congenital anomaly or birth defect in the offspring of the subject 
(whether the subject is male or female)   
 
• 
Necessitates medical or surgical intervention to preclude permanent impairment 
of a body function or permanent damage to a body structure. 
 
An event is considered “life-threatening” if it places the subject, in the view of the Investigator, 
at immediate risk of death from the reaction as it occurred; i.e., it does not include a reaction that, 
had it occurred in a more severe form, might have caused death. 
 
Important medical events that may not result in death, are not life-threatening, or do not require 
hospitalization may also be considered SAEs when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent one 

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of the outcomes listed in this definition.  Examples of such medical events include blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
 
An inpatient hospital admission in the absence of a precipitating, treatment-emergent, clinical 
adverse event may meet criteria for "seriousness" but is not an adverse experience, and will 
therefore, not be considered an SAE.  An example of this would include a social admission 
(subject admitted for other reasons than medical, e.g., lives far from the hospital, has no place to 
sleep). 
 
An unexpected adverse event is any adverse event, the specificity or severity of which is not 
consistent with expected risks of the study intervention. 
 
All unexpected and related SAEs will be reported to the Partners IRB within 24 hours of being 
aware of the event.  Death due to progression of disease, as expected in ALS, will not be 
reported in an expedited manner except in cases where the outcome of death is deemed related to 
study treatment.  
 
There will be ongoing monitoring of non-serious Adverse Experiences.  All AEs will be 
summarized and reported to the Medical Monitor on a monthly basis. 
 
10.5.1  Evaluating and Recording of Adverse Events 
 
At each visit all adverse events that are observed, elicited by the Principal Investigator, or 
reported by the subject will be recorded in the appropriate section of the Adverse Event log, 
entered into the EDC and evaluated by the Principal Investigator. 
 
Adverse events will be categorized according to the MedDRA coding system.  This is a 
descriptive terminology, organized by body system and including specific criteria for grading 
severity of Adverse Events.  This system will allow study coordinators to quickly search for the 
most relevant term for each event and will give specific criteria governing the reporting of 
severity for each term.  With this system, the event will be coded at the site and subsequently 
checked by the Data Manager.   
 
Minimum information required for each AE includes type of event, duration (start and end 
dates), severity, seriousness, causality to study intervention, action taken, and outcome. 
 
The relationship of the AE to the study intervention should be specified by the Site Investigator, 
using the following definitions: 
1.  Not Related:  Concomitant illness, accident or event with no reasonable association 
with treatment. 
2.  Unlikely: The reaction has little or no temporal sequence from administration of the 
study intervention, and/or a more likely alternative etiology exists. 
3.  Possibly Related:  The reaction follows a reasonably temporal sequence from 
administration of the intervention and follows a known response pattern to the 
suspected intervention; the reaction could have been produced by the study 

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intervention or could have been produced by the volunteer’s clinical state or by 
other modes of therapy administered to the volunteer. 
4.  Probably Related:  The reaction follows a reasonable temporal sequence from 
administration of study intervention; is confirmed by discontinuation of the 
study intervention or by rechallenge; and cannot be reasonably explained by the 
known characteristics of the volunteer’s clinical state. 
5.  Definitely Related:  The reaction follows a reasonable temporal sequence from 
administration of study medication; that follows a known or expected response 
pattern to the study medication; and that is confirmed by improvement on 
stopping or reducing the dosage of the study medication, and reappearance of 
the reaction on repeated exposure. 
 
If discernible at the time of completing the AE log entry, a specific disease or syndrome rather 
than individual associated signs and symptoms should be identified by the Site Investigator and 
recorded on the AE log.  However, if an observed or reported sign, symptom, or clinically 
significant laboratory anomaly is not considered by the Site Investigator to be a component of a 
specific disease or syndrome, then it should be recorded as a separate AE on the AE log.  
Clinically significant laboratory abnormalities are those that are identified as such by the Site 
Investigator and/or those that require intervention. The only exception to this will be disease 
progression symptoms as previously noted.  
 
 
 

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11 HUMAN SUBJECTS 
 
11.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
The PI will obtain approval from the Partners Human Research Committee (HRC, or Partners 
IRB) of this protocol and consent form.  Signed consent will be obtained from each subject.  The 
consent form will describe the purpose of the study, the procedures to be followed, and the risks 
and benefits of participation.  A copy of the consent form will be given to the subject, and this 
will be documented. 
 
The PI and all key personnel involved in the study will have completed the Collaborative IRB 
training initiative, a mandatory tutorial on the responsible conduct of human subject research, or 
will have completed a comparable, institution-approved tutorial regarding the protection of 
human subjects.  An independent Medical Monitor will review the study data for safety 
concerns.  The PI will be responsible to report adverse events experienced by study subjects to 
the MGH IRB, the Medical Monitor, and if requested the study sponsor.   
 
11.2 
Subject Confidentiality 
 
Confidentiality will be maintained, as all subject research data will be coded with GUID number 
and initials.  Blood samples for research will be de-identified and labeled using the GUID, prior 
to storage.  Participant files will be kept in a secure, double-locked area.  The electronic database 
used during the trial will be secure.  To date no breach of our security barriers has occurred, and 
we actively maintain a high level of security to assess the confidentiality of our databases.  Only 
key personnel in this proposal will have access to the data and the codes.  Subject results will 
never be discussed in any form in the presence of other subjects in the study or with non-
laboratory personnel.  A subject will be referred to by his/her GUID number only.  The PI, 
Steering Committee, and independent Medical Monitor will monitor privacy and confidentiality 
throughout the study.   
 
11.3  Inclusion of Women 
 
The gender distribution for subjects with sporadic ALS is approximately 60% male and 40% 
female.  The MGH patient population includes 53% men and 47% women.  The gender 
distribution for PD is approximately 66% to 33% while the gender distribution in HD is 50% to 
50%.  Dr. Wills’ own clinic population is approximately 60% female.  The study goal is to 
recruit men and women with ALS, PD and HD in an approximately equal ratio.  Advertising the 
study with several disease foundations and patient support groups will aid in the recruitment 
process and, in particular, with the recruitment of female subjects.  
 
 
11.4 
Inclusion of Minorities  
 
Potential study subjects will not be excluded from this study for reasons of race or gender and 
efforts will be made to enroll in representative numbers with respect to both gender and race.  In 
particular, no racial discrimination will be made in subject enrollment.  The participation of 
minority subjects will be actively encouraged throughout the study.   

Pr ot oc ol : Electr o nic -he alt h A p plic ati o n T o Me as ure O utc o mes R E m otely ( E A T M O R E) Cli nic al Tri al  
Versi o n Date: 0 3. 1 0. 2 0 1 6  
Cli nical St u d y Pr ot oc ol Versi o n 3 . 0 
 
C O N FI D E N TI A L I N F O R M A TI O N  
3 9  
 
1 1. 5 
St u d y M o dific ati o n/ Disc o nti n u ati o n  
 
T he st u d y ma y b e m o difie d or disc o nti n ue d at a n y ti me b y t he I R B ( or H u ma n Researc h 
C o m m ittee), t he st u d y s p o ns or, t he Office f or H u ma n Researc h Pr otecti o ns ( O H R P), or ot her 
g o ver n me nt a ge n cies as part of t heir d uties t o e ns ure t hat s u bjects are pr ot ecte d.  
 
1 2    P U B LI C A TI O N O F R E S E A R C H FI N DI N G S  
 
Dr. Wills will be res p o nsi ble f or p u blicati o ns of res ults fr o m t his trial  a n d will c o m pl y wit h 
NI N D S g ui deli nes o n p u blicati o n of NI H f u n d e d cli nical trials.  Her  res p o nsi bilities will i ncl u de 
t he f oll o wi n g: 
  A nal yze a n d i nter pr et dat a gat here d i n t his st u d y, a n d write p u blicati o ns fr o m t hese data. 
  S u b mit ma n uscri pts t o selecte d j o ur nals a n d a d dress peer re vie wers’ c o m m e nts. 
 S u b mit a bstracts t o selecte d meeti n gs a n d prese nt data at t he meeti n gs.  
 Deter mi ne a ut h ors hi p o n t he basis of t he U nif or m Re q uire me nts f or Ma n us cri pts 
S u b mitte d t o Bi o me dical J o ur nals (I nter n ati o nal C o m mittee of Me dical J o ur nal 
E dit ors, 1 9 9 7).  
 
 

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