Acute Effects of Medium Chain Triglyceride (MCT) Nutritional Ketosis on Parkinson s Disease (PD) Symptoms and Biomarkers (MCT-PD)
Phase: PHASE1
Conditions: Parkinson's Disease
Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)

The attached includes: 
 
Protocol:  Acute effects of medium chain triglyceride (MCT) nutritional ketosis on Parkinson’s 
Disease (PD) symptoms and biomarkers (MCT-PD) 
• Statistical Plan included within the protocol 
 
NCT04584346 
 
Document Date:  4.19.2021 

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Abbreviated Title: Feasibility and efficacy of ketogenic diet in Parkinson’s Disease  
Version Date: 04/19/2021 
 
Protocol version date 04/19/2021 
 
Abbreviated Title:  Feasibility and efficacy of ketogenic diet in Parkinson’s Disease  
Protocol: 20N0153 
Version Date: 04/19/2021 
Title: Acute effects of medium chain triglyceride (MCT) nutritional ketosis on Parkinson’s Disease (PD) 
symptoms and biomarkers (MCT-PD) 
 
 
 
NIH Principal Investigator: 
 
 
 
 
Debra Ehrlich, MD 
Human Motor Control Section, Medical Neurology Branch 
National Institute of Neurological Disorders and Stroke 
Building 10, Rm 7D57 
10 Center Drive 
Bethesda, MD 20892-1428 
Phone: 301-496-9526 
Fax: 301-480-2286 
E-mail: debra.ehrlich@nih.gov 
 
Investigational Agents  
Drug Name: 
Medium Chain Triglycerides oil 
IND Number: 
Enforcement discretion 
Sponsor: 
N.A. 
Manufacturer: 
Liquigen® (KetoCal)   
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Abbreviated Title: Feasibility and efficacy of ketogenic diet in Parkinson’s Disease  
Version Date: 04/19/2021 
 
Protocol version date 04/19/2021 
 
TABLE OF CONTENTS  
 
TABLE OF CONTENTS 
2-4 
STATEMENT OF COMPLIANCE 
5 
1 
PROTOCOL SUMMARY 
6 
1.1 
Synopsis 
6-7 
1.2 
Schema 
8 
1.3 
Schedule of Activities (SOA) 
9-12 
2 
INTRODUCTION 
13 
2.1 
Study Rationale 
13-17 
2.2 
Background 
17-18 
2.3 
Risk/Benefit Assessment 
18 
2.3.1 Known Potential Risks 
18-20 
2.3.2 Known Potential Benefits 
21 
2.3.3 Assessment of Potential Risks and Benefits 
22 
3 
OBJECTIVES AND ENDPOINTS 
23-24 
4 
STUDY DESIGN 
25 
4.1 
Overall Design 
25-33 
4.2 
Scientific Rationale for Study Design 
34-36 
4.3 
Justification for Dose 
36-37 
5 
STUDY POPULATION 
37 
5.1 
Inclusion Criteria 
37 
5.2 
Exclusion Criteria 
37 
5.3 
Inclusion of Vulnerable Participants 
38 
5.4 
Lifestyle Considerations 
38 
5.5 
Screen Failures 
38 
5.6 
Strategies for Recruitment and Retention 
38-39 
5.6.1 Costs 
 
39 
5.6.2 Compensation 
40 
6 
STUDY INTERVENTION 
40 
6.1 
Study Interventions(s) Administration 
40 
6.1.1 Study Intervention Description 
40-43 
6.1.2 Dosing and Administration 
43 
6.2 
Preparation/Handling/Storage/Accountability 
43 
6.2.1 Acquisition and Accountability 
43 
6.2.2 Formulation, Appearance, Packaging, and Labeling 
43 
6.2.3 Product Storage and Stability 
44 
6.2.4 Preparation 
44 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
44 
6.4 
Study Intervention Compliance 
45 
6.5 
Concomitant Therapy 
46 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
46 
7.1 
Discontinuation of Study Intervention 
46 
7.2 
Participant Discontinuation/Withdrawal from the Study 
47 
7.3 
Lost to Follow-up 
47 
8 
STUDY ASSESSMENTS AND PROCEDURES 
47 
8.1 
Screening Procedures 
47 

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8.2 
Efficacy Assessments 
48 
8.2.1 Clinical Evaluations 
49-50 
 
 
8.2.2 Biospecimen Evaluations 
50 
8.2.3 Correlative Studies for Research/Pharmacokinetic Studies 
50 
8.2.4 Samples for Genetic/Genomic Analysis 
51 
8.3 
Safety and Other Assessments 
52-53 
8.4 
Adverse Events and Serious Adverse Events 
53 
8.4.1 Definition of Adverse Event 
53 
8.4.2 Definition of Serious Adverse Events (SAE) 
53 
8.4.3 Classification of an Adverse Event 
54 
8.4.4 Time Period and Frequency for Event Assessment and Follow-Up 
54 
8.4.5 Adverse Event Reporting 
55 
8.4.6 Serious Adverse Event Reporting 
55 
8.4.7 Events of Special Interest 
55 
8.4.8 Reporting of Pregnancy 
55 
8.5 
Unanticipated Problems 
55 
8.5.1 Definition of Unanticipated Problems (UP) 
55 
8.5.2 Unanticipated Problem Reporting 
56 
8.5.3 NIH Intramural IRB Reporting of IND Safety Reports 
56 
9 
STATISTICAL CONSIDERATIONS 
56 
9.1 
Statistical Hypothesis 
56-57 
9.2 
Sample Size Determination 
57-58
 
Populations for Analyses 
58 
9.3.1 Evaluable for toxicity 
58 
9.3.2 Evaluable for objective response 
58 
9.3.3 Evaluable Non-Target Disease Response 
58 
9.4 
Statistical Analyses 
58 
9.4.1 Analysis of the Primary Endpoint 
58 
9.4.2 Analysis of the Secondary Endpoints 
58 
9.4.3 Analysis of the Exploratory Endpoint(s) 
58 
9.4.4 Safety Analyses 
59 
9.4.5 Baseline Descriptive Statistics 
59 
9.4.6 Planned Interim Analyses 
59 
9.4.7 Sub-Group Analyses 
59 
9.4.8 Tabulation of individual Participant Data 
59 
10 
REGULATORY AND OPERATIONAL CONSIDERATIONS 
59 
10.1 
Informed Consent Process 
59 
10.1.1 
Consent/Assent Procedures and Documentation 
59 
10.1.2 
Consent for minors when they reach the age of majority 
59 
10.1.3 
Telephone consent 
60 
10.1.4 
Telephone assent 
60 
10.1.5 
Participation of Subjects who are/become Decisionally Impaired 
60 
10.2 
Study Discontinuation and Closure 
60 
10.3 
Confidentiality and Privacy 
60 
10.4 
Future use of Stored Specimens and Data 
61 
10.5 
Safety Oversight 
61 
10.6 
Clinical Monitoring 
61 

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10.7 
Quality Assurance and Quality Control 
61 
10.8 
Data Handling and Record Keeping 
61 
10.8.1 
Data Collection and Management Responsibilities 
61 
10.8.2 
Study Records Retention 
62 
10.9 
Protocol Deviations 
62 
10.9.1 
NIH Definition of Protocol Deviation 
62 
10.10 
Publication and Data Sharing Policy 
62 
10.10.1 
Human Data Sharing Plan 
62 
10.10.2 
Genomic Data Sharing Plan 
62 
10.11 
Collaborative Agreements 
62 
10.11.1 
Agreement Type 
63 
10.12 
Conflict of Interest Policy 
63 
11 
ABBREVIATIONS 
63-64 
12 
REFERENCES 
65-71 
 

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Abbreviated Title: Feasibility and efficacy of ketogenic diet in Parkinson’s Disease  
 
Version Date: 04/19/2021 
Protocol version date 04/19/2021 
 
 
 
 
STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP) and the following:  
● United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 
46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible 
for the conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects 
Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled.  Any amendment to the 
protocol will require review and approval by the IRB before the changes are implemented to the study.  In 
addition, all changes to the consent form will be IRB-approved; a determination will be made regarding 
whether a new consent needs to be obtained from participants who provided consent, using a previously 
approved consent form. 

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Abbreviated Title: Feasibility and efficacy of ketogenic diet in Parkinson’s Disease  
 
Version Date: 04/19/2021 
Protocol version date 04/19/2021 
 
 
1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
Title: 
Acute effects of medium chain triglyceride (MCT) nutritional ketosis on 
Parkinson’s Disease (PD) symptoms and biomarkers (MCT-PD) 
 
Study Description: 
While three pilot studies of ketogenic diet (KD) in PD have shown either 
reduction in motor scores (UPDRS) or improved memory/fluency cognitive 
testing, there are gaps in knowledge of the time course and mechanisms of 
reported outcomes.  Furthermore, only a standard ketogenic diet was 
studied while there are variations such as MCT oil supplementation shown 
to increase keto-induction, and other adaptations may improve tolerability 
and micronutrient content. It is the goal of this proposed inpatient metabolic 
study to address the initial question of effect size and time course of 
ketosis. If suggestive of benefit in PD, this pilot study may lead to a 
subsequent larger study of long-term feasibility and effects on disease 
biomarkers and disease progression, which might also compare alternate 
diets of interest in PD such as Mediterranean diet. Thus, a pilot feasibility 
study is proposed, targeting retention rate >80% and adherence in the 
outpatient setting. Recruitment of 32 participants is based upon power 
analysis of secondary outcome, testing the Timed Up & Go mobility test 
that has reported validity in fall prediction, additionally plotting continuous 
and serially repeated direct/indirect ketosis measurements and motor as 
well as non-motor symptoms / exploratory disease biomarkers. It is 
hypothesized that, compared to a non-ketogenic, standard American diet 
(SAD, also referred to interchangeably as usual diet, see Section 2.1 table 
for description), ketogenic diet supplemented by MCT oil (MCT-KD) will 
improve mobility tested by Timed Up & Go (TUG), as well as akinesia, 
tremor, and memory/executive function tasks, and will reduce motor and 
non-motor fluctuations within the acute period of keto-induction and early 
ketogenic timepoints due to improved mitochondrial function and 
neurotransmitter signaling.    
 
Objectives: 
 
The primary objective is to test the hypothesis that nutritional ketosis (NK) 
supplemented by MCT oil in a PD cohort (MCT-KD) is feasible for a 
duration of three weeks. The secondary objective is to show that NK 
improves PD symptomatology in cognition (improved attention, recall, and 
executive function), mobility (TUG), and motor function (bradykinesia, 
akinesia and tremor) within three weeks.  
 
 
 
 
 
Outcomes: 
The primary outcome is feasibility, as determined by a composite outcome 
of recruitment and retention, acceptability and adherence, including full 
recruitment to study target of 32 participants; completion rate >80% in both 
inpatient 1-week and outpatient 2-week segments; adherence in the 
outpatient segment of estimated low carbohydrate diet <10% mean total 

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Abbreviated Title: Feasibility and efficacy of ketogenic diet in Parkinson’s Disease  
 
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daily energy defined as net carbs); and acceptability defined via exit survey 
(week 3) 4-point Likert efficacy and likelihood scales on how effective 
ketogenic diet appears on symptoms and how likely ketogenic diet, with or 
without MCT oil, participants estimate they will continue the diet on at 
least an intermittent basis in the future.   
 
The secondary outcome is Timed up & go (TUG) mean difference between 
groups at the end of admission (day 7). 
 
Exploratory outcomes include both group comparisons (mean difference) at 
day 7 and repeated measures days 1-7 between MCT-KD and SAD groups 
(in most but not all outcomes; refer to section 1.3 Schedule of Activities for 
details) and at week 3, when both groups combine to a single ketogenic diet 
group, and within-group pre vs. post intervention comparisons at 1 & 3 
weeks for both groups separately (SAD at 0 & 2 weeks of ketogenic diet vs. 
MCT-KD group at 1 & 3 weeks, respectively) and all participants, in the 
following: Stroop word-color interference latency (executive function), n-
back recall task (attention and working memory), finger tap speed and 
rhythm (MN and PQ keyboard tasks), accelerometry amplitude for tremor 
analysis; 9-hole pegboard test (9-HPT) (daily), heart rate variability HF 
power, total power (resting, daily), cardiovagal testing via deep breathing 
and Valsalva Maneuver (pre vs. post), mean subjective on vs. off time (pre 
vs. post), non-motor severity score (NMSS) pre vs. post, keto-induction 
symptoms, UPDRS (pre vs. post), EEG spectral power by frequency and 
connectivity analysis (day 1 vs. day 7 vs. week 3), Geriatric Depression 
Scale (GDS, pre vs. post) 
 
Study Population: 
Idiopathic Parkinson's Disease of moderate severity, Hoehn & Yahr Stage 
2-4, age >50, usual (carbohydrate predominant) diet at baseline. A total of 
32 PD patients will be recruited predominantly from the Parkinson’s Clinic 
at NIH and local sites given necessity of three visits to facilitate 
randomization and baseline data acquisition. Recruitment will continue as 
per power analysis for Timed Up & Go (TUG). 
 
Phase: 
1 
Description of 
Sites/Facilities 
Enrolling Participants: 
Enrollment will occur at Screening Visit, NIH Clinical Center Outpatient 
Clinic 5 (OP5). Admission will occur at NIH Clinical Center Metabolic 
Unit, 7SW. 
 
Description of Study 
Intervention: 
The study intervention is randomization to MCT-KD (ketogenic diet with 
80% energy from lipids including Liquigen® (KetoCal) comprising 25% of 
the daily lipid energy divided twice daily or typical, standard American diet 
(SAD) x 6 days, followed by 2 weeks ketogenic diet in both groups at 
home. The proposed diets are isocaloric and have the same ratio of protein 
(10-15% daily energy) with similar mealtime boluses to limit differences in 
L-DOPA absorption. Daily activity and exercise plans will be 
individualized upon admission including use of stationary bike, aiming to 
maintain baseline levels. Diet with MCT oil will begin on hospital day 2 

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Abbreviated Title: Feasibility and efficacy of ketogenic diet in Parkinson’s Disease  
 
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and be provided to both groups at outpatient day 1 Both diets will be 
double-blinded (combination of shakes and similar appearing snacks). 
MCT-KD will feature reduced carbohydrate intake of 5-10% daily energy 
requirement calculated in the Metabolic Unit. Safety monitoring will be 
performed by IMM. 
 
 
Study Duration: 
9 months 
Participant Duration: 
3 weeks 
 
 
 
1.2 
SCHEMA 
 
 
 
Visit 1:  
Timepoint 0 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
Visit 2: 
 
 
 
 
 
 
 
 
Visit 3: 
Screening / Enrollment Visit (#1). determine eligibility, provide informed consent and 
enroll, obtain medical history, fill out PDQ39, NMSS,  examination, UPDRS, MOCA, 
TUG, baseline labs, calculate energy expenditure,  
Arm B (Usual 
Diet) N=16 total 
 
Arm A 
(Ketogenic 
Diet) N=16 total 
 
Stratified Randomization, 2 covariates: 
Age >=65, <65;  Baseline TUG >=11.5s, <11.5s 
 
Instruct participants to collect baseline data at home: 1 week diet, exercise, and ON/OFF 
PD symptoms daily worksheets 
Outpatient assessment at 2 
weeks post-discharge, final 
study measurements (week 3) 
refer to Section 1.3 
Follow-up assessments of study endpoints and safety by unblinded PI / IMM 
(Refer to Sections 1.3 dand 10.5) 
Hospital Day in Metabolic Unit 
 
 1                 2                  3                  4                     5                     6                      7 
Perform baseline study measurements: metabolic labs, CGM*, RQ**, TUG, physiology, 
cognitive, EEG tests.    Start diet intervention on day 2 
*Continuous Glucose monitor 
 
Ketogenic Diet  
(suggested 
meals plan)  
 
Outpatient meal plans and tracking x 
2 weeks via 2x/week 24-hour review  

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1.3 
 SCHEDULE OF ACTIVITIES (SOA) 
 
Procedures 
Screening/ 
enrollment 
* 
Day 
1 (pre-
intervention
) 
Day 2 
(diet 
started) 
D 
3  
D 4  
D 5  
D 6 
D 7 
W 3 
(post) 
Fill out intake form and 
determine eligibility 
X 
 
 
 
 
 
 
 
 
Pregnancy test** 
X 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Randomization to 
Ketogenic Diet or Usual 
Diet group, stratified 2-
factor covariate 
X 
 
 
 
 
 
 
 
 
anthropomorphic 
measures (height, 
weight, abdominal 
circumference) 
X 
  
  
  
  
  
  
X 
X 
Vital signs, including 
orthostatic (exploratory 
outcome) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
History and Physical 
Exam 
X 
 X 
  
  
  
  
  
 
 
Focused Neurologic 
Exam 
X 
X 
 
 
 
 
 
 
X 
Bioelectric Impedance 
(BIA) 
X 
 
 
 
 
 
 
 
X 
MOCA 
X 
  
  
  
  
  
  
  
 
Screening BMP (to 
establish eGFR), hepatic 
panel, lipid panel, A1C, 
beta-HCG if female < 
age 60 
X 
  
  
  
  
  
  
  
 

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Procedures 
Screening  
 
Day 
1 
Day 2 
Da
y 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 / 
Post 
W 3 
(post) 
UPDRS part 3  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Total UPDRS 
X 
 
 
 
 
 
 
 
X 
Hoehn & Yahr Stage 
X 
  
  
  
  
  
  
  
 
Electrocardiogram 
(ECG) 
X* 
*(If ECG 
service is 
unable 
during 
screening, 
may be 
performed 
on Day 1 
prior to 
initation of 
diet) 
 
 
 
 
 
 
 
metabolic labs (A1c, 
insulin, CRP, 
apolipoprotein panel, 
HOMA-IR, cortisol, 
TSH, T3, free T4), 
BDNF (exploratory 
outcome), lipid panel 
(day 7, week 3), A1c 
(week 3 only) 
 
 X 
  
  
  
  
  
X 
X 
Non Motor Severity 
Scale (NMSS) 
(exploratory outcome) 
X 
  
  
  
  
  
  
 
X 
PDQ-39 questionnaire 
(exploratory outcome) 
X 
  
  
  
  
  
  
 
X 
Resting heart rate 
variability (2-10 min) 
  
X 
 X 
 X 
X 
 X 
X 
X 
X 

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Abbreviated Title: Tolerability and efficacy of ketogenic diet in Parkinson’s Disease  
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(exploratory outcome) 
Procedures 
Screening  
 
Day 
1 
Day 2 
Da
y 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 / 
Post 
W 3 
(post) 
Cardiovagal testing – 
Valsalva maneuver, 
deep breathing 
(exploratory outcome) 
 
X 
 
 
 
 
 
X 
X 
Timed up and Go 
(TUG) AM fasting 
(secondary outcome) 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
Simple reaction time 
(SRT) daily 
(exploratory outcome)  
  
X 
X 
X 
X 
X 
X 
X 
X 
9-hole pegboard test (9-
HPT) daily  (exploratory 
outcome) 
  
X 
X 
X 
X 
X 
X 
X 
X 
daily journal of 
ON/OFF and keto-
induction symptoms, 
(Likert scales) and 
mood (exploratory 
outcome) 
  
X 
X 
X 
X 
X 
X 
X 
X 
EEG spectral analysis 
and connectivity 
analysis (phase lag 
index) days 1, 7 
(exploratory outcome) 
  
X 
 
 
 
 
 
X 
X 
Respiratory Metabolic 
Cart quotient (pCO2, 
:pO2) for restingand 
energy expenditure 
 X 
 
 
 
 
 
 
 
 
X 
BMP, magnesium 
 
X 
 
X 
X 
X 
X 
*** 
 

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POG glc checks 
 
X 
X 
X 
X 
X 
X 
X 
 
Beta-OHB level twice 
daily, except once on 
day 7**** 
 
X 
X 
X 
X 
X 
X 
X 
X***
* 
Procedures 
Screening  
 
Day 
1 
Day 2 
Da
y 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 / 
Post 
W 3 
(post) 
Plasma dopamine twice 
daily 
 
X 
X 
X 
 
 
 
 
 
Continuous glucose 
monitoring (Precision 
Libre Pro) 
 
X 
X 
X 
X 
X 
X 
X 
 
n-back working memory 
test daily (exploratory 
outcome) 
  
X 
X 
X 
X 
X 
X 
X 
X 
Stroop word color 
interference test daily  
(exploratory outcome) 
  
X 
X 
X 
X 
X 
X 
X 
X 
MN and PQ keyboard 
tasks 
 
X 
X 
X 
X 
X 
X 
X 
X 
Safety monitor 
(telephone interview) 
survey 2-4 weeks post-
study completion 
 
 
 
 
 
 
 
 
X 
Depression screening 
tool: Geriatric 
Depression Scale (GDS) 
X 
 
 
 
 
 
 
X 
 
X 
Gastrointestinal motility 
/ symptoms diary (daily 
days 1-7)  
 
X 
X 
X 
X 
X 
X 
X 
 

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Gastrointestinal 
Symptom Rating Scale 
X 
X 
 
 
 
 
 
X 
X 
Exit Survey 
acceptability of 
ketogenic diet  
 
 
 
 
 
 
 
 
X 
Tracking diet via 
unscheduled calls***** 
X 
 
 
 
 
 
 
 
X 
*No Day 0 (7 days of 
baseline diet and 
history, then Day 1 is 
first day of admission)  
**women of 
childbearing potential 
***repeat BMP and 
magnesium on days 6 
and 7 if abnormal in 
prior days 
****check beta-OHB in 
fasted state at week 3 
visit  
***** To occur during 
week between screening 
visit/enrollment and day 
1 of admission and 
during 2 weeks after day 
7. See Section 4.1 for 
details. 
 
 
 
 
 
 
 
 
 
 
 

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2 
 INTRODUCTION 
2.1      STUDY RATIONALE 
Three pilot studies of evaluating use of the traditional ketogenic diet in PD have been reported. They 
showed either reduction in UPDRS, particularly non motor greater than motor scores (Van Itallie 2005, 
Phillips 2018), or improved cognition (Krikorian 2019). These studies all had limitations, in part related 
to pilot outpatient design, with gaps or deficiencies identified in the following: monitoring for adherence 
and reliability of the intervention; degree of ketosis attained; frequency of testing for ketosis; frequency of 
outcome assessment to obtain adequate signal : noise ratio with respect to biological fluctuations in the 
disease; reliability of UPDRS rating scale used as primary outcome for small cohort groups; lack of 
quantitative testing of cognitive and motor functions in the same cohort for comparison; lack of testing for 
disease mechanism engaged that might account for the proposed benefits. 
VanItallie et al reported results of an unblinded, at-home ketogenic diet for 28 days in terms of pre vs. 
post UPDRS scores of 5 individuals with PD (from 7 with 2 dropouts), 4/5 with Hoehn & Yahr stage 3, 
who had varying degrees of ketosis mostly high therapeutic range of beta-OHB levels reported (4.8 – 8.9 
mM) and one outlier range 1.13 – 1.56 mM). All five participants had decline in total UPDRS score, 
mostly (4/5 participants) being 21-46% from baseline.  There were clear study limitations of placebo 
effect in study lacking a control group; lack of rater blinding and placebo control; lack of reliable ketosis 
monitoring aside from infrequent (unreported frequency) serum betaOHB, whereas daily ketone 
measurement was only urine dipstick and therefore qualitative; lack of monitoring of the diet relying 
primarily upon self-report via telephone and intermittent patient visits to the dietician; limited study size, 
and strict 4:1 standard ketogenic diet regimen with 2 drop outs of 7 participants and additional 2/5 
remaining participants with reported dietary relapse.  
 
Phillips et al addressed some of these issues by comparing two randomized groups, a comparatively less 
stringent ketogenic diet vs. a low-fat diet prescribed by meal plans, each with approximately 18% protein 
and either 79% lipid / 3.7% net carb (KD) or 23% lipid / 59% net carb (low-fat diet), the latter also with 
greater dietary fiber, stratified by estimated daily energy expenditure, for longer duration (8 weeks) and 
checking for ketosis monitoring by daily (AM fasting) beta-OHB levels by a validated fingerstick ketone 
meter as well as monitoring adherence through daily ticking of meal plans that were outlined for the 
entire study period. However, this study also had some limitations including infrequent data capture and 
diet monitoring relying upon self-report, precluding correlative analysis between ketosis value and 
clinical rating scale (UPDRS) performed only pre vs. post intervention. Another possible limitation was  
mean beta OHB level being only 1.19 in the KD group, if greater degree of ketosis might be beneficial. 
 
Krikorian et al evaluated another less stringent ketogenic diet in a PD cohort with mild cognitive 
impairment (unlimited protein, <20g carb target), recognizing that impaired glucose tolerance / metabolic 
syndrome is a risk factor for higher comorbidity in PD than in the general population, and that the 
literature supports ketogenic diet as a therapy specifically for metabolic syndrome (Hyde et al, 2019). 
They similarly used pre vs. post intervention data capture of 8 weeks duration, assessing cognition as well 
as UPDRS, and the dietary manipulation of only carbohydrate may provide a more feasible approach with 
lower level of change required for participants, however even the less prescriptive guidelines were not 
exactly adhered to. They followed 10 subjects in KD group vs. 7 in low-fat group, however they reported 
low level ketosis (mean beta-OHB 0.31 mM by study end week 8) in the low carbohydrate group and 
mean carb daily intake of 36g (above 20g) in that group. Dietary monitoring was done by patients filling 
out three-day diaries in each study week. Interestingly, despite the low ketosis values they nonetheless 
found improvement in short-term memory and verbal fluency in the KD group compared to the high 

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Version Date: 04/19/2021 
 
Protocol version date 04/19/2021 
carbohydrate diet despite no motor differences on UPDRS-III or finger tapping speed, which raises the 
question of does ketosis matter for symptom improvement (whether cognitive or motor) in PD, as 
opposed to effects of lipid, carbohydrate or protein metabolism, such as improved insulin sensitivity / 
insulin brain signaling and increased BDNF expression, benefits attributed to ketogenic diet (please refer 
to Section 3.2.1 for details) but not specific to it. The question of macronutrient ratio contribution to the 
cognitive benefit in the study was not tested, and such comparison was not available given that all three 
macronutrient groups varied proportionally between the two groups. For instance, mean protein intake, 
which was not controlled, was higher in the low carbohydrate group (123 g vs. 89 g in the high 
carbohydrate group). Lack of controlling for protein intake appears to be a confounding issue for 
Parkinson’s studies given the results confirmed in multiple studies of levodopa absorption being affected 
by food intake, for instance large neutral amino acid L-leucine decreased intestinal absorption of 
levodopa by ~50% in healthy subjects (Lennernäs et al, 1993), which is meaningful particularly in 
moderate to advanced PD where dopamine-responsive fluctuations occur coupled with the 
pharmacokinetics of levodopa concentrations, and a single load of 0.4 g protein / kg body weight 
diminished response of levodopa in PD patients with motor fluctuations (Mena and Cotzias 1975; Nutt et 
al 1984; Juncus et al 1987; Pincus and Barry 1987).  
 
 
These limitations form the primary impetus behind the current study. The inpatient design is well suited 
for a pilot feasibility study, as it offers advantages in providing optimal adherence monitoring and 
generation of a time series through frequent ketosis values compared to symptom monitoring including 
repeated clinical, physiology, and cognitive tests that would be more difficult or simply not feasible in the 
outpatient setting. The overall goal is to test metabolic measures of a standard ketogenic diet with MCT 
oil supplement in an effort to improve upon feasibility issues identified in the other studies. A corollary 
objective is to test the effects of ketosis on symptom measures by comparing MCT-KD to a standard, 
American diet. The following table outlines macronutrient composition of diets proposed for study 
(italicized) and other diets with available data on ketogenesis or use in PD. While the proposed KD 
matches others such as Phillips et al in proportion of energy supply from lipids of around 80%, the 
addition of MCT supplement to replace a portion of the 80% lipids may be a useful adaptation, similar to 
a study in healthy volunteers that showed more rapid keto-induction and less keto-induction symptoms 
(Harvey et al, 2019) in order to better and more expeditiously achieve the primary objective of ketosis 
feasibility. 
 
Table 1 – macronutrient ratios of different diets used in clinical research for PD / other neurologic 
disorders 
 
Modified 
MD-KD 
(MMKD) 
 MCT diet 
 KD* 
SAD 
(high 
carb 
diet) 
MD 
LFD, aka 
AHAD 
Lipid 
60-70% 
45-70% 
80% 
30-40% 
45-50% 
15-20% (<7% 
saturated, 
<300mg 
cholesterol daily) 
Protein 
25-30% 
10-20% 
10-15% 
15% 
15-20% 
20-30% 

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Net Carb 
5-10%, max 
30 g  
10-35% 
5-10% 
45-55% 
30-40% 
55-65% 
Comment 
Studied 12 
weeks in 
obesity 
(Perez-
Guisado et al 
2008); in 
MCI/CN/SM
C (Neth et al 
2020) 
Improved 
compliance in 
pediatric epilepsy 
(Liu et al 2008)  
Studied in PD 
VanItallie et al 
2005; Phillips et al 
2018; in 
obesity/MetSx 
(Hyde et al, 2019); 
8 weeks in PD-
MCI Krikorian et 
al 2019 
As 
defined 
by 
Stephen 
Phinney; 
studied 
by 
Krikoria
n et al, 
2019 
Widely 
considered to be 
rich in 
vitamins/mineral, 
less risk of 
deficiencies 
Studied as 
control group in 
Phillips et al 
2018; Neth et al 
2020). AHA 
Guidelines: rich 
in fruit/vegetable, 
whole grains, fish 
2+ meals/ week, 
minimize added 
sugars,  
Ketosis 
values 
Mean 0.31 
mM 
(Krikorian 
MCI cohort) 
0.7 mM (Neth 
et al – 1.0 
mM in SMC 
vs 0.4 mM in 
MCI) 
Mean increase 
beta-OHB by 0.7 
mM by study day 
8-9 of 20 
randomized 30mL 
TID MCT vs. 
LCT, sunflower oil 
(Harvey et al, 
2019) 
Mean AM fasting 
betaOHB 1.15 mM 
vs. 0.16 mM in 
LFD (Phillips et al, 
2018) 
0 to 0.2 
mM 
(daily 
fasted 
state) 
No data found 
0 to 0.2 mM 
(daily fasted 
state) 
Glucose / 
other 
ancillary 
data 
Glucose 
decrease by 
16 mg/dL 
(109 to 93) 
Perez-
Guisado 
2008; 
decrease TG 
(-23 mg/dL) 
and VLDL (-
4.6 mg/dL) 
increase LDL 
17 mg/DL; 
body weight 
loss greater 
than AHAD 
(Neth et al) 
 
In cohort with 
MetSx x 4 wks: 
Reduction of 
glucose -10 
mg/dL, TG -60 
mg/dL, dense 
LDL, plasma total 
saturated fat, 
increased HDL (+4 
mg/dL), 
arachidonate 
compared to 
medium-carb and 
high carb diets 
(Hyde et al, 2019) 
Increased HDL, 
LDL, no difference 
TG compared to 
LFD (Phillips et al, 
2018). HbA1c 
trend not 
statistically 
significant. 
 
Reduced risk of 
prodromal PD in 
a populational 
cohort in Greece 
(Maraki 2019); 
consistently 
reduced LDL, 
central obesity 
and Met Sx 
(Babio et al 2014 
PREDIMED 
trial); many 
studies with 
reduced CV risk  
reduced 
mortality (Bo et 
al 2016) 
In 20 HV: No 
change in LDL, 
HDL, TG in 4 
mo. crossover 
study compared 
to decline in LDL 
& TG and 
increase in HDL 
after 4 mo. 
Paleolithic diet 
(40% lipid, 23% 
carb, 37% protein 
-- no dairy, 
grains, legumes, 
daily: <1/2 cup 
potato, <1oz 
dried fruit, <4oz 
wine daily, 
unlimited eggs) 
(Pastore et al, 
2015) 
Keto-
induction 
symptom
s / side 
effects 
Attrition rate 
22.5% (Perez-
Guisado), 
10% Neth et 
al and Nagpal 
et al for 
MMKD vs. 
5% for 
Shortened keto-
induction (0.5 
mM) from day 5 to 
day 3, vs LCT 
(sunflower) oil; 
decrease overall 
keto-induction 
symptoms but 
Attrition rate 28% 
VanItallie et al, 
18% Phillips et al 
(9% attributed to 
diet). No major 
adverse event. 
Initial symptoms 
of increased 
 
 
 

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AHAD. No 
adverse event 
occurred in 
any study. 
increased GI 
symptoms; 
reduced incidence 
kidney stones, 
hypoglycemia, 
ketoacidosis, 
constipation in 
pediatric epilepsy 
cohort (Liu et al, 
2006) 
tremor/rigidity 
irritability, hunger, 
thirst were self-
reported at higher 
frequency in KD 
weeks 1-4. All sx’s 
normalized in 
weeks 5-8 
compared to LFD 
aside from 
excessive thirst 
(5/22).   
*While ketogenic diet macronutrient ratios vary between studies, the targets are similar to those used in prior KD study in PD, 
Phillips et al, presumably better tolerated than strict 4:1 KD, and is proposed for the current ketogenic diet study. 
 
Despite the limitations of low subject numbers and infrequent data capture, these previous trials of 
nutritional ketosis in Parkinson’s suggest motor, cognitive and non-motor symptom benefit, particularly 
in symptoms including fatigue, depression, and urinary frequency, in comparison to high carbohydrate, 
low fat diets even at moderate reported ketosis values of 0.3-1.0 mM. The mechanisms and specific 
biomarkers of PD impacted by ketogenesis have not yet been defined, nor the time course of any effects. 
Furthermore, adherence as well as side effects related to micronutrient deficiency or extreme skew of 
macronutrient composition towards lipids remain barriers to wider adoption of studying ketogenic diet for 
treating PD. MCT ketogenic diet (MCT-KD) may require less stringent carbohydrate restriction and fewer 
micronutrient supplements than classic KD; may improve tolerability (Liu 2008); and has been shown to 
augment mean levels of ketosis in healthy volunteers (Harvey 2018). MCT-KD remains unexplored in 
PD, particularly as synergistic therapy. In this clinical study, an inpatient pilot design is proposed to study 
the effects of a carbohydrate-restricted ketogenic diet supplemented by MCT oil nutritional ketosis vs a 
standard non-ketogenic, low fat diet (SAD), within the keto-induction period and shortly thereafter over 
one week, on brain network connectivity via EEG cortico-cortical connectivity and motor waveform 
characteristics, motor physiology and clinical scale (UPDRS), cognition, autonomic function (heart rate 
variability, orthostatic blood pressure) and symptoms of PD with fingerstick beta-OHB levels and 
respiratory exchange ratio (RER) in the Metabolic Unit +/- continuous glucose monitoring (CGM) to 
establish which, if any, PD symptoms may be modulated by ketogenic intervention in relation to 
suspected or likely metabolic pathways, to inform subsequent study into symptomatic benefit and/or 
disease modification. To better address the primary aim of diet feasibility, a two-week outpatient segment 
is proposed to assess more long-term effects of a similar ketogenic diet and further estimate adherence 
using an online, web-based application. 
 
2.2 Background 
 
Sporadic PD is clearly a complex, multifactorial disorder. Several lines of evidence converge on 
mitochondrial insufficiency as a key factor in the pathophysiology of sporadic PD. Mitochondrial electron 
transport chain genes are downregulated in PD and incidental Lewy Body Disease (iLBD) at post-
mortem, particularly those activated by transcription factor PGC1alpha (Zheng et al, 2010). Genetic forms 
of PD, LRRK2 and Parkin, involve constituents of endoplasmic reticulum (ER) homeostasis and are 
implicated in pathologic ER stress (oxidative stress and apoptosis) related to impaired ubiquitin-
proteasome function. Furthermore, upstream impaired mitochondrial cycling produces alpha-synuclein 
misfolding as by MPTP toxin, with further impaired mitophagy and autophagy from lysosomal 

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downregulation (Colla et al, 2019, Lehtonen et al, 2019). The reactive oxygen species and damaged 
protein, lipid and DNA are proposed as biomarkers of PD (He et al, 2018), but the disease mechanism 
involves impaired mitochondrial function. 
 
Modulation of cellular energetics has become increasingly used as a therapeutic tool (Kossoff and 
Hartman, 2012), and monitoring the metabolic effects can provide a biomarker of the therapy, controlling 
the degree of modulation. Originally studied in epilepsy, nutritional ketosis (NK) is increasingly being 
studied, and given positive results, adopted in neurodegenerative disease such as PD, Alzheimer’s 
Disease, and amyotrophic lateral sclerosis that involve oxidative stress, impaired cellular metabolism, and 
toxic species accumulation (Bosco et al, 2006; Nakabeppu et al, 2007). Furthermore, there is the 
activation of NLRP3 inflammasome in both human post-mortem and animal models of PD (Wang et al, 
2019). The primary physiologic ketone body, Beta-OHB, attenuates inflammasome activity in LPS 
treated mouse monocytes in vitro and mouse models of NLRP3-mediated disease (Youm et al, 2015).  
Apolipoprotein, the main protein constituent of high density lipoprotein, is found to be abnormal in PD, 
specifically the A1 type (ApoA1) is consistently reduced and c-reactive protein (CRP) elevated with 
changes found to be correlated with more severe disease in a large cohort (Oxford Discovery cohort,  
Lawton et al, 2020) and may also be elevated by ketogenic diet (Kwiterovich et al, 2003, Mooradian et al, 
2006).  Elevated CRP also was associated with worse motor prognosis in a separate PD cohort (Umemura 
et al, 2015).  Thus, the plasma markers ApoA1 and CRP may be useful as exploratory biomarkers that 
may show improvement from ketogenic diet.  The mechanism of action and timecourse of symptom 
reduction of NK in PD remain unclear, but has theoretical benefits to mitochondrial function and gene 
expression, as detailed below. 
 
Ketogenesis has several proposed benefits for Parkinson’s Disease in keeping with its established 
pleiotropic effects. There are proposed direct and indirect benefits (Veech et al, 2017). The mechanism of 
action and time course of symptom reduction of NK in PD remain speculative, although in vitro and 
animal models suggest a direct benefit of ketone bodies that parallels the fasting state in signaling cell 
survival and longevity. The primary mechanism for this is described as epigenetic modification by histone 
acetylation towards an open configuration, specifically by repressing histone deacetylase 1 (HDAC1) 
(Shimazu et al, 2013).. Accordingly, gene expression of peroxisome proliferator-activated receptor 
gamma coactivator 1-alpha (PGC1A) leads to increased mitochondrial biosynthesis, and expression of 
transcription factor forkhead box O-3 (FOXO3) generates nucleotide coenzyme / reducing agent 
dihydronicotinamide-adenine dinucleotide phosphate (NADPH). According with the fasting / ketogenic 
state there is also increase in supply of adenosine monophosphate kinase (AMPK), which inhibits 
mammalian target of rapamycin (mTOR) and thereby augments autophagy. Finally, specific to PD, 
ketogenic researchers such as Dr. Veech hypothesized that KD would lead to increased  neuron / astrocyte 
neurotransmitter storage and signaling from increase in mitochondrial efficiency, as ketone bodies bypass 
tricarboxylic acid (TCA) cycle complex I, which is especially deficient in PD post-mortem RNA study 
(Zheng et al,  2010), as well as increasing the redox span and free energy of ATP hydrolysis by oxidizing 
CoQ10 to ubiquinone and reducing NAD+ to NADH (Veech, 2004). Another effect seen as beneficial in 
neurodegenerative disease as well as epilepsy relates to increase in the efficiency of TCA cycle 
conversion of oxaloacetate to acetyl-CoA and export from mitochondria for gluconeogenesis, limiting 
precursor availability for aspartate and thereby increasing glutamate availability for conversion to GABA, 
which is consistent with reported elevated seizure threshold to current-induced seizure models in rats and 
elevated GABA in brain synaptosomes (Erecinska 1996); that same group also reported increases in 
GABA production from a glutamine precursor radiolabeling study of rats receiving beta-OHB, and CSF 
study of children with refractory epilepsy on the ketogenic diet (Dahlin et al 2005). Furthermore, paired-
pulse TMS study of healthy volunteers on ketogenic diet showed increased short intracortical inhibition 
(SICI), widely attributed to GABA-A signaling as well as increased central beta power on EEG (Cantello 

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et al, 2007). Of potential relevance to PD, GABA is one of several neurotransmitters with deficiency by 
selective neurodegeneration both in striatum and in other sites including nuclei regulating REM onset, 
preoptic nucleus and nucleus reticularis (Brooks and Peever, 2011), GABA myenteric neurons involved 
in peristalsis (Grider and Markhlouf, 1992), and smell regulation by olfactory interneurons (Pirez and 
Wachowiak 2008). GABA agonism may be therapeutic in PD as suggested by a study of zolpidem, a 
GABA-A agonist, in an early, unilateral untreated PD cohort showing increase in M1 beta from the 
unaffected side and a reduction in pathologic beta from the affected side (Hall et al 2014) as well as GAD 
AAV2 gene therapy in STN at 12 months showing stable, modest reduction in UPDRS-3 motor score and 
reduced motor fluctuations (Niethammer et al, 2017). Neuroimaging correlates of GABA signaling may 
offer a biomarker of PD and potential effect of ketogenic therapy, with hypothesis that KD exerts an 
attenuation of pathologic hyperactivation of pallidal efferents through striatal GABA signaling, as well as 
potentially attenuating pathologic calcium-related oxidative stress in dopaminergic /non-dopaminergic 
neurotransmitter synthesizing cell groups with high metabolic rate affected by Parkinson’s. 
 
There are also potential indirect benefits related to adaptive response to decreased insulin / insulin-like 
growth factor 1 (IIS) signaling leading to growth factor expression, viz. Brain derived neurotrophic factor 
(BDNF) and fibroblast growth factor 2 (FGF2), which are implicated in substantia nigra dopaminergic 
neuron synaptogenesis and survival (Mattson et al, 2018). Plasma BDNF has furthermore been suggested 
as a biomarker of PD (He 2018), shown to be decreased in PD with and without depression compared to 
control cohorts (Rahmani et al 2019), furthermore found to be increased in plasma of healthy volunteers  
following 4 weeks of KD (Gyorkos et al 2019), while evidence for FGF 2 / other family types in PD and 
modulation by ketogenic diet remains less clear. While the relation of BDNF to PD symptoms is not clear 
in the literature, it is found to be a biomarker of exercise and possibly of ketogenic diet as well, thus is 
proposed as a KD biomarker pre vs. post intervention in PD. 
 
Using MRS in healthy subjects, brain (occipital lobe) beta-OHB ketone values correlated well with 
plasma ketosis values (r = 0.86) with brain-plasma slope of 0.26 (Pan et al, 2000). Experimentally, the 
pathway of ketone body (primarily beta-OHB, but also acetoacetate) entry across BBB has been described 
via active transport (MCT1/MCT2) as well as diffusion.  Plasma ketone values will be therefore used as a 
proxy for brain values. 
 
Within the short-term, 3-week follow-up of the proposed study, there is not thought to be sufficient time 
adequately to test disease modification effects such as clearance of alpha-synuclein oligomers or 
inflammation. Nonetheless, a two-fold acute effect: i) augmentation of mitochondrial efficiency 
(immediate, within hours of producing brain ketosis) and ii) production of neurotransmitters including 
dopamine and GABA, together provide improved signaling via intact neurons within the frontostriatal 
network underlying predicted symptomatic benefit within three weeks, possibly within days of keto-
induction, compared to a non-ketogenic, standard diet. Mitochondrial efficiency and neurotransmitters 
will not be tested directly, but rather indirectly via effects on systems of study, the frontostriatal network 
via EEG and the parasympathetic system via heart rate variability. As exploratory measures of the study, 
hypothetical mechanism underlying symptom improvement as above will be tested via purported 
biomarkers of ketogenic diet – 1) EEG beta power in central regions implicated in motor control, and 2) 
BDNF levels and cardiovagal function – rater-blinded to ensure objective testing of this hypothesis. 
 
2.3 Risk/Benefit Assessment 
2.3.1 
Known Potential Risks 
a. Risks associated with MCT oil 

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There are no current studies of MCT oil in Parkinson’s population, however several studies have been 
reported for Alzheimer’s Disease (AD) participants at doses reported as percentage daily energy intake of 
10-40% (Reger et al 2004, Henderson et al 2009, Taylor et al 2018, Ota et al 2019)  which is similar to 
the proposed study. The achieved doses were somewhat tolerance limited to 60-80% of target doses.  
Side effects were more frequently diarrhea (50%), and in a larger study of 86 AD participants randomized 
to receive a proprietary blend of MCT powder / emulsifier based on a Stepan product  (product name AC-
1202) at dose of approximately 1 tbsp vs. 66 participants in placebo group, GI events were reported in 
49% of MCT group, diarrhea in 24% vs. GI events in 27% of placebo group, diarrhea in 14% (Henderson 
2009). However, the GI side effects in the MCT group were reduced substantially after change in the base 
of dosing from water, milk, or juice to an Ensure meal replacement drink. In a study of healthy volunteers 
comparing MCT oil-supplemented ketogenic diet to standard ketogenic diet, there were overall less 
ketoinduction symptoms by daily self-report, however a higher incidence of GI upset / nausea / diarrhea 
(Harvey et al, 2018). 
Reported lipid profile effects are variable, ranging from no effect to increase in lipoprotein levels. The 
variation may be due to either population studied, e.g. Alzheimer’s Dementia or Healthy Volunteer (HV), 
or dose. No statistically significant effect was found at a dose of 1.5-3 tbsp per day in a cohort of 15 
participants with AD at 3 months (Taylor 2018), whereas in a study of 18 HV participants, 11% increase 
in total cholesterol and 12% increase in LDL cholesterol was found at a dose of 70g (65mL, about 4.3 
tbsp) at 21 days (Tholstrup 2004). It is important to consider elevated lipoprotein levels in the context of 
glycation status, as small dense, glycated (apoliprotein type B) LDL particles have correlated robustly 
with cardiovascular events, whereas non-glycated (large, non-dense) LDL has not. Any adverse 
lipoprotein effect from a three week study exposure is expected to be less than the other studies 
mentioned to be negligible. 
The refined fatty acid caprylic acid (C8) from MCT oil meets GRAS FDA exemption, GRAS Reference 
(FEMA No.) 2799. 
 
b. Risks of ketogenic diet 
Risks of ketogenic diet have varied based on population, with above studies of ketogenesis involving 
MCT oil and other ketogenic diet studies in PD, AD, and HV groups reporting GI side effects (nausea, 
cramps, diarrhea, constipation) as being most common. There are also known effects of ketogenesis  
natriuresis that may relate to a general fatigue/malaise, headache, which have been altogether termed 
“keto-induction symptoms” or “keto-induction flu” that may relate in part to the dehydration as well as 
reduced intake of certain dietary micronutrients, particularly potassium and magnesium, produced by 
some ketogenic diet regimens. The goal of MCT oil supplementation is to reduce the extent of keto-
induction symptoms by shortening keto-induction latency, which was in fact reported in a HV group 
(Harvey et al 2018). Other rare adverse events reported during ketogenic diet intervention in pediatric 
epilepsy population and attributed to the ketogenic diet are renal stones, vitamin D deficiency, 
pancreatitis, bone fractures, cardiomyopathy (due to selenium deficiency) and carnitine deficiency 
(Kossoff and Hartman, 2012). These side effects have not been reported in studies in the adult 
neurodegenerative studies reviewed and are unlikely to occur in this short-term study. Risk can be 
lowered by careful attention to hydration status, daily vitamin, mineral, and fiber supplementation, and 
vigilant monitoring of electrolytes for depletion or acidosis. However, adverse side effects of mild 
metabolic acidosis, vomiting and electrolyte derangement are possible and will be carefully screened and 
monitored and may lead to care escalation / study removal if severe. 
   

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Modest weight loss is a feature of ketogenic diet, and while this is considered beneficial in some studies 
of obesity/related disorders, it is not regarded as a health risk in this study (excluding BMI <22). 
 
Specific to participants who are hypertensive or diabetic, ketogenic diet is generally regarded as safe and 
beneficial in lowering blood pressure and fasting blood sugar levels. However, there can be risk if this 
occurs and medication is not adjusted due to overshoot of therapeutic effect. Risk will be mitigated by 
excluding uncontrolled hypertension defined as SBP > 180 or DBP > 105, and uncontrolled diabetes (A1c 
> 8.0%) and monitoring blood pressure and blood glucose levels frequently, with potential reduction of 
glucose or blood pressure lowering medication as per discretion of those study investigators who are 
licensed physicians credentialed at the NIH Clinical Center. 
 
 
Other procedures and measurements (venous blood draws, motor physiology, cognition, EEG 
recording) are expected to incur minimal risk similar to what is encountered in routine clinical evaluation.  
 
       c.   Risks of neurologic examination: 
There is minimal risk associated with a routine physical and neurologic examination or with PD screening 
questionnaires. 
  
  
d. Risks of surface ECG: 
Risk of skin irritation at the site of the ECG electrode may be minimal in some subjects. There is minimal 
risk associated with surface ECG. 
  
e.  Risks of EEG: 
There is minimal risk concerning the EEG technique itself. The electrode cap can be uncomfortably tight. 
There may be mild irritation of the skin and scalp from the mild abrasion needed to assure good contact or 
from the collodion, paste, or gels used. 
  
-if participant decides not to perform in any measurements, they will not be per se removed from the 
study. Options include re-testing at a later time and omitting specific declined tests.  
 
f.   Risks of video recording: 
There is minimal risk to patient confidentiality.  This is because video will be done only with participant’s 
signed informed consent, including option to blur facial features.  Video will be taken by NIH issued 
video camera kept locked in the office, and files will be transferred to secure NIH sever for later review 
by a separately blinded rater.  Videos may be viewed for official NIH teaching / educational purposes 
within NIH staff.  Any external sharing such as for academic conference presentation will be done only 
with participants’ written informed consent. 
 
g. Risks of Blood Draw 
There is minimal risk of bruising or prolonged bleeding from phlebotomy; local pain and fainting or 
infection at the needle entry site are possible but rare side effects. 
 
h.  Risks of completing study questionnaires 
The study questionnaires may be frustrating or stressful. Subject may refuse to answer any 
question or to stop a test at any time and for any reason.  

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2.3.2 
Known Potential Benefits 
MCT ketogenic diet has shown improved cognitive outcomes in several small AD trials (reviewed in 
Pinto et al 2018), and ketogenic diet reported improved lexical fluency and working memory compared to 
a high-carbohydrate, low-fat diet in PD cohort with mild cognitive impairment, despite low mean beta-
OHB level of 0.31 mM at study conclusion of week 8 measured in the ketogenic diet group  (Krikorian et 
al 2019). Other clinical trials, VanItallie et al 2005 and Phillips et al 2018, recorded UPDRS as primary 
outcome and found reduction in total scores and all sub-scores, and in the larger KD study group of 18 
participants by Phillips et al, there were reported greatest improvement in UPDRS-I and less 
improvement in UPDRS-III compared to low-fat group (with actual more improvement of UPDRS-III in 
low-fat group and greater side effects of subjective tremor / rigidity in the ketogenic group, which 
accounted for ½ of 4 KD arm dropouts). Perhaps correlating with non-motor symptom reduction that was  
found, BDNF expression is increased directly by exogenous beta-OHB through NFKB activation and 
HDAC inhibition. BDNF levels are increased independently by exercise (Kang et al 2020) and ketogenic 
diet (Mohorko et al 2019), mediated by norepinephrine circuits in mice (Garcia et al 2003; Chen, Russo-
Neustadt 2009) and BDNF is found to be an obligate intermediary of hippocampal dependent learning 
and memory as per single nucleotide polymorphism in mice / neuronal culture studies and impact on 
human neuropsychiatric disease (Hariri et al 2003). CREB is also increased in fasting and exercise animal 
models, mediating long term potentiation (LTP), which is considered a proxy of learning and memory. 
BDNF is also associated with brain cholinergic development and heart rate parasympathetic regulation in 
mice through genetic mice knockdown study (Wan R et al 2014). BDNF is reduced in PD (Rahmani et al 
2019) but does not clearly correlate with PD severity. BDNF was increased in subjects with metabolic 
syndrome following 4 weeks of ketogenic diet as well as 4 weeks of exercise in additive fashion by 20% 
and 38% respectively via crossover study (Gyorkos et al 2019). Therefore, there appears to be an indirect 
correlation with PD as a biomarker of disease, as well as with depression, and a potential therapeutic 
biomarker with KD.  BDNF may also be elevated therapeutically in PD via 12 weeks intensive exercise as 
reported in MDS poster Fall 2019 in Nice, France: “High Intensity Interval Training May Elevate Serum 
BDNF Levels in Parkinson’s Disease Patients.”  
 
Related to mitochondrial quality, ketogenic diet, fasting, and exercise upregulate the mitochondrial 
deacetylase “silent information regulator 3” (SIRT3), which is found to serve multiple roles in 
mitochondrial integrity including mitochondrial biogenesis, protein oxidative stress response (unfolded 
protein response) and mitochondrial DNA repair, and also found to be active in NMDA/glutamate-
induced excitotoxicity (Hasan-Olive 2019, 30027365). PGC-1alpha provides a serum marker of 
mitochondrial biogenesis. 
 
In addition to the above, low carbohydrate diets are consistently associated with reduced insulin secretion, 
reduced hunger, greater weight loss and may produce greater energy expenditure than low-fat (high 
carbohydrate) diets (Ebbeling et al, 2012) although contrary studies on energy expenditure are found (e.g. 
Tagliabue et al, 2012). Ketogenic diets have also been associated with slight reductions in blood pressure 
(e.g. Cicero et al, 2015). Furthermore, there are reported reductions in dyslipidemia (reduction in 
triglyceride:HDL, a marker of coronary artery disease, Lemos da Luz et al, 2008) and non-alcoholic fatty 
liver disease (Tendler et al, 2007).  
 
Potential immediate benefits (obtained during the study) are as follows: 
 
·      Increased insulin sensitivity with reduced body weight and possibly reduced   
       triglyceride level 
·      Mildly reduced blood pressure, possibly involving reduced pathologic sympathetic tone 

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·      Possible improvement in PD symptoms such as: inattention, fatigue, depression, tremor,   
       bradykinesia, pain, urinary frequency, daily off time         
 
Insulin sensitivity (decreased fasting insulin levels, decreased HOMA-IR) is consistently increased by NK 
related to increase in the gastrointestinal incretin glucagon-like peptide 1 (GLP1) signaling. Due to fuel  
from adipocyte stores via beta oxidation, reduction in total body weight and in abdominal fat are also 
consistent findings of NK. 
 
Potential long-term benefits irrespective of continuing study intervention 
 
 
·     Social benefits from participating in support groups / ketogenesis or other diet and fitness  
                    interest groups 
·     Indirect benefit from involvement in science to better understand and treat Parkinson’s  
      Disease (humanitarian / service work) 
 
2.3.3 
Assessment of Potential Risks and Benefits 
The diet has already been suggested to benefit Parkinson’s Disease outcomes as per standardized clinician 
rating scales (UPDRS) and cognitive tests. However, the data are not compelling to adopt ketogenic diet 
as medical guideline given use of mostly clinician rating scale with known interrater and intrarater 
reliability limitations in small studies. Additionally, there are key questions that remain unanswered, such 
as when the benefit occurs; if benefit correlates with plasma ketosis value;  if so, at what ketosis value; 
and whether motor or non-motor systems seem to be most responsive when tested together on the same 
participants serially in the short-term. The participants may benefit in terms of nutritional education 
through the dietary intervention and better knowledge of their disease symptoms in response to metabolic 
measures such as glucose, dietary changes, and close attention to on/off fluctuations via self-report. MCT 
oil has not been studied in Parkinson’s Disease and may improve tolerability of the diet. The risks of 
ketoinduction symptoms and GI upset are known in other populations and so will be closely monitored, 
tracked and intervention adapted as needed to minimize them. Overall, the risks of this study from simple 
dietary changes that have been studied in other populations are expected to be comparatively low relative 
to disease-modifying pharmaceutical agents studied for PD. One unknown potential benefit from long-
term continuation of ketogenic diet (outside the present study) would be disease modification, such as 
from increase in uric acid / reduction in oxidized metabolites, and by augmentation of mitophagy / 
autophagy of toxins such as hyperphosphorylated alpha-synuclein. As a short-term study, there is not 
expected to be direct long-term benefit. However, the justification in addition to scientific value of 
understanding ketosis in PD is an indirect benefit to participants, whereby they are expected to gain better 
understanding of their own diets, irrespective of study group, by working with study investigators in 
objective measurements of physiologic effects and receive recommendations about healthy diet.   
 
3. OBJECTIVES AND ENDPOINTS 
  
OBJECTIVES 
OUTCOME MEASURES 
JUSTIFICATION 
FOR ENDPOINTS 
Primary 
 
 
Feasibility of MCT-KD x three 
weeks 
Composite outcome (all of the 
following measures must be met): 
 
MCT-KD has never 
been studied in PD 
population (expected to 

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Protocol version date 04/19/2021 
 
1) Recruitment reaches target of 32 
participants or as per pre-set interim 
analysis 
 
2) Study retention rate >80% of all 
participants at 3 weeks  
3) Adherence (</= 10% mean daily 
energy from net carb over 2 weeks 
MCT-KD outpatient, assessed by 
2x/week unscheduled phone calls by 
CC Nutrition staff)  
 
4) Acceptability – Likert scale >/=2 
(at least somewhat likely to use diet in 
future and at least somewhat effective 
in improving PD symptoms) at end of 
study (week 3)  
 
 
 
 
 
augment ketosis) and 
feasibility has not been 
established.  
 
 
 
Secondary 
 
 
Timed Up & Go (TUG) time, mean 
difference between groups on study 
day 7 
Mobility on the Timed Up and Go 
(TUG) test, daily (fastest of three 
trials per session) units: seconds 
Range: 8-18s 
 
TUG time is generally 
regarded as an index of 
fall risk – estimated 
20% risk reduction 
with 4s faster time 
(Nocera et al, 2013) 
 
Tertiary/Exploratory  
 
 
Nutritional ketosis (NK) improves 
PD symptomatology at three weeks 
in the following: in cognition 
(improved attention, recall, and 
executive function), and motor 
function (reduced akinesia and 
tremor).  A low fat (standard 
American) diet (SAD) does not. 
NK reduces non-motor symptoms, 
subjective motor fluctuations and 
daily off time within the immediate 
keto-induction period, while SAD 
does not (mean difference at 1 
Stroop word-color interference 
latency (unit: ms, range: 110-135 ms), 
0,1,2,3 back recall task (unit i: % 
error  of missing true n-back letter 
presented; range i: 0-back 0-10%, 1-
back 4-20%, 2-back 15-30%, 3-back 
20-32%; unit ii reaction time (RT) 
ms, range ii 0-back 500-740 ms; 1-
back 600-980 ms; 2-back 700-1200 
ms; 3-back 700-1200 ms); fingertap 
speed and rhythm (MN and PQ 
keyboard tasks; units MN and PQ 
keystroke speed, in keys/s; range MN 
All of these tests have 
been shown to be 
impaired in  PD cohorts 
and are at least semi-
quantitative and 
amenable to serially 
repeated measures with 
good test-retest 
reliability 
 
 
Scalp EEG is non-
invasive, easy to 
perform in the setting 
of intervention, and as 

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week). NK increases heart rate 
variability, (mean difference 
baseline vs. 3 weeks).  
 
 
 
2-5 keys/s; range PQ 0.6-1.5 keys/s); 
latency of placing and returning to 
dish 9 holes on pegboard (9-HPT) 
units: s, range 15-45 s) 
Non-motor symptom scale (NMSS, 
total score out of 360 total) Waking 
ON time (daily subjective worksheets, 
unit: hours (h), range 2-15h), keto-
induction symptoms (daily 
worksheets or self-report, Likert scale 
0-3 for various symptoms related to 
ketogenesis), UPDRS-III motor score 
(range 0-72), heart rate variability 
(SDNN, units ms, range 20-130 ms), 
simple reaction time, units ms, range 
360-400 ms), plasma BDNF 15.4 +/- 
3.5 pg/mL (Gyorkos et al, 2019),  
Geriatric Depression Scale (GDS) 
normal 0-9 mild depression 10-19 
severe depression > 20; 
Gastrointestinal Symptom Rating 
Scale (GSRS) Avg total score 1.50-
1.55; EEG premotor cortex (M1) 
waveform characteristics (unitless 
ratios, asymmetric steepness, rise:fall 
or steepness ratio range 0.025-0.15 
and peak:trough or sharpness ratio, 
range 0.01-0.075 (that were shown to 
have high correlation to phase-
amplitude coupling, which is also a 
unitless measure by modulation 
index, range 0.01-0.037) . Possible 
measurement of quantitative EEG 
(qEEG) power spectra mv2/hz 
qualitatively assessed vs. normative 
distribution (high, med, low), phase 
lag index (0-1) and weighted network 
cluster coefficient, path length by 
frequency band 
 
 
shown to provide a 
biomarker correlating 
with PAC (which 
correlates with 
UPDRS), if validated in 
this study will be a 
relatively reproducible 
neuroimaging test for 
future studies. 
 
ON/OFF symptom 
computer-based survey 
daily assessment 
(PsyToolkit) will help 
to further show 
correlation of PD 
symptoms with ketosis 
values 
  
Non-motor symptom 
severity (NMSS) scale 
and Geriatric 
Depression Scale 
(GDS)  are NINDS 
Common Data 
Elements for PD 
 
Effect of KD on 
UPDRS included for 
consistency with 
existing literature 
 
HRV / cardiovagal 
responses to Valsalva / 
deep breathing show 
autonomic function. It 
is unknown if 
ketogenic diet will 
reduce deficits in these 
tests in the acute 
period. 
 
 

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4. STUDY DESIGN 
4.1 OVERALL DESIGN 
The experiment will take place predominantly in the Metabolic Unit, 7SW-S (1-week inpatient) and at 
home (2 weeks outpatient). Additionally, EEG, TUG, and heart rate variability tests will be performed in 
the HMCS labs within the 7SW-Neurotesting area. 
 
This study is a single center (NIH Clinical Center), phase 1 feasibility/tolerability assessment of MCT oil 
subtype of ketogenic diet in a PD cohort, randomized, double-blinded vs. standard American (high-
carbohydrate) diet based on macronutrient percentages of calculated daily energy expenditure using 
measured pCO2 and pO2 and Weir formula for indirect calorimetry, performed on screening visit, to give 
caloric macronutrient ratios 50-55% carb, 35% lipid, 10-15% protein in SAD group and 5-10% carb, 80% 
lipid, 10-15% protein in MCT-KD group on the 7SW-S Metabolic Unit with assistance of CC Nutrition 
Department staff. Consent, baseline lipid panel, BMP, and pregnancy test will be done at screening visit. 
Randomization will occur upon screening visit, stratified by age >=65 or <65 and baseline TUG score >= 
11.5 s or <11.5 s.  Protein macronutrient percentage of individual calculated daily energy intake will be 
the same between the two groups. Diet will be within subject factor for both groups, as pre-diet 
intervention baseline testing is planned for hospital day #1. The potential confound of changes in 
activity/exercise level while in the hospital on physiologic and clinical outcomes is recognized. To 
address this, study investigators will form an individualized exercise plan incorporating baseline exercise 
and activity levels to involve stationary bike at target HR based on age-adjusted HR max target using 
Tanaka's formula validated in the elderly population, 208-0.7 × age, in order to approximate each 
participant’s daily baseline intensity levels from questionnaires. 
Ketosis values in the MCT-KD group will be correlated indirectly with respiratory quotient and 
continuous glucose monitor (Freestyle Libre Pro Glucose Monitoring System, continuous glucose 
monitoring (CGM) system, FDA approved for blinded professional use in clinics). The hypothesis is that 
nutritional ketosis will improve mobility and also motor and non-motor symptoms through a direct, 
homeostatic return of frontostriatal signaling by mitochondrial restoration that will occur within hours of 
reaching ketosis on inpatient day 3, and through an indirect mechanism of increased dopamine / GABA 
availability (reduction in pathologic glutamatergic hyperexcitability) that will develop more gradually, 
over several days.  
 
Care will be taken to reduce bias through blinding rater(s) to intervention group ketogenic or non-
ketogenic and by blinding participants to intervention or control diet given, with randomization scheme 
kept only by a study investigator not involved in any of the ratings or measurements (study 
biostatistician) and by using video rating (aside from muscle tone) of UPDRS-III by the average of AI 
and another movement disorders specialist outside the study, the latter rating scrambled in random 
assortment with respect to intervention day. Study duration will be three weeks, and total time for 
participants approximately four weeks including initial study visit and period of at least one week 
baseline prospective diet, activity and ON/OFF PD symptom fluctuations self-report, and for baseline diet 
collection also using unscheduled twice weekly phone calls by study nutritionist / investigator (non-rater). 
By the time of discharge, participants will receive daily suggested ketogenic diet meal plans for the 
upcoming two weeks of diet at home. Assessment of MCT-KD adherence will be made by twice weekly 
unscheduled phone calls by NIH CC Nutrition staff (LAI).  There is anticipated accrual of up to two 
participants admitted at once. MCT oil from Liquigen® (KetoCal) will be given at 25% calculated daily 
lipid energy expenditure, similar to prior studies (refer to Section 2.3.1 for details of prior studies using 
MCT oil). 
 

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While a longer duration ketogenic diet study, e.g. longer than 8 weeks that are the current limit of study 
follow-up in PD, would address a key gap in the literature on long-term outcomes and potential disease 
modification, there are other gaps that can be addressed via an acute, short term study, such as target 
ketosis value, relation of ketosis to symptoms and the time course, tolerability of novel diet adaptations 
(MCT oil), and biomarker of the therapy such as EEG. These gaps altogether appear to be well addressed 
by an inpatient trial, a unique resource of the NIH Intramural Research Program, and altogether provide 
an opportunity for a contribution to the field of PD therapeutic research. Additionally, given the 
constraints of metabolic inpatient study, with an estimated predominance of short-lived adjunctive 
therapeutic benefits rather than long-term benefits, recruiting for a longer duration of inpatient stay would 
likely be more difficulty to reach target recruitment; more difficulty to carry out as the study 
measurements are to be predominantly performed by one rater (AI); and difficult to justify, amounting to 
a phase 2+ trial when a pilot, phase 1 trial appears important to do first in order to test the therapy in a 
rigorous fashion. Therefore, an inpatient/outpatient three-week study is proposed to conduct first in order 
to address the feasibility and time course questions.  
 
A recognized potential confounder of assessing the effect of ketogenic diet on Parkinson’s Disease 
symptoms is possible effect on levodopa / dopaminergic (DOPA/DA) medications. Literature search 
using PubMed and Google search engines shows some studies of effect of KD/modified Atkins diet on 
plasma AED levels ranging from no effect (Dahlin et al, 2006; Coppola et al, 2010) to modest reduction 
in some plasma AED levels (Kverneland et al, 2015; Heo et al, 2017), however no relevant 
pharmacokinetic data for effects of ketogenic diet on DOPA/DA metabolism. The fed state with light 
breakfast (% lipid not specified) was found to slightly increase immediate release Sinemet bioavailability 
compared to overnight fasted state in healthy volunteers coinciding with delayed gastric emptying with no 
clear effect on peak concentration in the small study (Wilding et al, 1991). By contrast, pharmacokinetic 
study in healthy volunteers of the effect of a mixed 38% fat, 52% carb, 11% protein meal (1046 kcal) on 
single dose of a dual rapid/slow release formulation of levodopa + COMT inhibitor benserazide 
(Madopar) showed reduction of plasma levodopa peak concentration by 32% (2.09 to 1.41 mg/L) and 
prolonged time to peak by 2 hours (3.1h vs 1h) with however no effect on bioavailability by total AUC  
(Crevoisier et al, Eu Jnl Pharmac and Biopharm 2003;55).  Another levodopa formulation, Numient in 
preclinical study (Europe European Medicines Agency / CHMP / 672104 / 2016) similarly showed 
dietary fat delayed and reduced plasma levodopa peak concentration without affecting bioavailability.  
Similarly, in a study of single dose extended release formulation of carbidopa-levodopa (Rytary) in 
healthy volunteers in either overnight fasting or post-high-fat, high-calorie breakfast conditions, the initial 
rise in concentration of levodopawas delayed by 2 hours, peak concentration was reduced by around 21%, 
and total AUC was modestly increased by 13% (Mittur A et al, 2017 28236251).   
Protein is well-established to affect oral bioavailability and pharmacokinetics of levodopa through shared 
transporters with large, neutral amino acids and clinical studies, as outlined and referenced in the 
protocol, and is not considered to be a factor between the two groups given that dietary protein will be 
controlled over a small range (10-15% total daily energy). Importantly, as confirmed in multiple studies 
including the above, the fed state itself introduces delayed gastric emptying, and the diet used in the 
control arm, SAD while not ketogenic is not low fat at 35% daily energy, thus also would reduce peak 
concentration as per above studies. Another variable in effect of meals on oral pharmacokinetics 
including PD medications is the formulation, as solid meal boluses delay gastric emptying and more 
likely impact peak concentration than solutions and suspensions such as proposed in this dietary study, 
the same in both groups. 
Therefore, while literature search reveals no pharmacokinetic studies on the effect of ketogenic diet on 
levodopa or other medications indicated for Parkinson’s Disease, inference from studies of dietary fat as 

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above would impute lower and delayed peak concentration (potentially sub-threshold for therapeutic 
window, especially in more advanced disease such as defined by Hoehn & Yahr stage 4) and therefore 
potentially bias towards the null hypothesis. To better account for effects of diet on levodopa metabolism, 
plasma dopamine will be measured twice daily at the time of blood draw for beta-hydroxybutyrate on 
inpatient study days 1 (baseline, pre-dietary intervention) vs. days 2-3. 
 
Independent variable: The effect of intervention MCT-KD vs. standard diet control group (see section 
2.1 table for macronutrient ratios under KD and SAD, respectively) will be measured in three ways: a) 
twice daily phlebotomy beta-OHB levels to be drawn #1 in fasted morning time and #2 in the evening 2 
hours after dinner b) daily respiratory quotient (pCO2:pO2) looking for stabilization of decline to the 0.7 
– 0.8 range, and c) continuous glucose monitor (CGM) in Metabolic Unit, looking for fluctuations, 
possibly correlated to symptoms, as well as trend of stable reduction < 100 mg/dL.  
 
The interventional food-based product, Liquigen® (KetoCal), will be administered by NIH CC Nutrition 
staff to MCT-KD group participants as per defined blinded diet. 
 
Primary Outcome: feasibility will be assessed in a composite fashion by retention rate >80% at study 
end (week 3) ; study adherence in the outpatient segment defined by maintaining mean carbohydrate limit 
</= 10%, as by CC nutrition staff twice weekly unscheduled calls data input to online application); 
reaching recruitment target of 32 participants, unless otherwise defined by interim analysis (see Section 
9); and acceptability by likelihood to use the diet in the future and effectiveness in reducing PD symptoms 
both “somewhat” >/=2/4 on Likert scales. All criteria must be met. 
 
Secondary outcome: Timed Up & Go (TUG) time at between MCT-KD and SAD groups mean 
difference on inpatient day 7.  
 
Exploratory outcomes:  
Effort will be taken in establishing medication and testing schedules, for outcomes to be assessed at the 
same time from last dopaminergic medications and other psychotropic medication administrations 
including cholinergic and muscle relaxants (see table 2). All exploratory outcomes will be assessed pre 
(admission day 1) and post (day 7 and week 3) diet intervention. Additionally, reaction time, Stroop test, 
N-back test, MN/PQ fingertapping tests, 9-HPT, UPDRS-3, and resting HRV will be tested daily on 
admission days 2-6.  
Stroop word color interference latency (Stroop test B), N-back test (3-back letter), MN and PQ keystroke 
tasks, tremor accelerometry, 9-hole pegboard test (9-HPT), and simple reaction time (SRT), EEG 
waveform analysis (steepness ratio, sharpness ratio, modulation index), and quantitative (q)EEG 
assessment; daily assessments of  heart rate variability (SDNN, pNN50, rMSSD, power spectral analysis), 
and supine to standing blood pressure and heart; resting heart rate (5 min recordings daily), UPDRS 
including daily UPDRS-3, daily ON time, daily PD symptoms, daily keto-induction symptoms, pre vs. 
post intervention Non-Motor Symptom Severity Score (NMSS) 
All testing to be done by AI, at a certain scheduled time daily or specified testing schedule with respect to 
last meal and dopaminergic medications or others potentially modulating neuromuscular system (see 
Table 2 description for list). If patient has DBS, the settings will not be adjusted unless there is the 
impression of study investigators including PI who are movement disorders specialists that a significant 
motor complication has occurred during the intervention that might be improved by DBS adjustment. For 

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example, dyskinesia has been reported in prior ketogenic PD trial (Phillips et al, 2018) and could be 
improved by reducing DBS stimulation. For more details on adverse events please refer to Sections 9.5-
9.6. 
 
Table 2 – flowchart / schedule of testing 
Care will be taken to minimize participants’ test/retest variability from psychotropic medications. 
Accordingly, medications from the following classes will be taken up to the night prior to testing (held for 
testing): anticholinergics, NMDA antagonists, dopamine blocking agents, muscle relaxants, 
anticonvulsants, GABA agonists.  Tests will occur in the same order; and care will be taken to control 
timing of AM dopaminergic dose in relation to testing, providing instruction for participants to take their 
dopaminergic medications at a set 30 min prior to breakfast. Morning dopaminergic medications will be 
taken in the overnight fasting state to minimize group differences in pharmacokinetics related to diet, as 
outlined in section 4.1 above. For each participant, testing will be done in a single session lasting 
approximately 1.5-2 hours, and time from dopaminergic medication dose to end of testing will be around 
2-3 hours. No changes will be made to dopaminergic medication prescription, unless clinical emergency 
as per credentialed clinician assessment. If participant’s levodopa or agonist dose interval requires repeat 
dose during testing, we will make no changes but maintain the same dose schedule throughout the testing 
days 1-7 and week 3. 
 
 
Note: The times listed on the chart are the target timepoints, and while every effort will be made to keep 
testing as close to the target time as possible, it is expected that there will be some variation in actual 
testing times.  Times will be recorded.  Variation in testing times is expected and will not be considered a 
protocol deviation. Home dose of dopaminergic medications will be given in the morning of the testing in 
the fasted state approximately 30 minutes prior to breakfast, allowing for at least 1 hour after dose prior to 
the start of testing to decrease variability in absorption. 
 
Mobility assessment: Timed Up & Go (TUG) test 

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To test the hypothesis of improvement occurring acutely (within days of reaching ketosis) due to 
improved mitochondrial function and neurotransmitter signaling, TUG will be tested by AI between 
group mean difference on study day 7 to target TUG power analysis (see section 9 for details). Pre-
intervention screening visit time >/= 11.5s or <11.5s will be used as covariate for group randomization. 
Power analysis was chosen for TUG as a measure showing good intra-rater reliability (Dal Bello-Haas et 
al, 2011) and correlated with fall risk (Nocera et al 2013), hence meaningful for motor function. 
TUG will be done in the hallway of 7SW Neuro testing with distance of 10 ft demarcated by tape, using 
chair and stopwatch, best of three trials, daily as per table 2 testing schedule above.  
To control for biological / Levodopa variability, all secondary/exploratory tests will be done at 
approximately the same time with respect to dopaminergic Parkinson medication and other psychotropic 
medication dose and at approximate same time of day and same order of tests. Additionally, plasma 
levodopa will be measured twice daily at the times defined for BOHB blood draw. 
 
Simple reaction time  
Simple reaction time has been consistently shown to be impaired in PD (Flowers 1978; Evarts et al, 
1981), and the increased latency is found to correspond to motor symptoms of tremor and rigidity in 
patients with asymmetrically lateralized symptoms and to be furthermore increased bilaterally in patients 
with bilaterally symmetric symptoms (Yokochi 1985). SRT also is found to be improved after levodopa 
therapy (Zappia 1994). Furthermore, SRT has been compared to complex reaction time (CRT) and it was 
found that the same degree of deficit was found in both, suggesting that the deficit is not a function of 
complexity (Sagar et al, 1992), as has been reported elsewhere (Jahanshahi, Brown, Marsden 1993). SRT 
is therefore considered to be a potentially useful test of motor benefit related to hypothesis of increased 
neurotransmitter availability and signaling related to ketogenic diet, with improvement in reaction times 
on the diet but not on a non-ketogenic, healthy diet. 
 
As per pre-determined scheduled time, the subject will be asked to sit comfortably before a computer 
screen and look at the white box in neutral fixation space, and when ready to press spacebar with less 
affected or dominant thumb on a keyboard as soon as seeing an X appear within the box; 8 practice 
repetitions will be followed by 20 test repetitions. Immediately afterwards, subject will be asked to look at 
a row of 4 white boxes and press one of the following keys, z x , (using fingers 2 and 3 bilaterally) 
corresponding to the X within the box, 8 practice followed by 40 test repetitions. Testing will occur daily. 
 
  
 
https://www.psytoolkit.org/c/3.0.0/run_exp?name=Simple_and_Complex_RT 

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Stroop Word-color interference test  
At pre-determined scheduled time as per Exploratory Outcome heading, from 40 stimuli, colored (red, 
green, blue, yellow) number words will be displayed on a computer screen, and the difference in latencies 
between incongruent (color and word of the color different) congruent (color and word of the color same) 
time to correct response will be recorded, a minimum of 20 correct responses. The % correct from total 
responses will also be recorded. Following is URL to perform the test: 
https://www.psytoolkit.org/lessons/experiment_stroop.html 
 
As explained in the software instructions, the fixation in PsyToolkit occurs for 200 ms, and then the 
colorword trial is shown for 2s - the program records correct and incorrect (or no keystroke) responses 
separately and averages the latencies over 40 trials. 
Testing will occur daily. 
Stroop word-color interference is to be tested on day 1, week 3 final visit, and daily on the same testing 
schedule as a function of the intervention over 7 days. 
N-back task  
As per pre-determined scheduled time, 3-back task will be tested at a certain time daily with letters 
A,B,C,D,E,H,I,K,L,M,O,P,R,S,T presented for maximum 2000 ms, at a rate of new stimulus ever 2500 
ms, for 20 trials. 
 
If the stimulus is the same as 3 trials ago, participants press the ‘M’ key. If the stimulus is not the same as 
3 trials ago, participants press the ‘N’ key. (M for memory, N for No) 
At the end of 20 trials, error % is given for missing 3-back items, and reaction time (ms) is calculated. 
A demo of the test is found here: 
https://www.psytoolkit.org/experiment-library/experiment_nback.html 
Testing will occur daily and at week 3. 
 
MN and PQ keyboard tasks  
As per pre-determined scheduled time, testing to occur based on a computer system developed at NINDS 
7SW Neuro Testing area (Patrick McGurrin, PhD Neurophysiology), with software prompt to begin 
tapping back and forth between M and N as rapidly as possible within 30 seconds, and the number of taps 
are recorded as well as the time stamps on the computer processor, subsequently prompting the next test 
to alternate between the P and the Q keystrokes as rapidly as possible, counting #seconds for 30 
repetitions and time of each keystroke also recorded. Each task is repeated three times per arm and 
averaged. Thus, speed (correct repetitions / minute) and rhythm (keystroke vs. time) can both be plotted. 
This will be helpful to assess bradykinesia and dysrhythmia of Parkinson’s Disease as a function of the 
intervention, in daily testing over 7 days and at week 3.  
 
9-hole pegboard task (9-HPT) (Rolyan A851-5) 
As per pre-determined scheduled time, testing to occur as per this commonly employed measurement in 
clinic / rehabilitation specialists such as occupational therapists to assess finger dexterity. Normative data 
has been established (Mathiowetz et al, 1985). This consists of a square board with 9 holes spaced 1.25 in 
apart, each hole ½ depth and drilled with a 9/32 in drill bit, next to a container for the pegs. In Parkinson’s 
Disease, means of 26.6s to 36.7s were found at Hoehn & Yahr stages 2-3 in dominant hand, and 27.5s to 
36.8s in non-dominant hand (Earhart et al 2011). SEM was found to be 1.02 s for dominant hand and 0.82 
s for nondominant hand, indicating good test-retest reliability, to be tested daily as a function of the 
intervention over 7 days. 

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The test (Rolyan A851-5) is done with dominant arm first, with stopwatch giving one practice trial per 
arm provided to the timing, starting when participant touches the first peg and stopped when patient 
places last peg in the hole. Participants will be instructed that, if a peg is knocked from the tray or hole 
onto the table, they should replace it themselves according to the test phase (in vs. out of the holes), and if 
it is knocked off the table, the rater will return the peg to its place of origin. This is to minimize potential 
timing variability. (Instructions adapted from www.rehabmeasures.org, test instructions derived from 
Mathiowetz et al, 1985). Testing will occur daily over 7 days and at week 3. 
 
Geriatric Depression Scale (GDS) 
Given some literature on ketogenic diet and mood interaction and proposed clinical use as therapy for 
mood disorders (reviewed in Brietzke et al, 2018), depression will be screening using GDS, a validated 
instrument listed under Common Data Elements for Parkinson’s Disease. The survey will be self-
administered pre (screening visit) and post (day 7, week 3 visit) intervention. 
Available at: < https://web.stanford.edu/~yesavage/GDS.html > 
 
EEG waveform analysis / qEEG assessment (7 SW Neuro testing area) 
As per pre-determined scheduled time, EEG recording (Brainproducts, not FDA approved) will be done 
as following:  64 EEG electrodes will be positioned according to 10-20 International System, with every 
impedance kept under 5 kOhm and single earlobe used for reference. EEG data will be amplified, filtered 
(DC-100 Hz), digitized at 1000 Hz (Brain Products GmbH, Gilching, Germany), and stored on a 
computer for offline analysis. To keep track of common artifacts, to monitor blinks and eye movements, 
electrooculogram (EOG) will be recorded from two extra electrodes near the right eye on the supra-orbital 
ridge. To monitor the heart activity, electrocardiogram (ECG) will be recorded from two extra electrodes, 
one under the collarbone on the right shoulder, and another one on the abdomen on the lower left side.  
Subjects will be asked to enter a relaxed, wakeful state minimizing movements, first 5 minutes with eyes 
open and then 5 minutes with eyes closed.  The following metrics will be analyzed: 
 
Spectral analysis (quantitative EEG) will be assessed in MatLab (EEGLab application)  after pre-
processing (removing artifacts, re-referencing) by Fast Fourier Transformation (FFT) to give frequency 
vs. time analysis and derive power per band, focused on: theta (4-8Hz), alpha (8-13 Hz,), and beta (13-30 
Hz, also divided into slow beta 13-20 Hz and fast beta >20 to 30 Hz)), particularly investigating theta 
power as a correlate of cognitive impairment (reviewed in Geraedts et al, 2018). Additionally, elevated 
spectral power across frequency bands was found centrally and decreased posterior alpha power with 
slower alpha dominant rhythm was reported in a mixed phenotype PD cohort compared to controls 
(Moazami-Goudarzi et al, 2008). It is of interest in the proposed pilot study to attempt to replicate these 
spectral changes in PD as a putatitive biomarker of compensation and elevated coherence in the 
frontostriatal network with reduced parietal coherence, as has been described via functional MRI at 
HMCS. It is an exploratory aim to assess if these changes are potentially amenable to modification by 
ketogenic diet through GABA or other neurotransmitter effects. 
In addition, it is planned to analyze the frequency vs. voltage2/frequency for two questions: 
- is there abnormal slowing (e.g. loss of posterior alpha rhythm) that is detected initially and normalizes 
post-intervention; 
- Is there a change pre vs. post intervention in central (peri-Rolandic) beta power, reportedly increased by 
ketogenic diet in healthy volunteers (Cantello et al, 2007) and decreased centrally in the lesional 

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hemisphere post-zolpidem dose in a PD cohort (Hall et al, 2014), presumably due to elevated GABA tone 
as an effect of ketogenic diet. 
EEG is to be tested pre/post intervention on study days 1, 7 and week 3. 
Functional connectivity will be tested by frequency specific (via FFT) weighted minimal norm estimate 
(WMNE) for time and phase synchronization by phase locking value method for connectivity strength, a 
quantitative measure of phase (ranging from 0 to 1) (Hassan et al, 2014) that has been modeled via graph 
theory network with decreased local integration measures in alpha1 band in PD-MCI group compared to 
PD-CN and Control groups (Utianski et al, 2016). EEG connectivity measure of coherence can be 
assessed via magnitude squared coherence (inputting both phase and amplitude of electrode pairs, and by  
phase lag index (PLI), which calculates asymmetry of distribution of instantaneous signal phase 
differences between two signals (brain regions), ranging from 0 (uncoupled or phase locked) to 1 (perfect 
coupling, non-zero, non- π modifier). There is a consistent finding of reduced PLI in the alpha 1 (8-10) 
and alpha 2 (>10-13) bands broadly distributed and increased PLI in theta bands in temporal regions 
associated with PD-MCI compared to PD with normal cognition (Chaturvedi et al, 2019). Therefore, 
assessing PLI per frequency bands in defined regions is of interest as exploratory measure of the 
ketogenic diet intervention (pre vs. post intervention), with hypothesis of increased alpha PLI at 1 week 
post-intervention in the ketogenic diet group, sustained at 3 weeks. 
Additionally, waveform analysis will involve metrics of M1 slope and amplitude at defined intervals 
surrounding each extrema (e.g. 3 point before/after) to derive sharpness ratio (amplitude peak to trough) 
and steepness ratio (slope rise:fall) correlated with pathologic phase-amplitude coupling in motor 
striatocortical loops as per Jackson et al, 2019. 
Heart rate variability 
As per pre-determined scheduled time, subjects will receive monitoring daily on study days 1-7 for 5 
minutes using Elite HRV finger monitor and Android application in relaxed waking state in the reclined 
seated position. Additionally, on study days 1, 7, and week 3 (pre/post intervention), at the time of 
sessions with rsEEG (see table 2 for testing schedule), trials of Valsalva Maneuver (VM) and deep 
breathing (DB) will be conducted as follows: VM with coaching to blow into mouthpiece attached to 
manometer to pressure of 40 mmHg x 15 seconds, and the recording of heart rate cardiovagal gain over 
the subsequent 1 minute (max RR / min RR interval); average of 3 trials will be used for analysis. DB will 
occur for 1 minute with 6 cycles per minute, average of 2 trials. Recording for cardiovagal testing will be 
conducted study day 1, 7, and week 3 via ECG electrodes using Natus Neurology machine (not FDA 
approved).  Analysis will be done using EliteHRV and Biopac Acqknowledge software to extract using 
artifact removed R-R wave (N-N) intervals SDNN, pNN50, rMSSD, and power spectral analysis (LF, HF, 
VLF, LF/HF ratio). 
Orthostatic vital signs 
Orthostatic blood pressure and heart rate will be recorded daily, study days 1-7 and week 3 - supine for 10 
minutes or more, then standing immediate followed by standing at 3 minutes. 
UPDR parts 1, 2, and 4 will be tested pre vs. post intervention (day 1, week 3). UPDRS-3 will be assessed 
daily, similar time each day and relation to medications in ON state, with video recording. UPDRS-3 
measures to be assessed by board certified neurologist, either directly by AI or rated by blinded rater not 
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ON-time, PD symptoms, and keto-induction symptoms will be captured daily via online survey provided / 
collected to participant daily to check PD / keto symptoms and daily waking hours in the “off” state 
without effect of dopaminergic medications. Psytoolkit URL:  
https://www.psytoolkit.org/c/3.0.0/survey?s=RQFaX 
Pre vs. post intervention non-motor symptom severity scale (NMSS, Chaudhuri et al 2007, validated by 
MDS) will be tested for presence/absence of fatigue, pain, urinary disturbance, and other non-motor 
symptoms (day 1, week 3).  
Gastrointestinal Symptom Diary: to be administered daily (days 1-7), designed by International 
Foundation for Gastrointestinal Disorders. URL: https://www.iffgd.org/publications-
library/library/341.html 
 
Gastrointestinal Symptom Rating Scale (GSRS): Developed for dyspepsia / IBD, normative values 
available in population study (day 1, 7, week 3). J. Svedlund, E. Dimenäs, I. Wiklund 1995  
 
Metabolic labs (venous phlobotomy)– baseline (day 1) vs. post-intervention (day 7, week 3) A1c 
(baseline, week 3), lipid panel*, insulin, HOMA-IR, cortisol, TSH, T3, free T4, CRP, Apolipoprotein, 
BDNF; twice daily (at pre-determined times with respect to medications and meals) BOHB (days 1-7) 
and dopamine (days 1-3) 
*lipid panel drawn at screening, day 7, and week 3 
Ketogenic diet has been consistently linked with increase in insulin sensitivity, modest reduction in 
glucose levels, increase in brain and plasma BDNF levels, and has been shown to reduce plasma 
triiodothyronine (T3) hormone levels with unknown significance.  
Bioelectric impedance pre vs. post intervention (Screening  and week 3): This provides an indirect 
measure that correlates with total body adiposity, and will be performed in the Metabolic Unit to assess if 
the weight loss expected with dehydration may in part be due also to reduction in adipose tissue from 
beta-oxidation. 
Exit survey Likert scales (0-4) for likelihood of using the diet, with or without MCT oil, and effectiveness 
in symptom control, with space for comments on which, if any, symptom(s) responded best. 
PsyToolKit URL: https://www.psytoolkit.org/c/3.0.0/survey?s=2SZqS 
 
4.2   SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The core rationale for the inpatient portion of the study is to provide more depth of analysis as well as the 
increased monitoring than is possible in outpatient settings, to investigate whether PD symptoms are still 
impacted beyond placebo, and if impacted in the several days following keto-induction as opposed to at 
three weeks. Corollary to these aims and underlying the pilot design and primary objective, adherence 
will be ensured rigorously in the inpatient setting, and feasibility of inpatient dietary intervention for PD 
will be assessed in comparison to the more realistic outpatient setting. Outpatient comparison is used to 
allow for greater time for possibly delayed therapeutic effect as is postulated due to epigenetic effects 
related to histone deacetylase complex inhibition and other metabolic-related changes gene expression, in 
which one week may be inadequate whereas three weeks offers a better window. Outpatient comparison 
will also allow for useful consideration of feasibility of the diet in real-world setting for consideration as 
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The mechanisms and specific biomarkers of PD impacted by ketogenesis have not been defined, nor the 
time course of any effects. Furthermore, adherence and tolerability as well as side effects related to 
micronutrient deficiency or extreme skew of macronutrient composition towards lipids remains barriers to 
a wider adoption of studying ketogenic diet for treating PD. Acute metabolism switching via standard 
ketogenic diet supplemented by MCT oil as described by Phillips et al in healthy volunteers as an 
alternative means of inducing nutritional ketosis remains unexplored in PD in terms of the relation of 
different ketosis values to symptom measurements over the keto-induction period in comparison to usual 
diet. Given the lack of data on ketosis value in PD and mechanism, a pilot study appears useful to assess 
novel adaptation of MCT oil and exploratory biomarkers EEG, HRV, and BDNF. While there is a 
knowledge gap for the mechanism of purported acute benefits of nutritional ketosis in PD even within one 
week that motivates this study, there are additional hypothesized benefits that would appear only on a 
longer time scale for which this study would be a pilot for future, phase 2+, larger scale and longer study 
duration in the outpatient setting to study effects of therapeutic diet on disease progression. Such disease 
markers might include decrease in oxidation protein products (AOPPs), oxidized lipid metabolites and 
urinary nucleotides, increase in autophagy via CSF markers, and increased brain perfusion without 
increase in FDG-PET uptake, as was reported in recent ketogenic diet trial in AD by Neth et al 2020 at 
Wake Forest. It would certainly be of interest to conduct a ketogenic trial for longer duration than the 
other three pilot studies to test for disease modification. On the other hand, acute effects also require 
further study and are the aim of this proposed pilot study to establish feasibility and biomarkers of therapy 
in relation to the disease. 
 
PD motor pathology of rigidity and bradykinesia is clearly associated with pathologic hypersynchrony in 
striatal-frontal beta oscillation along with abnormally long bursts of beta activity (Brown and Williams, 
2005), and the severity of motor symptoms correlates with phase (beta frequency) amplitude (gamma 
frequency) coupling in motor cortex and STN (van Wijk et al, 2016), which are ameliorated with DBS (de 
Hemptinne et al., 2015) as well as L-DOPA (Cole et al, 2017). Also clear in the pathobiology of PD, 
parasympathetic and sympathetic nodes of the autonomic nervous system are involved with impaired 
functional testing, which can precede motor symptoms (Goldstein 2014).  
 
Proposed acute effects of ketogenic diet in relation to symptom benefit may include increased 
parasympathetic tone seen in animal studies of KD related to production of BDNF, which can be 
directedly tested, and increase in peri-Sylvian beta power on EEG, reported in healthy volunteers on KD 
as a correlate of increased SICI / cortico-cortical GABA-A signaling (Cantello et al 2007), particularly 
relevant for PD with morbidity of depression and GI disturbances implicating non-dopaminergic 
neurodegeneration, for which GABA deficiency and related calcium overload are hypothesized 
mechanistically (reviewed in Blaszczyk 2016). The acute effects of the intervention are putatively related 
to increase in GABA tone, for which EEG and parasympathetic testing appear to be promising as acute 
biomarkers of the intervention. 
 
The diet intervention duration of 3 weeks is limited to assess tolerability and is too short to observe effect 
on disease progression. However, the purpose is to provide a pilot feasibility study while generating time 
course in the inpatient setting for symptomatic effects and possible mechanism via EEG spectral power 
and connectivity, as a forerunner to long-term study. The significance of this clinical trial as being a pilot 
study is that while it is designed to test feasibility as well as symptomatic effects and biomarker signal 
within the acute period, it is contingent upon a future study that would provide a longer time period and 
ideally study more subjects to validate the feasibility of the approach adopted in this intervention in both 
symptoms and disease modification. While ketogenic diet is validated as being therapeutic in certain 
types of epilepsy and considered useful for many types of epilepsy by epileptologists, and the approach is 

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often to prescribe the diet for a period of time such as 6 months or 1 year because the therapeutic benefit 
of seizure reduction/cessation often endures long after switching back to a regular diet, such data are not 
available for Parkinson’s and will require further study, which this study does not attempt to address. 
Rather, this study proposes to address what level of ketosis can be achieved through an MCT oil 
supplemented, monitored diet with less stringent carbohydrate restriction and therefore presumably better 
tolerated as a long-term therapy; whether there may be particular biomarkers to indicate success of the 
diet, such as EEG central beta power, heart rate variability or BDNF; if side effects of MCT oil are 
tolerable in this population with known gastro-intestinal paresis; and what effect does a given ketosis 
value have compared to another on serially repeated, validated measurements in PD. 
 
Anecdotally, PwP adhering to ketogenic diet or other low-carbohydrate diets such as Paleolithic diet have 
reported that both diets, avoiding carbohydrate and large amounts of protein, improve symptoms such as 
walking speed, tremor and fatigue, even at low or undetectable values of ketosis as measured from a 
ketone meter reagent strips, a validated method for beta-OHB levels 0.1 – 6.0 mM (for further details of 
community engagement please refer to section 5.6). Accordingly, the mechanism underlying benefits of a 
low carbohydrate diet appears to be more multifaceted than simply ketosis, potentially involving 
differences related to fatty acid metabolism, levels of PUFA (polyunsaturated fatty acids), glycolysis, 
insulin sensitivity, levels of antioxidants, DNA repair, and buffers for coenzyme activation. This 
remaining question drives the study, with the question of “do ketosis values matter,” which is well posed 
for inpatient metabolic unit study.  
 
Of methodological importance, a learning effect is expected in repeated tests, more so in the proposed 
tests involving preparation and decision such as Stroop word-color interference, TUG, and 3-back recall. 
However, the underlying assumption of learning effect is that it is expected to be equivalent in both 
randomized study conditions, and moreover is of study interest for between-group effect though not 
directly measured. The tests were selected as ones with established reliability of repeated testing, which is 
operationally validated for simple motor tasks - simple reaction time (18 trials, Hamsher 1977), 9-hole 
pegboard test, MN-PQ keyboard tapping speed, and TUG. On the other hand, there is greater potential 
learning bias in cognitive tasks, particularly visuoverbal 3-back working memory task (Soveri et al 2018) 
where test-retest reliability has been reported as moderate, whereas simple reaction time reliability is 
much higher. Nonetheless, it is the aim to adjust for learning effect by randomization between the groups 
stratified by age. Learning effect could account for some of the difference in performance between the 
groups particularly in cognitive tasks. The goal is to capture which types of testing improve, whether ones 
more (n-back test, Stroop word-color interference) or less (reaction time, tapping speed, TUG) subject to 
learning effect, to infer appropriately whether or not learning effect may be considered to be operative in 
any difference between the groups.  
 
The combination of inpatient and outpatient parts of the study involves some degree of discontinuity of 
the diet, at least in terms of monitoring but also in the diet itself. The latter difference is due to the desire 
to maintain double-blinding in the inpatient part of the study to minimize placebo effect, while also 
wanting to assess feasibility of a diet that is thought to be better tolerated than traditional, strict 4:1 (4 
grams lipid to 1 gram carb + protein) ketogenic diets. The inpatient diet is predominantly liquid via 
blended nutrients to facilitate the blinding, but this is not practical to recommend for long-term outpatient 
therapy. Furthermore, while there is possibility to maintain a control group in the outpatient part of the 
study, it is felt preferable to prescribe ketogenic diet to all participants outpatient for a few reasons. First, 
study power will be increased for the key portion of the study: feasibility of MCT-KD in the home. 
Second, regardless of inpatient randomization group, all participants will have opportunity to try the 

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ketogenic diet as possible therapy, which should improve study recruitment and limit possible “nocebo” 
effect that an outpatient control group might otherwise be subject to. 
 
Herein is proposed an inpatient pilot study of MCT ketogenic diet (MCT-KD) compared to standard 
American diet (SAD) in randomized, double-blind participant groups followed by outpatient study of a 
similar ketogenic diet with education and meal preparation guidelines, monitored for the inpatient portion 
with fingerstick beta-OHB levels, continuous glucose monitoring, and respiratory quotient and outpatient 
via online meal planning app, Diet tracking, correlating with motor physiology, cognitive inhibition and 
short-term recall, and EEG characteristics to establish which, if any, aspects of known PD test 
impairments may be modulated by ketogenic intervention in relation to suspected or likely metabolic 
pathways, to inform subsequent study into symptomatic benefit and/or disease modification.  
 
4.3 JUSTIFICATION FOR DOSE 
MCT ketogenic diet has been shown to be non-toxic (Traul 2000) and well tolerated at a dose of 30mL 
three times daily (Harvey et al 2018). This dose led to a mean increase in beta-OHB of 0.8mM by day 7 
and shorter latency of keto-induction (more participants achieving level of 0.5mM by days 1-2), as well as 
lower mean glucose values, with mean beta OHB in the MCT oil group >1mM by day 6. Due to the 
reported higher incidence of GI side effects in that study, and expected lower GI motility due to 
autonomic dysfunction, a more moderate dose of 20% calculated daily resting energy expenditure or 
approximately 45-60 mL daily will be used. A similar dose of 40mL once daily in a cohort of AD 
participants the morning fasted state showed increase of beta-OHB by approximately 0.5mM at peak-
dose, 90 minutes later (Reger et al, 2004). MCT as a supplement to ketogenic diet has also been studied in 
pediatric epilepsy and found to be useful to achieve a therapeutic effect in that population with a wider 
range of carbohydrate intake (reviewed in Liu et al, 2008). A similar use in PD might be established, and 
such determination would require further study such as proposed in this study. MCT permits a 
manipulation of ketogenesis between a ketogenic and non-ketogenic group while maintaining a similar 
diet composition, including same levels of protein, which is an important potential confound through its 
reported effect on L-DOPA intestinal absorption neutral large amino acid transporter. 
 
5 
STUDY POPULATION 
5.1 INCLUSION CRITERIA 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
 
1. Must be able to speak English 
2. Able and willing to provide informed consent 
3. Male or female older than age 50 years 
4. Clinically probable diagnosis of Parkinson’s Disease by UK Brain Bank Criteria, of moderate 
severity (Hoehn & Yahr Stage 2-4), with ability to safely walk independently for at least a short 
distance (20 feet) as determined on screening visit 
5. BMI > 18.5, to minimize potential risk from expected mild weight loss from ketogenic diet 
6. eGFR > 60 by MDRD equation (established on screening visit serum chemistry)  
7. MOCA > 20, as well as having in the investigators’ assessment the ability and willingness to 
adhere to either of the study diets 
8. Agreement to adhere to Lifestyle Considerations (see section 5.4) throughout study duration 
9. Adhering to Usual Diet (SAD) at baseline, as per investigator determination 
 

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                 5.2 EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
 
1. Atypical Parkinsonism or symptoms suggestive of a diagnosis other than PD by clinical criteria 
2. Family history of early onset PD (<age 40) or known personal genetically causal etiology of PD 
(e.g. SNCA duplication, Parkin, PINK, DJ1) by previously obtained genetic testing 
3. Currently pregnant 
4. Sarcopenia defined as low BMI (<22 Bahat et al, 2019) with clinically defined weakness 
5. Medical history of cardiac arrhythmia, heart failure, stroke / cerebral hemorrhage, epilepsy, other 
disease of the central nervous system, active cancer, end-stage liver disease, advanced kidney 
disease (CKD stage 3 or ESRD), beta thalassemia, or any other medical condition deemed by the 
PI to pose an increased risk for taking part in the study. 
6. Inherited or other metabolic disease known to be worsened by ketogenic diet, e.g. inherited defect 
of lipid or amino acid metabolism 
7. Diabetes on SGLT2 inhibitor or uncontrolled diabetes, defined as Hemoglobin A1c > 8.0% on 
screening test 
8. History of kidney stones or gallbladder surgery 
9. Biliary / liver disease, defined on screening labs, by presence of any of the following: Total 
bilirubin (TB) > 2x ULN or > 2 mg/dL;  AST  >3x ULN; or ALT >5x ULN 
10. Uncontrolled hypertension, defined as SBP > 180 mmHg or DBP > 105 mmHg on screening visit 
11. Hyperlipidemia, defined by LDL >/= 160 mg/dL, as per ATP-III guidelines 
12. Medical / psychiatric condition identified via clinical assessment in screening visit felt to impede 
completion of the study* 
13. Presence of PD Psychosis or dementia, or other neuropsychiatric or psychiatric illness impeding 
consent and fidelity to the study intervention and/or measurements 
14. Dietary or allergy restrictions as determined by research team to be prohibitive for the study 
15. Inability to communicate and provide informed consent in English 
16. No history of previous use of ketogenic or similar diet to a degree that could interfere with study 
blinding 
 
*A thorough medical and social history will be performed during the screening visit including 
questions regarding alcohol and substance abuse.  If active alcohol abuse or other current substance 
abuse is identified which could increase the risk of study participation, then participants will be 
excluded.   
 
5.3   INCLUSION OF VULNERABLE PARTICIPANTS 
N/A 
 
5.4     LIFESTYLE CONSIDERATIONS 
During this study, participants are asked to: 
● Participants who use tobacco products will be instructed that use of nicotine-containing products 
(including nicotine patches) will not be permitted while they are in the clinical unit.  

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● Abstain from strenuous exercise for 4 hours before each blood collection for clinical laboratory 
tests. Participants may participate in light recreational activities during studies (e.g., watching 
television, reading).  
5.5 SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently assigned to the study intervention or entered in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants, to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a 
significant systemic comorbidity, concern of potential atypical or secondary parkinsonism, or PD 
psychosis or dementia may be rescreened. Rescreened participants should be assigned the same 
participant number as for the initial screening. 
 
5.6 STRATEGIES FOR RECRUITMENT AND RETENTION 
Community engagement was obtained by involving People with Parkinson’s (PwP) who either adhere to 
ketogenic diet or who are interested in modifying their diet for PD or general nutritional health. These six 
individuals were identified through NIH PD Clinic as attendees of the clinic and initiated discussion about 
ketogenic, Paleolithic, otherwise low-carbohydrate diet or requesting dietary recommendations. With all 
of these individuals, the following was asked: 
 
 -what do you think about this study concept – comments, questions, concerns? 
-what do you think about ketogenic diet? (if you have a sense about it at all) 
-have you received dietary recommendations regarding PD or your general health, if so would you be 
willing to share what the gist of those are? 
-do you consider your diet to have any particular impact on your symptoms, if so how? (excessive protein 
is well established to worsen PD symptoms in those who have more advanced disease with fluctuations, 
excessive carbohydrate not as clear, although metabolic syndrome is a clear risk factor for PD). 
-do you think a one-week study with non-invasive testing aside from blood draws is reasonable without 
monetary compensation aside from travel expenses, on the basis of the potential therapeutic value of 
dietary modification and learning about its effects on your symptoms? 
 
Initial feedback (n=25, predominantly via PD Facebook interest groups and also email) has been that 
ketogenic diet has been attempted by few of these individuals, and dietary recommendations are not 
standard in medical care for PD. There is agreement that both excess carb and protein can perturb 
symptoms of fatigue, tremor, bradykinesia, and so forth. There is some expressed concern from a few 
individuals that a one-week inpatient study with a standard diet vs. ketogenic diet might have difficulty 
garnering recruitment, with limitation in exercise regimen raised as a potential barrier. It will be important 
to distribute questions about the current study concept and dietary interest / engagement to a wider 
sampling of the community, which will be targeted via in-person discussion at local support groups, and 
continue through online media such as Facebook support groups. Additionally, one of the associate 
investigators is a PwP who has adhered to ketogenic diet for ten years and has provided valuable insight 
on the diet’s anecdotal long-term effects on symptoms, tolerability and ADLs, guiding this study design. 
 
Recruitment will include contacting PD patients who have been previously seen at NIH under protocol 
01-N-0206, 93-N-0202, or 14-N-0086. The informed consent documents associated with the protocols 

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contain language that permits subjects to be recontacted for future studies and will be contacted via email, 
telephone or a mailed letter. 
 
Recruitment will also occur through listing on ClinicalTrials.gov direct presentation) at local support 
groups. 
 
Accrual will occur up to 2 screening visits / admissions per week, and expected average of less than that, 
perhaps 1-2 per 2 weeks. 
 
There is one study site, NIH Clinical Center due to the specific inpatient study design. There will be no 
specific effort aimed at recruiting internationally. This is because the goal is to show feasibility and time 
series in a small-power pilot study, addressing mechanistic questions prior to any larger study that could 
show external validity in different disease populations.   
 
5.6.1 
Costs 
The main cost to participants would be in local transportation across two study visits, defined as <(50) 
miles from the NIH Clinical Center. Travel expenses could be incurred in traveling for longer distances 
but would be eligible for reimbursement. Additionally, some additional cost may be associated with the 
two week outpatient ketogenic diet above usual food expenses, but given that MCT oil (approximately 
25% of the daily fat) will be supplied, this is not expected to be a major cost and meal plans will be 
designed with cost in mind. The inpatient intervention and all testing would be provided to the 
participants free of charge. There is the potential for acute decompensation in vital function from 
relatively frequent causes - infection, cardiac arrhythmia, or thromboembolic event - or other cause, for 
which emergent acute care would be provided by Clinical Center without cost to patient, and transfer to 
nearby, affiliated or other medical facility could be performed at cost to the patient for services (e.g. tPA 
for stroke) not available at the Clinical Center.  Due to the short duration of the study, the possibility of 
costs for emergency medical care is relatively low.  
 
5.6.2 
Compensation 
For travel expenses to/from Screening Visit (#1) and/or Admission Visit (#2) and/or Outpatient 
Final Visit (#3): 
● Reimbursement for Lodging if travel >50 miles: as per scale used for 01-N-0206 protocol 
● Reimbursement for travel < 50 miles as per scale used for 01-N-0206 protocol 
● Compensation will not be provided 
 
 
6. STUDY INTERVENTION 
6.1 STUDY INTERVENTIONS(S) ADMINISTRATION 
6.1.1 Study Intervention Description 
Study Type and Design 
Patients will undergo age and TUG time 2-factor stratified randomization to MCT-KD or MD groups by 
biostatistician who will keep the randomization scheme (see 9.2, Sample Size Determination). 
Randomization will not factor PD medications or DBS status, because there is no clear data to suggest 

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that certain medications, medication dosages, or DBS status will interact with dietary composition, either 
ketogenic or standard at standard protein intake. Study raters will remain blinded to diet group, because 
randomization scheme will be kept only by biostatistician and intervention status will be known otherwise 
only by nutrition staff, none of whom are involved in study rating. A possible exception is unblinding due 
to serious adverse event determined by study PI (non-rater) in consultation with safety monitor in which 
participant continues in the study, in which case data will be demarcated and not included in statistical 
analysis.  Prior to admission, participants will be instructed to complete a log for 1 week of activities and 
diet at home. Upon admission to the Metabolic Unit and during hospital day 1, they will continue a 
regular, healthy hospital diet (carbohydrate predominant) and undergo baseline testing in mobility, 
physiologic and cognitive measures as per Section 3, Objectives and Endpoints). On hospital days 2-7, 
they will begin one of two diets:  diet A, MCT-KD, according to set macronutrient ratios by daily energy: 
lipid 80% (25% of which is MCT oil), carb 5-10%, protein 10-15%, expected to be better tolerated than 
traditional NK, vs. diet B, standard American diet, lipid 30-35%, carb 55%, protein 10-15% . The goal is 
study time series of betaOHB, respiratory quotient, and continuous glucose ketosis measurements with 
tests of symptomatic impairment, with the hypothesis that nutritional ketosis augments mitochondrial 
function within hours of keto-induction and provides further benefit over days due to better functional 
neurotransmitter supply to key motor and cognitive synapses, aside from any long-term disease 
modification. Added benefits of an inpatient trial include monitored adherence and a look at biomarkers 
such as respiratory quotient in the metabolic chamber (CO2:O2 expected to go down due to diet), as well 
as easier access to daily repeated testing such as cognitive focused testing on executive function, memory 
and learning, as well as quantitative motor assessment of bradykinesia (keyboard, 9-hole pegboard), 
blinded UPDRS, and pain / fatigue assessment by subjective report.  
Overview of Trial Flow and Events. Figure 1 highlights MCT-KD trial flow and events. We propose a 
screening enrollment of 1-2 participants per week for total of 32 participants. Upon meeting study criteria 
and consent, participants are asked to provide one week baseline diet and activity/exercise intake, and 
then be admitted to NIH CC for a one week study intervention assessing ketosis and symptom outcomes, 
safety monitoring and potential biomarkers of the diet on Parkinson’s EEG and BDNF levels. During 
admission and discharge, communication will be maintained with participants regarding the requested 
outpatient portion, in which participants are provided meal plans to continue (or in the case of standard 
diet participants, begin) a standard ketogenic diet, with MCT oil in the home. The outpatient diet will be 
given as recommended meals and instructions to be reachable via telephone for twice weekly unscheduled 
calls from NIH CC Nutrition staff to populate diet adherence using diet tracking linked to study 
investigator’s account. Additionally, study nutritionist / investigator (not involved in study rating) will 
perform unscheduled twice weekly phone calls to obtain post-screening baseline diet (one week) and 
outpatient KD intervention adherence assessment (two weeks). Participants will then be asked to return 
for a follow-up visit in NIH CC OP5 two weeks after discharge date. If the appointment date varies from 
two weeks for any reason, the same visit and measurements will occur, but visits will be demarcated 
separately for statistical analysis.   

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Screening procedure:  Following recruitment, potential subjects will be pre-screened by telephone, in 
person, or via email communication according to the inclusion / exclusion criteria, discussion of the scope 
of the study and study design, expected potential benefits and side effects. If the potential candidate  
meets the study eligibility criteria, a screening visit will be scheduled at NIH CC outpatient clinic.  The 
estimated duration of the screening visit is 4 hours, and may be spread over 2 seperate days if necessary. 
Upon registration, an order will be submitted for metabolic tracking (PCO2:PO2 gas exchange) for 
calculation of daily resting energy expenditure.  
 
Informed consent will be obtained prior to any tests or procedures being conducted at the screening visit.   
 
During the screening visit, history, physical exam, focused neurologic exam, Unified Parkinson’s Disease 
Rating Scale (UPDRS), Geriatric Depression Scale (GDS), Non-Motor Severity Scale (NMSS), blood 
draw consisting of 1 gel-barrier tube (gold, red, or mottled red-gray) for BMP, HCG for women of 
childbearing potential), and Timed Up and Go test, as well as randomization by study biostatistician.  
Results of study group allocation will be conveyed by biostatistician to study dietician to prepare for 
inpatient diet formulation. 
 
Active Intervention: The Ketogenic Diet. The typical American diet contains ~50% carbohydrate, 35% 
fat, and 15% protein calories. The proposed KD proposes decreased carbohydrate (5-10%), greatly 
increases fat (80%), which becomes the primary energy source, and leaves protein unchanged (15%) 
calories. The ratio of lipid (fat) to non-lipid content (carbohydrate and protein) defines different NK 
plans. Unlike “Western” high fat diets that do not restrict carbohydrates, NKs do not significantly 
increase or may decrease triglycerides, insulin resistance, and body weight. 
   
MCT oil consumption can increase overall fat intake, enhance ketosis, and allow more absolute 
carbohydrate consumption. Furthermore, in the outpatient part of the study, complex carbohydrates will 
be given through diverse vegetables including non-starchy green leafy vegetables and tomatoes. The lipid 
ratio will be MCT: other lipids at a 1:3. Multiple trials of AD patients (e.g. Reger et al 2004, Ota et al 
2019) demonstrated this approach is feasible for AD patients, and thus toleration is not considered to be 
of significant concern. MCTs, though, can cause gastrointestinal discomfort, and this will be monitored. 
In the Reger et al and Henderson et al studies cited, an emulsified MCT formulation and gradual titration 
schedule minimized this complaint. 
   

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Blood fingerstick ketone concentrations quantify depth of ketosis. Adherence will be ensured through 
clinical provider/nurse check-ins and meal preparation in coordination with dieticians and Clinical Center 
nutrition staff. We will determine fingerstick β-hydroxybutyrate levels at baseline and at two daily 
defined intervals from meals and medications (once daily on day 7).  Ancillary proxy testing of ketosis 
will additionally occur via continuous glucose monitoring (Freestyle Libre Pro System sensor, Abbott, 
FDA approved for healthcare professional use with diabetes, for non-FDA approved research use in this 
study, to gauge indirectly ketosis value in continuous fashion). 
All participants will receive dietary counseling and educational material from study dietician/nutritionist. 
Counseling will include planning outpatient meals that are ketogenic incorporating MCT oil, with the 
goal of prioritizing accessibility in grocery stores for participants to obtain relatively easily; relatively 
lower cost ketogenic foods; and considering nutritional value. 
 
Because the intended use of MCT oil is to facilitate a ketogenesis state along with diet and nutrition to 
mitigate symptoms of Parkinson’s disease, MCT oil may be considered to be a drug for the purpose of the 
study. The use of MCT oil  is not intended to support a new indication for use or any other significant 
change to the labeling; the drugs are already approved and marketed and the investigation is not intended 
to support a significant change in advertising; and the investigation does not involve a route of 
administration or dosage level in use in a patient population or other factor that significantly increases the 
risks (or decreases the acceptability of the risks) associated with the use of the drug product.  
 
MCT oil will be used as a means to facilitate achieving ketogenesis in a manner that is expected to be 
more feasible for patients than the ketogenic diet alone.  MCT oil is commercially available and meets 
GRAS FDA exemption (see protocol 2.3.1a).  While MCT oil is novel in the study population and has 
not yet been studied in patients with Parkinson’s disease, the expectation is that adverse events to be 
similar to those reported in several studies of patients with Alzheimer’s disease.  The oil is not being 
modified in any way and will be used according to approved parameters as a dietary supplement to 
achieve a ketogenic state, which is the primary goal of this study.  
 
An IND exemption was filed with the FDA, and the final outcome was FDA determination that the study 
does not appear to raise safety concerns and accordingly, the research study is not expected to comply 
with the IND reporting requirements for this study.  The use of MCT oil in this research study will be 
within the parameters and standards of the GRAS FDA exemption for this product. 
 
 
6.1.2 
Dosing and Administration 
Dose of the Liquigen® (KetoCal)  MCT oil will be calculated individually based on 20% participant daily 
energy expenditure using the Weir formula. Meals will be combination of solid and blended liquid with 
care taken for blinding study subjects to ketogenic or standard diet composition.  
 
6.1.2.1 Drug Administration 
The MCT oilLiquigen® (KetoCal  will be incorporated into food / beverages for participants in the MCT-
KD group by NIH CC Nutrition Department staff, who will not disclose group identity to study raters. 
Record of food and beverage consumption will be maintained using weight and data entry as per usual 
practice in nutritional studies at the NIH CC.  The purpose of the notification will be to ascertain the 

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degree of missing data for ketosis intervention; determine if any quality control might be helpful; and see 
if additional ketosis data are required. 
 
The standard and ketogenic diets will be provided by the Nutrition Department of the Clinical Center. 
Both diets will be as per provided menu in collaboration with Metabolic Unit staff (study dietician and 
others). Standard diet will adhere to macronutrient composition lipid 35%, protein 10-15%, carbohydrate 
50-55%. Ketogenic diet will incorporate restriction of carbohydrates to reach 80/5-10/10-15 
(lipid:carb:protein daily energy) values. The total daily energy will be calculated from respiratory gas 
exchange in the Metabolic Chamber using the Weir formula (Weir, 1949): Metabolic rate (kcal per day) = 
1.44 (3.94 VO2 + 1.11 VCO2). Both ketogenic and standard diets will be eucaloric, providing 
recommended daily calories. 
 
6.2 PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
N.A. 
6.2.1 
Acquisition and Accountability 
The Liquigen® (KetoCal)MCT oil is carried by the Clinical Center Nutrition Department and will be 
made available for the diet preparation. 
 
6.2.2 
Formulation, Appearance, Packaging, and Labeling 
As per Liquigen® (KetoCal)  Product Bulletin  
(URL: < https://shop.myketocal.com/product/liquigen>): 
• 
Ingredients:  Refined coconut and/or palm kernel oil, water, citric acid esters of mono and 
diglycerides (emulsifier), mono and diglycerides (emulsifier), citric acid. 
• 
UnflavoredFor oral or enteral use 
• 
kcal/mL: 4.5  
• 
Caloric Distribution (% of kcal) 
- Protein: 0% 
- Carbohydrate: 0% 
- Fat: 100% 
Recommended Usage: 
- Oral Administration: It may be mixed into beverages and foods. 
 

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6.2.3 
Product Storage and Stability 
 
This product will be stored in the original plastic 250 mL bottle.  
 
6.2.4 
Preparation 
MCT Oil® (Nestle)  MCT oil will be mixed by Nutrition Department Dietary services at the 
Clinical Center. It will be added to other ketogenic foods prepared as per the study menu. 
 
Outpatient ketogenic diet 
According to participant decision after discussion during the screening and admission, willing participants 
are instructed to continue ketogenic diet as defined by CC nutrition staff customized from provided meal 
plans provided to each participant. 
 
Diet tracking with information on macronutrient and micronutrient composition will occur via 
unscheduled phone calls by study dieticians conducting 24 hour food recall, input to NDSR04 software. 
6.3 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
As described in Section 9.2 (refer for details), study participants will be randomized after screening visit 
by study biostatistician. The intervention allocation will be withheld from all study investigators and 
raters until after the conclusion of all measurements, who will remain blinded to participant allocation for 
the duration of the study. Refer to Section 9 for details of randomization. 
 
The study nutrition staff will remain unblinded in establishing participant-individualized meal plans. S/he 
will not disclose any diet details of the admitted participants and will not participate in any of the study 
measurements. Other investigators will be blinded except due to adverse event or inadvertent event. 
Nutrition staff (CC Nutrition Department) will design the blinded diets according to the macronutrient 
ratios and MCT oil supplementation specified in the study (from calculated daily total energy expenditure 
by gas exchange on screening visit using Wier formula).  Aside from the addition of MCT oil comprising 
25% of daily lipids, the diet will be similar to what was used in existing study at the NIH CC Metabolic 
Unit, NCT03255031 Ketogenic Diet in Alcoholism, as per clinicaltrials.gov description:  
Dietary Supplement: Ketogenic Diet (KD) / Standard American (SA) Snacks and Shakes  

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“Ketogenic Diet (KD) / Standard American (SA) Meals and Shakes: Participants will be randomized to a 
meal plan of either a ketogenic diet (KD) or standard American (SA) diet at the time they sign the 
consent. For each meal at breakfast, lunch and dinner, the diets will consist of SA meal (carbohydrate 
rich) or KD meal depending on treatment randomization... [ ]...To ensure that the diet is double blind...[ 
]...solid snacks are always ketogenic and shakes are either KD or SA.”  
From conversation with NIAAA study PI and study nutrition staff, when participants were asked about 
which diet they believed they received, they usually thought they were receiving ketogenic diet, which 
appears to support the integrity of the dietary blind.  
 
Based on the literature of ketogenic diet pilot studies (of 3 months duration or less) that no major adverse 
event was reported in three ketogenic studies in PD and another three in AD, it is unlikely that a serious 
adverse event (SAE) related to the intervention will occur. Monitoring will occur by daily clinical 
assessment (AI / metabolic unit staff) and electrolyte testing. 
 
If there is a major adverse event, including but not limited to: Na <135, K < 3.4, Mag <1.0, HCO3 < 22, 
and/or vomiting,  study investigators including PI will be immediately made aware by Metabolic Unit 
staff, discussion will occur with the Independent Medical Monitor within 24 hours as to recommendations 
for therapy, and participant will be withdrawn from the study and study investigators unblinded to the 
participant’s intervention status unless there is consensus by the IMM and Metabolic Unit staff that 
ketogenic diet can be continued with other measures taken (e.g. fluid rehydration, anti-nausea medication) 
or participation continued on a modified / less stringent ketogenic diet. 
 
Despite double-blind design, unblinding may occur inadvertently. The participants will be instructed 
beforehand to make no mention of their diet, same as Metabolic Unit nurses and dieticians. If however 
unblinding of study rater(s) does unexpectedly occur, participants will by default remain in the study but 
be discounted from study power calculation and marked separately for statistical analyses. 
 
6.4 STUDY INTERVENTION COMPLIANCE 
Study adherence will be assessed primarily through blood and respiratory ketosis values, both 
directly via beta-OHB phlebotomy at defined intervals (three times daily) and indirectly via POC glucose 
checks, continuous glucose monitors, and daily respiratory quotient (pCO2/pO2, expected to decrease 
from approximately 1.0 towards 0.7 as a function of predominantly glucose to predominantly fatty acid 
metabolism). Adherence will be assessed also through records of diet consumption made by Nutrition 
Department staff (AI) using instructions to consume 100% of provided meals and weighing meals 
before/after consumption, logging data using ProNutra software. All willing study participants will be 
counseled on ketogenic diet in preparation for the outpatient portion of the study unless they have 
communicated that they will decline the outpatient study. They will receive a schedule of possible meals 
to select from for the two weeks of outpatient study and to establish a means of contact with study 
nutritionists for adherence estimation. During these two weeks, study nutritionists will call them twice 
weekly at unscheduled times for 24-hour food recall review, and data from these calls will be used to 
determine outpatient adherence.  
 

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6.5 CONCOMITANT THERAPY 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications to be reported in the Case Report Form (CRF) are 
concomitant prescription medications, over-the-counter medications and supplements.  
 
No adjustments will be made to patient’s home medication regimen including all Parkinson’s Disease 
medications. Any omissions whether in error or patient choice will be recorded in CRIS. 
 
7. STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL  
                  7.1    DISCONTINUATION OF STUDY INTERVENTION 
Discontinuation from dietary intervention does not mean discontinuation from the study, and remaining 
study procedures should be completed as indicated by the study protocol.  If a clinically significant 
finding is identified (including, but not limited to changes from baseline) after enrollment, the investigator 
or qualified designee will determine if any change in participant management is needed. Any new 
clinically relevant finding will be reported as an adverse event (AE). 
 
Holding criteria: Study intervention(Liquigen® (KetoCal) ) and ketogenic diet) will be withheld if 
clinically significant cardiac arrhythmia is detected on baseline ECG (please refer to Clinical Evaluations 
Section 8.2 for details).  
 
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
diet menu and record 
• 
patient interview with worksheets and symptoms 
• 
height, weight, vital signs including orthostatic (supine x 10min, immediately and 3min after 
standing); physical examination with focused neurologic examination 
Stopping criteria: 
 
1.) Patient request 
2.) If any investigator judges that continuing the procedure would be detrimental to the patient’s 
health and well-being or that clinically meaningful data is not being obtained for other 
reasons. 
 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
• 
Completion of study intervention 
• 
Disease progression which requires discontinuation of the study intervention 
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best interest 
of the participant 
• 
Investigator discretion 
• 
Positive pregnancy test 
• 
Participant unable to receive study intervention for more than 1 day  
 

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7.2   PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Prior to removal from study, effort must be made to contact all study participants via telephone to 
determine safety regarding the intervention approximately 2-4 weeks following the last dose of study 
therapy. 
Participants are free to withdraw from participation in the study at any time upon request.  
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
• 
Significant study intervention non-compliance  
• 
If the participant meets an exclusion criterion (newly developed) that precludes further study 
participation 
• 
Subject has completed the study follow-up period 
 
• 
Screen Failure 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (CRF). Subjects who sign the informed consent form and are randomized but do not receive 
the study intervention may be replaced.  Subjects who sign the informed consent form, and are 
randomized and receive the study intervention, and subsequently withdraw, or are withdrawn or 
discontinued from the study,  will not be replaced. 
7.3 LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for the admission following 
the screening visit and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
● The site will attempt to contact the participant and reschedule the missed visit over the course of 
the following one week and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain if the participant wishes to and/or should continue in the study. 
● Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, a 
certified letter to the participant’s last known mailing address or local equivalent methods). These 
contact attempts should be documented in the participant’s medical record or study file.  
● Should the participant continue to be unreachable, he or she will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 SCREENING PROCEDURES 
Recruitment will occur from existing cohort of PD patients that have enrolled in NIH protocols 01-N-
0206, 93-N-0202,  and14-N-0086. All informed consent documents associated to the referenced protocols 
contains language that obtains permission from subjects for their information to be saved and to be re-
contacted by study investigators for future research studies at the NIH.  There will be access to prior 
records in CRIS, paper chart, and genetic testing. The data are accessible by associate investigators of all 
the above protocols. All federal and state laws as well as requirements of the NIH will be followed 
regarding patients’ PHI.  
.  
Participants either previously seen under the protocols listed above, or otherwise contacted or who contact 
study investigators with interest in the study will be pre-screened with the request for /in most cases 

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obtaining outside documentation of Parkinson’s Disease clinical care, with exception being made only if 
the records are not available upon request, however a thorough attempt will be made at verification of 
existing diagnosis. These outside documents will be requested of participants to be faxed to the Study 
Investigator (PI), or permission be granted for PI to request this from the participant’s physician office 
directly. For participants pre-screened who have participated in 01-N-0206, prior documentation by the 
protocol investigators will likely be considered to be sufficient without outside documentation. 
 
At the screening visit after participant’s informed consent is obtained, data will also be obtained from 
patient self-report, however effort will be made to verify this with physician or ancillary medical care 
documentation.  
 
8.2 EFFICACY ASSESSMENTS 
As one of the study aims is to determine feasibility of MCT supplemented ketogenic diet, the efficacy of 
primary objective of study feasibility as per recruitment, retention, acceptability, and adherence will be 
determined by a composite outcome, in which all criteria are met: completion rate of both inpatient 1 
week and outpatient 2 week segments, with target of >80% for each; recruitment target of 32 participants 
reached; adherence to outpatient diet with mean daily carb </= 10%; intervention is acceptable to all 
participants by Likert scale >/= 2/4 of likelihood of using this therapy in the future and effectiveness in 
symptom reduction. 
 
 Efficacy of secondary objective of TUG reduction will be assessed by between-group mean difference at 
7 days (MCT-KD vs. SAD). It is presumed that the standard (control) diet will not provide any issues of 
feasibility. Refer to Section 4.1 Study Design for direct and indirect determinations of ketosis. 
  
 
Timed Up & Go (TUG) 
Efficacy of TUG will also factor effect of time, via repeated measures ANOVA for TUG that will be 
tested three times per session and fastest time used, with same timing relation to dopaminergic 
medications. 
Efficacy will be tested further in the between group difference between the two diets on outcomes of the 
following, again with same timing regarding dopaminergic medications: 
 
Exploratory measures will be done as per test schedule in Section 4.1, generally once daily or less.  
 
Stroop Word-Color Interference  
this test has been shown to be impaired in PD as part of the executive network of actively choosing the 
stimulus while inhibiting the background. The latency will be determined from a computer test. 
 
N-Back Task (% correct) 
 This test (Kirchner, 1958) involves a series of visual stimuli such as letters, and then participants are 
asked if each stimulus matches a stimulus n trials before. Performance is shown to be impaired in PD to a 
greater degree than  in normal aging 
 
Simple Reaction Time (SRT) 
SRT (same cue on computer screen, press button; machine is used already for Chronic Fatigue Syndrome 
protocol studies and will be made available for the study). PD is consistently shown to have increased 
latency that is attributed to the akinesia as cardinal motor symptom. The increase in latency is reduced by 

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Levodopa therapy (Muller 2001, 23729617), relatively unaffected by repetition / motor learning, and is 
hypothesized also to improve with metabolic ketosis. 
 
Keyboard MN and PQ speed and rhythm analysis 
The Keyboard test is used already for the SCA7 protocol by Human Motor Control neurophysiologist and 
will be made available for the study. Rhythm can be obtained from the raw data, which imputes the time 
of the keystroke into a text document and can be analyzed in frequency vs. speed analysis. PD 
bradykinesia involves a sequence effect of both reduction in amplitude and speed of repetitive fine motor 
movements that is well established. Therefore, as speed decreases there is expected greater variability in 
frequency). 
 
9-hole pegboard test 
This standardized, quantitative test of finger dexterity has been studied in Parkinson’s Disease (e.g. 
Earthart 2011) and found to correlate with Hoehn & Yahr disease severity with times of 20s for stage I 
ranging to 40s for stage IV. It can be done with a single investigator, stopwatch on a table, and the 
equipment is already available (being used for Neuro testing in 7SW for SCA7). 
 
8.2.1 
Clinical Evaluations 
Physical examination 
Participants will be examined at screening visit by board certified neurologist and movement disorder 
specialist with focused examination: 
general, cardiopulmonary auscultation, neurologic exam with focus on motor or other system disorders 
(such as sensory, musculoskeletal) related to Parkinson’s. There will also be UPDRS and request for 
video recording. Video record would require separate signed informed consent as per NIH protocol. 
Video recording is done for research purpose only (quality assessment by averaging scores of in-person 
rater with a separately blinded video rater).  
Examination with requested video recording as per above will be repeated on day of discharge (post-
intervention). Examination as per above will also be repeated on day of admission (pre-intervention), 
without request for video recording unless a significant clinical finding is observed in difference from the 
screening visit. 
 
Vital signs and Heart rate variability 
Vital signs will be done as per routine care in the Metabolic Unit and will also include daily orthostatic 
check to be done by Metabolic Unit staff or credentialed study investigator. Daily heart rate variability 
will be performed with pre/post intervention (daily days 1-7 and at week 3) heart rate responses to a) deep 
breathing at 6 cycles per minute (5 cycles E:I ratio) and difference between average max and min heart 
rates; and b) Valsalva Ratio (HR max : HR baseline) with Valsalva Maneuver x 15s at 30-40 mmHg (days 
1, 7, and week 3). 
 
Radiographic or other imaging assessments 
ECG – ECG will  be performed at screening or Day 1 of admission (depending on availability), however 
must be performed prior to diet intervention.  A routine ECG will be performed for confirmation of 
normal cardiopulmonary function. If arrhythmia is detected, Cardiology will be consulted and 
incorporating their recommendations, decision about remaining or withdrawing from the study based 
upon the underlying etiology sinus (more likely stay in the study) vs. non-sinus rhythm aberrancy (more 
likely withdraw from study) as per inclusion/exclusion criteria. 
EEG - regional changes in spectral power (theta, alpha, beta) and nonlinear corticocortical 
synchronization measure via phase lag index (focusing on frontotemporal, parietotemporaloccipital areas 

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in alpha1 and alpha2 frequencies, and reduction in theta power in temporal-central regions) as per 
Chaturvedi et al, 2019. 
EEG will be performed pre and post intervention in 7SW Neuro Testing area for a period of 20-30 
minutes (1 hour session), under the supervision of a neurophysiologist and/or a neurologist trained in the 
technique (AI). 
 
8.2.2    Biological specimen collection and laboratory evaluations. 
Blood tests will be drawn twice daily for plasma beta-OHB levels and plasma dopamine through 
contracted vendor(s), to be determined based on competitive bid process and stored at -4 C as per 
recommended processing/batching.  Blood draws will also occur on screening visit, hospital days 1 and 7 
of admission, and week 3 visit for metabolic tests at a CLIA certified laboratory (NIH Clinical Center 
Laboratory) as per section 8.2.2 below.  
Blood draws: 1 x (screening) + twice daily (admission days 1-6) + 1x (admission day 7) + 1x (week 3 
final visit)  
 
Study total:          - volume of blood: 38 small tubes (1-2 mL each), approximately 40-80 mL  
                             - blood draws: 15 
 
8.2.3   Correlative Studies for Research/Pharmacokinetic Studies 
Special assays or procedures required:  
Continuous glucose monitoring (Freestyle Libre Pro System sensor, Abbott) 
The monitor will be provided to participants upon enrolling at the screening visit (#1) to obtain one week of 
baseline data on usual diet, and continued for the duration of the admission. Two weeks of data are 
provided in the system memory. If there is a delay between the screening visit and the admission, 
participants will be instructed to stop the monitor at one week in order to preserve the second week 
memory storage for the admission. 
 
Venous beta-OHB level and dopamine level 
Blood draws will be performed at defined intervals twice daily - at 7am, and at 2 hours after dinner (8pm). 
Timing of the blood draws is regarded as important to be as accurate as possible. Plasma dopamine will 
be tested on inpatient days 1-3, and plasma BOHB will be tested on inpatient days 1-7 and at week 3. The 
testing and reporting will be done in accordance with CLIA-certified NIH Clinical Center Core 
Laboratory. 
 
 
Respiratory exchange ratio (quotient), pCO2:pO2 
Will be performed on the Metabolic Cart at screening and week 3 outpatient clinic visits as per previously 
described method (Hall 2015, 26278052) 
 
Metabolic labs (blood): Hgb A1c, lipid panel, insulin, glucose, cortisol, TSH, T3, free T4,, BDNF 
Will be drawn day 1, day 7, and week 3 (final study visit), except for HgbA1C (screening, week 3) and lipid 
panel (screening, day 7, week 3) 
Non-heparinized sterile tube will be used for transport / storage in the NIH Clinical Center Core Laboratory.  
The testing and reporting will be done in accordance with CLIA-certified NIH Clinical Center Core 
Laboratory. 
 
Electrolytes (BMP, Magnesium) will be checked daily on inpatient days 2-6. If there is abnormality 
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investigators, it will be repeated on study days 6 and 7 and appropriate additional steps taken (e.g. 
hydration, anti-nausea medication, decreasing the lipid or MCT ratio of the diet, and possibly additionally 
including blood gas monitoring / transfer to ICU) in coordination with metabolic unit staff and the 
independent medical monitor. 
 
Daily survey: Parkinson symptoms, ketoinduction symptoms and gastrointestinal motility  
Two surveys will be administered daily, one detailing common Parkinson-related motor and non-motor 
symptoms (drawn from PI / AI clinical experience) as well as typical keto-induction symptoms (adapted 
from Harvey et al, 2018) and the other survey detailing gastrointestinal motility, adapted from IFFGD, 
URL: https://www.iffgd.org/publications-library/library/341.html 
 
 
Blood and urine samples will be discarded as per routine policy. 
8.2.4 
Samples for Genetic/Genomic Analysis 
PD inherited genes and family/linkage studies will be reviewed when available (prior enrollment in 01-N-
0206 or other neurogenetic study). There will be no samples collected for genetic analysis under this 
protocol. 
8.2.4.1 Description of how privacy and confidentiality of medical information/biological specimens 
will be maximized 
Participants will be provided a study number, and storage/reporting will be only via this number. Study 
number will be linked to PHI only via a document maintained by unblinded NIH staff investigator not 
involved with study measurements (biostatistician) that will be removed from other investigators except 
for instances of unblinding due to adverse events or study withdrawal. 
Measures of securing participants’ PHI will be maintained as follows: 
● Generation of study number by unblinded investigator (AI) in place of PHI for records of 
independent / dependent measures 
● No PHI in daily measurement records (study number and recorded values, including daily self-
report worksheets) 
● All records maintained in locked cabinet or on NIH Secure server 
● PHI for purpose of clinical care provided during admission maintained on password protected 
CRIS electronic medical record 
● Data sharing with other researchers such as NINDS supervisors, co-workers, or Grand Rounds 
will be in de-identified fashion, except where Video Consent was obtained with provision of 
removing facial / identifying features was provided to participant but declined 
● Data will not leave NIH except in the format of publication or presentation at professional 
meeting as per Data Sharing bullet item above 
 
8.2.4.2 Management of Results 
Results will be provided to participants in two formats: a discharge summary and a debriefing 
on the day of discharge or as otherwise determined with the participant. The discharge (DC) 
summary will include all laboratory results, including lipid profile, A1c, insulin, that in 
combination with blood pressure/height/weight/BMI and body fat % (bioelectric impedance) are 
significant to the metabolic and cardiovascular health, e.g. criteria for metabolic syndrome, 
HOMA-IR (insulin resistance calculation), and Framingham Risk score. DC summary will also 
include results of clinical assessments (e.g. Parkinson motor and non-motor symptoms / 
phenotypes / severity) and validated rating scales such as UPDRS, MOCA, and NMSS. Results 

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will not include ketosis values, EEG results, and cognitive / physiology / autonomic measures 
obtained for research purposes that lack current health implication. The debriefing will review 
DC summary results as well as give opportunity for researcher (PI / Metabolic Unit staff) to 
present clinical synopsis and share aspects of the participant’s research data as per expressed 
interest, as well as to provide education on diet given, general dietary recommendations, and 
summary of the intervention and research overview. Participants will be invited to review any 
publications and will be contacted for permission prior to presentation of any video.  
 
The NIH Clinical Center Laboratory is CLIA certified, CLIA ID Number - 21D0665373 
 
8.2.4.3 Genetic counseling - Not applicable 
8.3  SAFETY AND OTHER ASSESSMENTS 
● Biological specimen collection and laboratory evaluations.  
For metabolic analysis, blood samples will be drawn at screening visit (basic metabolic panel), 
baseline (admission pre-intervention) and at discharge (admission post-intervention), as per 
Section.  Additionally, blood will be drawn for beta-OHB levels at defined intervals (see Section 
1.3 Schedule of Activities for details) 
• 
Special assays or procedures required - continuous glucose monitoring 
● No storage of specimen required. The data will be downloaded from the sensor attached to skin of 
the back of the upper arm to the Reader twice, on admission and on discharge.  
● Heart rate variability monitor 
● No storage of specimen involved. Data will be stored on a central application 
 
● Counseling procedures, including any dietary or activity considerations  
Counseling will occur at study debriefing visit on day of discharge or as otherwise arranged, and 
may also occur at any point during the one-week admission (Visit #2) or during the screening 
visit (#1). Counseling will be primarily focused on healthy diet, including low glycemic index, 
DASH diet, and Mediterranean diet as per USDA guidelines, and will emphasize that ketogenic 
diet remains a matter of research interest regarding previously found / putative benefits for 
Parkinson’s Disease, however is congruent with aspects that are recommended by dieticians and 
physicians, such as minimizing salt and high glycemic index refined carbohydrates. 
 
● Assessment of study intervention adherence - see Study Intervention Compliance, section 6.4 
Administration of questionnaires or other instruments  
At screening visit (#1), participant will be asked to fill out PDQ39, and UPDRS (Parts 1, 2 and 4) 
and NMSS will be administered by PI. On the day of discharge, UPDRS and NMSS will be 
repeated. 
 
● Assessment of adverse events.  
 
There will be daily monitoring performed by metabolic unit staff and communicated to PI if concern, in 
turn discussing with independent medical monitor (IMM) and possibly unblinding AI if additional care 
required such as stopping the intervention, transfer to ICU. There will be no modification to the diets as 
outlined, to facilitate maintaining blinding and primary and secondary objectives of feasibility and ketosis 
ascertainment, respectively. There will be weekly meetings by investigators if any adverse events 
occurred as per Policy 801 (Refer to Section 8.4 for descriptions).  

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Intervention side effects will be identified by the study LIP who is monitoring the patient during the 
admission and has daily contact with the participant. With blood glucose monitoring during the study, the 
nurses will contact study investigators for blood glucose value < 70 mg/dL.  The hospital protocols are 
triggered for BG <40mg/dL that involve sending sample to NIH CC lab, including contacting study 
investigators for emergent care.  For blood glucose 40-70, there will be the following procedure: if 
asymptomatic and fully alert, 1 cup juice / crackers, recheck in 30 minutes, repeat as necessary. If 
symptomatic (such as light-headedness, headache, nausea) / mental status lethargy, provide juice / 
crackers and contact study investigators for possible IV D50 administration.  
 
The literature on safety of the ketogenic diet in adults in clinical trials is robust, including several trials in 
Parkinson’s disease (Krikorian et al 2019, Phillips et al 2018, Vanitallie et al 2005) .  The majority of 
these trials were conducted in the outpatient setting and adverse events were quite rare and typically 
minor in severity.  Similarly, MCT powder/oil as a supplement to accelerate ketogenesis is reported to be 
safe in Alzheimer’s Disease patients (Reger et al, 2004) as well as healthy volunteers (Harvey et al, 
2018).  Participants will be provided with contact information for the study team and asked to report any 
concerns, problems or new symptoms.  During the 2-week outpatient phase, telephone monitoring may 
also occur as needed.  
 
8.4 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.4.1 
Definition of Adverse Event 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
8.4.2 
Definition of Serious Adverse Events (SAE) 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, or a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions. Important medical 
events that may not result in death, be life-threatening, or require hospitalization may be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the participant and may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples 
of such medical events include cardiac arrhythmia requiring intensive treatment in an emergency room or 
at home, or pancreatitis / kidney stones that do not result in inpatient hospitalization. 
 
8.4.3    Classification of an Adverse Event 
 
8.4.3.1      Severity of Event 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 

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• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or incapacitating.  
Of note, the term “severe” does not necessarily equate to “serious”.] 
 
Serious adverse events associated with ketogenic diet are rare and reported predominantly in pediatric 
epilepsy population with different comorbidities and varying neurodevelopmental impairment, thus are 
not directly applicable to the adult population with Parkinson’s disease. Potential risks associated with 
ketogenic diet include dehydration related to natriuresis, electrolyte depletion, metabolic acidosis, 
vomiting, and elevated cholesterol and lipoprotein levels. Adverse events associated with these risks are 
not defined in frequency. Three pilot studies of ketogenic diet in Parkinson’s Disease did not report any 
serious adverse events.  
 
As a preventative measure, PD patients with cardiovascular and other major comorbidities will be 
excluded from the study, and EKG will be performed at admission baseline. Daily electrolyte testing will 
occur in all participants on study days 2-5, and daily clinical assessment for volume status will occur by 
metabolic unit staff and AI with maintaining blinding as possible in the absence of adverse events. 
Reporting of events such as vomiting or other ketogenic diet induction symptoms will occur to metabolic 
unit staff and relayed to study PI (not involved in rating) and independent medical monitor (IMM), except 
when medically necessary for unblinding to occur immediately (i.e. to provide emergent medical care). 
Baseline and end of study lipid panel will be measured and results made available to participants, with 
medical counseling to be provided in debriefing session on further checking outpatient with primary care 
physician if elevated or showing an upward trend. 
 
Relationship to Study Intervention 
All adverse events (Aes) must have their relationship to study intervention assessed by the investigator 
who examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect.  
 
• 
Related – The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
 
8.4.3.2   Expectedness  
IMM will be responsible for determining whether an adverse event (AE) is expected or unexpected.  An 
AE will be considered unexpected if the nature, severity, or frequency of the event is not consistent with 
the risk information previously described for the study intervention. 
 
8.4.4      Time Period and Frequency for Event Assessment and Follow-Up 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 

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All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of onset, 
clinician’s assessment of severity, relationship to study product (assessed only by those with the training 
and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs occurring 
while on study must be documented appropriately regardless of relationship. All AEs will be followed to 
adequate resolution. 
 
AE will be solicited through daily keto-induction symptom worksheets. Opportunity for unsolicited AE 
will be provided / encouraged, with instructions for conversation to occur initially with study PI / IMM to 
maintain blinding of study raters, when AE is not serious and is non-emergent.  
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any time 
during the study, it will be recorded as an AE.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
Study PI will communicate to IMM and record all reportable events with start dates occurring any time 
after informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of 
study participation. Study AI will also be involved in evaluation after study completion when non-
emergent. Events will be followed for outcome information until resolution or stabilization. 
8.4.5       Adverse Event Reporting  
Reportable events will be tracked and reported in compliance with Policy 801. 
 
8.4.6       Serious Adverse Event Reporting  
The study investigator will immediately report to the IRB any serious adverse event, whether or not 
considered study intervention related, including those listed in the protocol and must include an 
assessment of whether there is a reasonable possibility that the study intervention caused the event. Study 
endpoints that are serious adverse events (e.g., all-cause mortality) must be reported in accordance with 
the protocol unless there is evidence suggesting a causal relationship between the study intervention and 
the event (e.g., death from anaphylaxis). In that case, the investigator must immediately report the event 
to the IRB. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. Other supporting documentation of 
the event may be requested by the Data Coordinating Center (DCC) and should be provided as soon as 
possible. 
 
The Principal Investigator (PI) will be responsible for notifying the Food and Drug Administration (FDA) 
of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case 
later than 7 calendar days after the PI’s initial receipt of the information.  In addition, the sponsor must 
notify FDA and all participating investigators in an Investigational New Drug (IND) safety report of 
potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later 
than 15 calendar days after the PI determines that the information qualifies for reporting. 
Reportable events will be tracked and reported in compliance with Policy 801. 
 

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8.4.7     Events of Special Interest - N/A 
 
8.4.8     Reporting of Pregnancy - N/A 
8.5 UNANTICIPATED PROBLEMS 
8.5.1 
Definition of Unanticipated Problems (UP) 
Any incident, experience, or outcome that meets all of the following criteria: 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; and 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others (which many include research staff, family 
members or other individuals not directly participating in the research) at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known or 
expected. 
8.5.2 
 Unanticipated Problem Reporting  
The investigator will report unanticipated problems (UPs) to the NIH Institutional Review Board (IRB) as 
per Policy 801. 
8.5.3 
NIH Intramural IRB Reporting of IND Safety Reports 
Only IND Safety Reports that meet the definition of an unanticipated problem will need to be reported to 
the NIH Intramural IRB. 
 
1 
STATISTICAL CONSIDERATIONS 
9.1 STATISTICAL HYPOTHESIS 
 Primary hypothesis:  
Nutritional ketosis supplemented by MCT oil is feasible within a Parkinson Disease cohort as defined by 
an acceptable retention rate and outpatient adherence. 
Primary outcome: Feasibility of nutritional ketosis( ketogenic diet with 80% lipid including MCT oil, 10-
15% protein, 5-10% carbohydrate), in Parkinson Disease cohort defined as a composite outcome meeting 
all of the following criteria: recruitment target of 32 or as per interim power analysis defined in Section 
9.4.6; retention rate > 80% at study end; adherence to ketogenic diet in the outpatient portion defined as 
mean carbohydrate energy intake <10%, and intervention is acceptable to all participants by Likert scale 
>/= 2/4 of likelihood of using this therapy in the future and effectiveness in symptom reduction, from all 
study participants at 3 weeks.  
Secondary hypothesis:  

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Nutritional induced ketosis (NK) increases mobility based on TUG score in a Parkinson Disease cohort at 
7 days compared to usual diet (35% lipid, 10-15% protein, 50-55% carbohydrate). Secondary outcome: 
timed Up & Go test (TUG score) at study day 7 (fastest of three trials) 
H0: µ1 = µ2, where µ1 and µ2 are the population means for the NK diet group and usual diet group 
respectively vs. H1: µ1≠µ2. 
  
Exploratory hypotheses:  
Hypothesis A: Nutritional ketosis improves PD symptomatology in cognition (improved attention, recall, 
and executive function, and motor function akinesia and tremor within six days, as assessed by: Stroop 
word-color interference latency (executive function), n-back recall task (attention and working memory), 
simple reaction time (akinesia); fingertap speed and rhythm MN and PQ keyboard tasks (fine motor), and 
autonomic function (heart rate variability at rest and with deep breathing / Valsalva Maneuver tests)  
Hypothesis B: The mechanism of symptomatic reduction of NK in PD is both augmented mitochondrial 
metabolism (direct, rapid) and augmented neurotransmitter and growth factor synthesis (indirect, 
delayed), especially GABA and dopamine, as assessed by resting state EEG spectral power, phase 
coherence, and M1 waveform normalization. Accordingly, effect sizes for exploratory outcomes will be 
greater at 3 weeks than 7 days. 
Exploratory outcomes daily (days 1-7), week 3 
ON/OFF time (daily subjective worksheets), keto-induction symptoms (daily worksheets or self-report), 
UPDRS-III motor score, MN and PQ keyboard tasks, simple and complex reaction time, 9-hole pegboard 
test, 3-back recall, Stroop word color interference and latency, tremor amplitude, heart rate variability 
heart rate variability (SDNN, pNN50, rMSSD, power spectral analysis). 
Exploratory outcomes day 1, 7, and week 3: 
Valsalva Maneuver and deep breathing cardiovagal tests), plasma BDNF, Geriatric Depression Scale 
(GDS), EEG sensorimotor spectral power (Hall et al, 2014) and M1 waveform peak:trough asymmetry 
(Voytek and Cole, 2017).   
As an effect of the intervention at three weeks, there is expected to be decrease in EEG beta power on the 
more affected hemisphere clinically, relating to attenuation of pathologic pallidal GABA efferents to a 
greater extent than at 7 days or baseline. Similar trends are anticipated for attenuation of M1 waveform 
asymmetry, reduction in UPDRS total and subtotal scores, decreased latencies and total time of motor 
task performance tests, improved accuracy and speed of cognitive tasks, and increase in plasma BDNF 
and heart rate variability measures. The effect on depression symptoms is unclear but reduction is 
proposed. 
9.2    SAMPLE SIZE DETERMINATION 
Power analysis was performed based second outcome, TUG score, rather than feasibility outcome due to 
clinical significance of the former for both mobility and fall risk that is felt to be an important justification 
for this intervention as a pilot study, whereas feasibility ascertainment does not justify the study but 
merely indicates lack of existing clinical use of this ketogenic diet protocol. 

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Considering range of TUG tests reported in Parkinson’s Disease off dopaminergic medication of 8-17s 
(Foreman 2011), mean of 10-15s with SD 2.15-3.7s (Foreman 2011, Brusse 2005, Dal Bello-Haas 2011), 
and association of 1s increase in TUG time with 5.4% increase in odds of reporting a fall (Nocera 2013), 
it is suggested that fall rate can be reduced by 20% with a 4s reduction in TUG time, which is therefore 
considered to be a clinically meaningful difference. Minimal detectable change is reported as 4.85s (Dal 
Bello-Haas 2011) and 3.5s (Huang 2011).  
Based on these studies, the difference of 4.5s between the group means, which was considered as 
clinically important, and standard deviation (SD) of 4s (or effect size of 1.125) were used for power 
analysis. A two-sample t-test was applied to estimate sample size by assuming that the primary outcome, 
TUG, followed normal distributions, and the variances of the two groups were equal. Power analysis 
indicated that a total of 28 subjects, 14 per group, will be needed to achieve a power of 80% to detect the 
difference of 4.5s at significant level of 0.0492. The sample size calculation considered one planned 
interim analysis scheduled to be conducted when 8 subjects per group have completed. Using O'Brien-
Fleming approach, the interim analysis will be conducted with bound, p=0.0054 (t-value=3.287, df=16) 
and final analysis with bound p=0.0492 (t-value=2.06, df=26).  By anticipating 10% dropout rate, we will 
need to recruit a total of 32 subjects (16 per group).  
 
Randomization 
Stratified randomization method will be used to control the covariates of age (<=65 vs.  >65) and TUG 
baseline score (>=11.5s, vs. <11.5s Nocera 2013). With these two covariates, there are 4 possible block 
combinations (TUG<=11.5s & age<=65, TUG<=11.5s & age>65, TUG>11.5s and age<=65, TUG>11.5s 
& age>65).  
 
 
9.3    POPULATIONS FOR ANALYSES  
32 subjects randomized to either ketosis diet or a low fat (standard American) diet 
9.4   STATISTICAL ANALYSES 
9.4.1 Analysis of the Primary Endpoint 
Descriptive statistical analysis will be performed to assess the feasibility. 
 
9.4.2 Analysis of Secondary Endpoint 
To evaluate the diet effect on the TUG score, analysis of covariance (ANCOVA) will be performed with 
age and TUG score at day 1 as covariates, and TUG score on day 7 as a dependent variable.  
 
Repeated measures ANCOVA with age as a covariate will also be performed to evaluate the within-
subject effect: baseline day 1 vs. day 7 (inpatient) vs. 3 weeks (outpatient) of the intervention, and 
between subject-effect (diet): ketogenic diet vs. standard American diet.  
 
9.4.3   Analysis of the Exploratory Outcomes 
ANCOVA will be also used to examine the diet effect on the other exploratory outcomes, where each 
outcome measure over time will be used as a dependent variable with age and the outcome at day 1 as 
covariates. 
Longitudinal analysis methods, such as repeated measures ANCOVA, random coefficient model or mixed 
model, will be used to examine the change in the exploratory outcomes over the six days. Within-subject 

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(mixed model) and across-subject (spearman or Pearson) correlation analysis will be applied to evaluate 
the relationship between outcome variables. 
 
9.4.4   Safety Analyses 
N/A 
9.4.5   Baseline Descriptive Statistics 
Descriptive statistics, such as mean, median, standard deviation, frequency, will be calculated to 
demonstrate patients’ baseline demographics and clinical characteristics 
9.4.6   Planned Interim Analyses  
We plan to perform one Interim analysis which is scheduled when the primary outcome (TUG) data is 
collected from 8 patients from each group (mid-way).  O'Brien-Fleming approach was used to prespecify 
efficacy boundary. The bounds are set as p=0.0054 (df=14, t-value=3.287, or effect size=1.64) and final 
analysis with bound p=0.0492 (df=26, t-value=2.06, effect size=0.78).   
 
9.4.7    Sub-Group Analyses  
N/A 
 
9.4.8    Tabulation of individual Participant Data 
N/A 
 
10. REGULATORY AND OPERATIONAL CONSIDERATIONS 
10.1  INFORMED CONSENT PROCESS 
10.1.1 Consent/Assent Procedures and Documentation 
All participants will receive a verbal explanation of the purposes, procedures and potential risks of the 
study and of their rights as research participants in terms appropriate for their level of comprehension. 
Participants will have the opportunity to carefully review the written consent form and ask questions 
regarding this study prior to signing.  
 
If the investigator feels the individual’s capacity to give informed consent is questionable, they will not 
participate in the study.  
 
The consent form contains all required elements.  
 
10.1.2 Consent for minors when they reach the age of majority  
N/A 

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10.1.3 Telephone consent  
N/A  
10.1.4 Telephone assent 
N/A 
10.1.5 Participation of Subjects who are/become Decisionally Impaired 
Adults unable to give consent are excluded from enrolling in the protocol. However, re-consent may be 
necessary and there is a possibility, though unlikely, that subjects could become decisionally impaired. 
For this reason and because there is a prospect of direct benefit from research participation (section 2.3.3), 
all subjects will be offered the opportunity to fill in their wishes for research and care, and assign a 
substitute decision maker on the “NIH Advance Directive for Health Care and Medical Research 
Participation” form so that another person can make decisions about their medical care in the event that 
they become incapacitated or cognitively impaired during the course of the study. Note: The PI or AI will 
contact the NIH Ability to Consent Assessment Team(ACAT) for evaluation as needed for the following: 
an independent assessment of whether an individual has the capacity to provide consent; assistance in 
identifying and assessing an appropriate surrogate when indicated; and/or an assessment of the capacity to 
appoint a surrogate. For those subjects that become incapacitated and do not have pre-determined 
substitute decision maker, the procedures described in NIH HRPP SOP 14E for appointing a surrogate 
decision maker for adult subjects who are (a) decisionally impaired, and (b) who do not have a legal 
guardian or durable power of attorney, will be followed. 
 
10.2 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to <study participants, investigator, funding agency, the 
Investigational New Drug (IND) or Investigational Device Exemption (IDE) sponsor and regulatory 
authorities>.  If the study is prematurely terminated or suspended, the Principal Investigator (PI) will 
promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will provide 
the reason(s) for the termination or suspension.  Study participants will be contacted, as applicable, and be 
informed of changes to study visit schedule. The stopping of the study will occur in the event of a major 
medical event, such as cardiorespiratory or cerebrovascular event or other major organ acute dysfunction 
requiring elevation in level of care.  Ketogenic diet has been widely studied in various populations 
including Parkinson’s Disease and these studies have not demonstrated an elevated the risk occurance of 
this type of event. 
 
 Circumstances that may warrant termination or suspension include, but are not limited to: 
● Determination of unexpected, significant, or unacceptable risk to participants 
● Demonstration of efficacy that would warrant stopping    
● Insufficient compliance to protocol requirements 
● Data that are not sufficiently complete and/or evaluable 
● Determination that the primary endpoint has been met 
● Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and 
satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 

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10.3 CONFIDENTIALITY AND PRIVACY 
All research activities will be conducted in as private a setting as possible. 
  
Data will be stored using codes that we assign. Data will be kept in password-protected computers and 
locked storage. Only study investigators and auditors will have access to the data. Medical records will be 
stored in locked storage or the electronic medical record and Medical Records Department per NIH 
procedures. 
  
The PI will train study staff to respect the privacy and confidentiality of NIH employees/staff through 
staff discussions and written branch/section procedures. The subjects will be informed that these results 
may be published for scientific purposes, provided their identity is not revealed. NIH may have access to 
the study data for auditing purposes. 
  
Upon study completion, de-identified results may be posted to: https://clinicaltrials.gov. 
 
10.4 FUTURE USE OF STORED SPECIMENS AND DATA 
Data will be maintained on secure, password-protected NIH computers and servers for future use.  
 
10.5 SAFETY OVERSIGHT 
Safety oversight will be provided by the Principal Investigator. 
  
 
10.6 CLINICAL MONITORING 
N/A 
10.7 QUALITY ASSURANCE AND QUALITY CONTROL 
Quality assurance monitor 
The NINDS Quality Assurance (QA) Audit Committee will periodically monitor the protocol. 
Quality assurance plan 
This protocol will undergo periodic review by the QA Audit Committee as outlined in the NINDS QA 
Standard Operating Procedure (SOP).  
 
This protocol will undergo random review by the NINDS Quality Assurance (QA) Office as outlined in 
the NINDS QA Standard Operating Procedure. The purpose of the QA audit is to assess compliance with 
applicable regulatory requirements, good clinical practice guidelines, NINDS/NIH policies, as well as to 
provide recommendations for improving the management of clinical research data. The protocol will be 
audited according to the decision algorithm as described in the NINDS SOP.  
 

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10.8 DATA HANDLING AND RECORD KEEPING 
10.8.1 Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of 
data.   
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case report form 
(eCRF) derived from source documents should be consistent with the data recorded on the source 
documents.  
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into CiStar a 21 CFR Part 11-compliant data capture 
system provided by the NINDS. The data system includes password protection and internal quality 
checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate. Clinical data will be entered directly from the source documents. 
10.8.2 Study Records Retention 
Study documents will be retained as per the NIH Intramural Records Retention Schedule.  
 
10.9 PROTOCOL DEVIATIONS 
 
It is the responsibility of the investigator to use continuous vigilance to identify and report deviations to 
the NIH Institutional Review Board as per Policy 801.  All deviations must be addressed in study source 
documents, reported to NINDS Program Official and section chief.  The investigator is responsible for 
knowing and adhering to the reviewing IRB requirements. 
10.9.1 NIH Definition of Protocol Deviation 
A protocol deviation is any changed, divergence, or departure from the IRB-approved research protocol.  
● Major deviations: Deviations from the IRB approved protocol that have, or may have the 
potential to, negatively impact the rights, welfare or safety of the subject, or to substantially 
negatively impact the scientific integrity or validity of the study. 
● Minor deviations: Deviations that do not have the potential to negatively impact the rights, safety 
or welfare of subjects or others, or the scientific integrity or validity of the study. 
10.10 PUBLICATION AND DATA SHARING POLICY 
10.10.1 Human Data Sharing Plan 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-
Funded Clinical Trial Information and the Clinical Trials Registration and Results Information 

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Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and results information from 
this trial will be submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results 
in peer-reviewed journals.  De-identified data from this study may be requested from other researchers 5 
years after the completion of the primary endpoint by contacting NINDS study PI Dr. Debra Ehrlich and 
will be available in NINDS public repository: data.ninds.nih.gov. 
10.10.2 Genomic Data Sharing Plan  
N/A 
 
10.11 COLLABORATIVE AGREEMENTS  
10.11.1 Agreement Type  
N/A 
 
10.12 Conflict of Interest Policy 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  The study leadership 
in conjunction with the <specify NIH Institute or Center (IC)> has established policies and procedures for 
all study group members to disclose all conflicts of interest and will establish a mechanism for the 
management of all reported dualities of interest. 
 
11 ABBREVIATIONS 
 
AD 
Alzheimer’s Disease 
AE 
Adverse Event 
AI 
associate investigator 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
ECR 
extensor carpi radialis 
eCRF 
Electronic Case Report Forms 
FCR 
flexor carpi radialis 

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FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
HIPAA 
Health Insurance Portability and Accountability Act  
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
LFD 
Low Fat Diet 
LSMEANS 
Least-squares Means 
MCT-KD 
medium chain triglyceride ketogenic diet 
MD 
Mediterranean diet 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NMSS 
Non-Motor Symptom Severity scale 
NIH  
National Institutes of Health 
NK 
nutritional ketosis 
PD 
Parkinson’s Disease 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAD 
Standard American Diet 
SAE 
Serious Adverse Event 
SRT 
simple reaction time 
SOP 
Standard Operating Procedure 
TUG 
Timed Up & Go test 
UD 
usual diet 
UP 
Unanticipated Problem 
UPDRS 
Unified Parkinson’s Disease Rating Scale 
 
12 REFERENCES  
Bahat G, Tufan A, Kilic C, Ozturk S, Akpinar TS< Kose M, ERten N, Karan MA< Cruz-Jentoft AJ. Cut-
off points for weight and body mass index adjusted bioimpedance analysis measurements of muscle mass. 
Aging Clin Exp Res 2019;31(7):935-942. PMID 30267332. 
Blaszczyk JW. Parkinson’s Disease and neurodegeneration: GABA-collapse hypothesis. Front Neurosci 
2016;10:269. PMID 27375426. 
Bloxham CA, Dick DJ, Moore M. Reaction times and attention in Parkinson’s disease. Jnl Neurol, 
Neurosurgy, Psych 1987;50:1178-1183. 

66 
Abbreviated Title: Tolerability and efficacy of ketogenic diet in Parkinson’s Disease  
 
Version Date: 04/19/2021 
 
Protocol version date 04/19/2021 
Bo S, Ponzo V, Goitre I, Fadda M, Pezzana A, Beccuti G, Gambino R, Casseder M, Soldati L, Broglio F. 
Predictive role of the Mediterranean diet on mortality in individuals at low cardiovascular risk: as 12-year 
follow-up population-based cohort study. J Transl Med 2016;14:91. PMID 27071746. 
Bosco DA, Fowler DM, Zhang Q, et al. Elevated levels of oxidized cholesterol metabolites in Lewy body 
disease brains accelerate alpha-synuclein fibrilization. Nat Chem Biol 2006;2(5). PMID 16565714. 
Brietzke E, Mansur RB, Subramaniapillai M, Balanza-Martinez V, Vinberg M, Gonzalez-Pinto A, et al. 
Ketogenic diet as a metabolic therapy for mood disorders: evidence and developments. Neurosci and 
Biobehavioral Rev 2018;94:11-16. 
Brooks, P. L., Peever, J. H. Impaired GABA and glycine transmission triggers cardinal features of rapid 
eye movement sleep behavior disorder in mice. J Neurosci. 2011;31 (19), 7111–7121.  
Brown P, Williams D. Basal ganglia local field potential activity: character and functional significance in 
the human. Clin Neurophysiol 2005;116(11):2510-2519. PMID 16029963. 
Brusse KJ, Zimdars S, Zalewski KR, Steffen TM. Testing functional performance in people with 
Parkinson disease. Phys Ther 2005;85(2):134-141. PMID 15679464. 
Burne JA, Hayes MW, Fung VS, Yiannikas C, Boljevac D. The contribution of tremor studies to 
diagnosis of parkinsonian and essential tremor: a statistical evaluation. J Clin Neurosci 2002;9(3):237-
242. PMID 12093126. 
Cantello R, Varrasi C, Tarletti R, Cecchin M, D’Andrea F, Veggiotti P, Bellomo G, Monaco F. Ketogenic 
diet: electrophysiological effects on the normal human cortex. Epilepsia 2007;48(9): 1756-1763. PMID 
17561954. 
Chaturvedi M, Boaarts JG, Kozak VV, Hatz F, Gschwandtner U, Meyer A, Fuhr P, Roth V. Phase lag 
index and spectral power as QEEG features for identification of patients with mild cognitive impairment 
in Parkinson’s disease. Clinical Neurophys 2019;130:1937-1944. 
Chaudhuri KR, Martinez-Martin P, Brown RG, Sethi K, Stocchi F, Odin P, et al. The metric properties of 
a novel non-motor symptoms scale for Parkinson’s Disease: results from an international pilot study. 
Movement Disorders 2007;22(13):1901-1911. 
Chen MJ, Russo-Neustadt AA. Running exercise-induced up-regulation of hippocampal brain-derived 
neurotrophic factor is CREB-dependent. Hippocampus 2009;19(10):962-972. PMID 19294650. 
Cicero AFG, Benelli M, Brancaleoni M, Dainelli G, Merlini D, Negri R. Middle and long-term impact of 
a very low-carbohydrate ketogenic diet on cardiometabolic factors: a multi-center, cross-sectional, 
clinical study. High blood Pres Cardiovasc Prev 2015; 22(4):389-394. PMID 25986079. 
Cole SR, Roemer vdM, Peterson EJ, Hemptinne Cd, Starr PA, Voytek B. Nonsinusoidal beta oscillations 
reflect cortical pathophysiology in Parkinson’s Disease. Jnl Neurosci 2017;37(18):4830-4840. 
Colla E. Linking the endoplasmic reticulum to Parkinson’s Disease and alpha-synucleinopathy. Front 
Neurosci 2019;13(560). PMID 31191239. 
Coppola G, Verrotti A, D’Aniello A et al. Valproic acid and phenobarbital blood levels during the first 
month of treatment with the ketogenic diet. Acta Neurol Scand. 2010; 122:303–7. PMID 21077847. 
Dahlin M, Elfving A, Ungerstedt U, Amark P. The ketogenic diet influences the levels of excitatory and 
inhibitory amino acids in the CSF in children with refractory epilepsy. Epilepsy Res 2005;64(3):115-125. 
PMID 15961283. 
Dahlin MG, Beck OM, Amark PE. Plasma levels of antiepileptic drugs in children on the ketogenic diet. 
Pediatr Neurol. 2006; 35:6–10. PMID 16814078. 
Dal Bello-Haas V, Klassen L, Sheppard MS, Metcalfe A. Psychometric properties of activity, self-
efficacy, and quality-of-life measures in individuals with Parkinson Disease. Physiother Can 
2011;63(1):47-57. PMID 22210979. 
De Hemptinne C, Swann NC, Ostrem JL, Ryapolova-Webb ES, San Luciano M, Galifianakis NB, Starr 
PA. Therapeutic deep brain stimulation reduces cortical phase-amplitude coupling in Parkinson’s disease. 
Nat Neurosci 2015;18:779-786. 

67 
Abbreviated Title: Tolerability and efficacy of ketogenic diet in Parkinson’s Disease  
 
Version Date: 04/19/2021 
 
Protocol version date 04/19/2021 
Duchesne C, Lungu O, Nadeau A, Robillard ME, Bore A, Bobeuf F, Lafontaine AI, et al. Enhancing both 
motor and cognitive functioning in Parkinson’s disease: aerobic exercise as a rehabilitative intervention. 
Brain and Cogn 2015;99:68-77. 
Earthart GM, Cavanaugh JT, Ellis T, et al. The 9-hole peg test of upper extremity function: average 
values, test-retest reliability, and factors contributing to performance in people with Parkinson Disease. 
JNPT 2011;35:157-163. 
Ebbeling CB, Swain JF, Feldman HA, Wong WW, Hachey DL, Garcia-Lago E, Ludwig DS. Effects of 
dietary composition on energy expenditure during weight-loss maintenance. JAMA 2012;307(24):2627-
2634. PMID 22735432. 
Erecinska M, Nelson D, Daikhin Y, Yudkoff M. Regulation of GABA level in rat brain synaptosomes: 
fluxes through enzymes of the GABA shunt and effects of glutamate, calcium, and ketone bodies. J 
Neurochem 1996;67(6):2325-2334. PMID 8931464. 
Evarts EV, Teravainen H, Calne DB. Reaction time in Parkinson’s Disease.Brain 1981;104(1):167-186. 
Flowers KA. Some frequency response characteristics of Parkinsonism on pursuit tracking. Brain 101;19-
34. 
Foreman KB, Addison O, Kim HS, Dibble LE. Testing balance and fall risk in persons with Parkinson 
disease, an argument for ecologically valid testing. Parkinsonism Relat Disord 2011;17(3):166-171. 
PMID 21215674. 
Garcia C, Chen MJ, Garza AA, Cotman CW, Russo-Neustadt A. The influence of specific noradrenergic 
and serotonergic lesions on the expression of hippocampal brain-derived neurotrophic factor transcripts 
following voluntary physical activity. Neuroscience 2003;119(3):721-732. 
Geraedts VJ, Boon LI, Marinus J, Gouw AA, van Hilten JJ, Stam CJ, et al. Clinical correlates of 
quantitative EEG in Parkinson disease: systematic review. Neurology 2018;00:1-13. 
Goldstein DS. Dysautonomia in Parkinson disease. Compr Physiol 2014;4(2):805-825. PMID 
24715569. 
Grider JR, Makhlouf GM. Enteric GABA: mode of action and role in the regulation of the 
peristaltic reflex. Am J Physiol 1992;262(4):G690-694. PMID 1566850. 
Gyorkos A, Baker MH, Miutz LN, Lown DA, Jones MA, Houghton-Rahrig LD. Carbohydrate-
restricted diet and exercise increase brain-derived neurotrophic factor and cognitive function: a 
randomized crossover trial. Cureus 2019;11(9):e5604. PMID 31700717. 
Hall KD, Bemis T, Brychta R, Chen KY, Courville A, Crayner EJ, et al. Calorie for calorie, dietary fat 
restriction results in more body fat loss than carbohydrate restriction in people with obesity. Cell Metab 
2015;22(3). PMID 26278052. 
Hall SD, Prokic EJ, McAllister CJ, Ronnqvist KC, Williams AC, Yamawaki N, et al. GABA-mediated 
changes in inter-hemispheric beta frequency activity in early-stage Parkinson’s disease. Neuroscience 
2014;281:68-76. PMID 25261686. 
Hamsher K, Benton AL. The reliability of reaction time determinations. Cortex 1977;13(3):306-310. 
PMID 923269. 
Hariri AR, Goldberg TE, Mattay VS, Kolachana BS, Callicott JH, Egan MF, et al. Brain-derived 
neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and 
memory performance. J Neurosci 2003;23:6690-6694. 
Harvey CJ, Schofield GM, Williden M, McQuillan JA. The effect of medium chain triglycerides on time 
to nutritional ketosis and symptoms of keto-induction in healthy adults: a randomised controlled clinical 
trial. Nutr Metab 2018;22:2630565. PMID 29951312. 
Hasan-Olive MM, Lauritzen KH, Ali M, Rasmussen Lj, Storm-Mathisen J, Bergersen LH. A ketogenic 
diet improves mitochondrial biogenesis and bioenergetics via the PGC1alpha-SIRT3-UCP2 axis. 
Neurochem Res 2019;44(1):22-37. PMID 30027365. 

68 
Abbreviated Title: Tolerability and efficacy of ketogenic diet in Parkinson’s Disease  
 
Version Date: 04/19/2021 
 
Protocol version date 04/19/2021 
Hassan M, Chaton L, Benquet P, Delval A, Leroy C, Plomhause L, Leentjens AFG, van Kranen-
Mastenbroek V, Defebvre L, Derambure P. Functional connectivity disruptions correlate with cognitive 
phenotypes in Parkinson’s disease. Neuroimag: Clinical 2017;14:591-601. 
He R, Yan X, Guo J, Xu Q, Tang B, Sun Q. Recent advances in biomarkers for Parkinson’s Disease. 
Front Aging Neurosci 2018;10:305. PMID 30364199. 
Heo G, Kim SH, Chang MJ (2017) Effect of ketogenic diet and other dietary therapies on anti-epileptic 
drug concentrations in patients with epilepsy. J Clin Pharm Ther. 2017;42(6):758-764. PMID 28626875. 
Hermens HJ, Freriks B, Disselhorst-Klug C, Rau G. Development of recommendations for SEMG sensors 
and sensor placement procedures. J Electromyogr Kinesiol 2000;19(5):361-374. PMID 11018445. 
Henderson ST, Vogel JL, Barr LJ, Garvin F, Jones JJ, Costantini, LC. Study of the ketogenic agent AC-
1202 in mild to moderate Alzheimer’s disease: A randomized, double-blind, placebo-controlled, 
multicenter trial. Nutr Metab (Lond) 2009;6(31). 
Huang SL, Hsieh CL, Wu RM, Tai CH, Lin CH, Lu WS. Minimal detectable change of the timed “up & 
go” test and the dynamic gait index in people with Parkinson’s disease. Phys Ther 2011;91(1):114-121. 
PMID 20947672. 
Jackson N, Cole SR, Voytek B, Swann NC. Characteristics of waveform shape in Parkinson’s Disease 
detected with scalp electroencephalography. eNeuro 2019;6(3):1-11. PMID 31110135. 
Jahanshahi M, Brown RG, Marsden CD. A comparative study of simple and choice reaction time in 
Parknison’s, Huntington’s, and cerebellar disease. J Neurol Neurosurg Psychiatry 1993;56(11):1169-
1177. PMID 8229028. 
Jahanshahi M, Brown RG, Marsden CD. A comparative study of simple and choice reaction time in 
Parkinson’s, Huntington’s, and cerebellar disease. J Neurol Neurosurg Psychiatry 1993;56:1169-1177. 
Jordan N, Sagar HJ, Cooper JA. Cognitive components of reaction time in Parkinson’s disease. J Neurol 
Neurosurg Psychiatry 1992;55(8):658-664. 
Juncos JL, Fabbrini G, Mouradian MM, Serrati C, Chase TN. Dietary influences on the antiparkinsonian 
response to levodopa. Arch Neurol 1987;44(10):1003-1005. PMID 3632369.  
Kang DW, Bressel E, Kim DY. Effects of aquatic exercise on insulin-like growth factor-1, brain-derived 
neurotrophic factor, vascular endothelial growth factor, and cognitive function in elderly women. Exp 
Gerontol 2020;132:110842. PMID 31954186. 
Kossoff EH, Hartman AL. Ketogenic diets: new advances for metabolism-based therapies. Curr Opin 
Neurol 2012;25(2). PMID 22322415. 
Krikorian R, Shidler MD, Dangelo K, Cough SC, Benoit SC, Clegg DJ. Dietary ketosis enhances memory 
in mild cognitive impairment. Neurobiol Aging 2012;33(2):19-27. PMID 21130529. 
Krikorian R, Shidler MD, Summer SS, Sullivan PG, Duker AP, Isaacson RS, Espay AJ. Nutritional 
ketosis for mild cognitive impairment in Parkinson’s disease: a controlled pilot trial. Clin Parkinson Rel 
Disord 2019;1:41-47.  
Kverneland M, Taubøll E, Selmer KK, Iversen PO, Nakken KO. Modified Atkins diet may reduce serum 
concentrations of antiepileptic drugs. Acta Neurol Scand. 2015; 131(3):187-90. PMID 25312999. 
Lawton M, Baig F, Toulson G, Morovat A, Evetts SG, Ben-Shlomo Y, Hu MT. Blood biomarkers with 
parkinson’s disease clusters and prognosis: the oxford discovery cohort. Mov Disord 2020;35(2):279-287l 
PMID 31693246. 
Lehtonen S, Sonninen TM, Wojciechowski S, et al. Dysfunction of cellular proteostasis in Parkinson’s 
Disease. Front Neurosci 2019;13(457). PMID 31133790. 
Lemos da Luz P, Favarato D, Faria-Neto Jr JR, Lemos P, Palandri Chagas AC. High ratio of triglycerides 
to HDL-cholesterol predicts extensive coronary disease. Clinics 2008;63(4):427-4732. PMID 18719750. 
Lennernäs H, Nilsson D, Aquilonius SM, Ahrenstedt O, Knutson L, Paalxow LK. The effect of L-leucine 
on the absorption of levodopa, studied by regional jejunal perfusion in man. Br J Clin Pharmacol 
1993;35(3):243-250. PMID 8471400. 

69 
Abbreviated Title: Tolerability and efficacy of ketogenic diet in Parkinson’s Disease  
 
Version Date: 04/19/2021 
 
Protocol version date 04/19/2021 
Liu YM. Medium-chain triglyceride (MCT) ketogenic therapy. Epilepsia 2008;49(8):33-36. PMID 
19049583. 
Marosi K, Kim SW, Moehl K, Scheibye-Knudsen M, Cheng A, Cutler R, Camandola S, Mattson MP. 3-
hydroxybutyrate regulates energy metabolism and induces BDNF expression in cerebral cortical neurons. 
J Neurochem 2016;139(5):769-781. PMID 27739595. 
Mathiowetz V, Weber K, Kashman N, Volland G. Adult norms for the nine hole peg test of finger 
dexterity. The Occupational Therapy Journal of Research 1985;5;1:24-38.   
Mattson MP, Moehl K, Ghena N, Schmaedick M, Cheng A. Intermittent metabolic switching, 
neuroplasticity and brain health. Nat Rev Neurosci 2018;19(2):63-80. PMID 29321682. 
Mavrommati F, Collett J, Franssen M, Meaney A, Sexton C, Dennis-West A, et al. Exercise 
response in Parkinson’s disease: insights from a cross-sectional comparison with sedentary 
controls and a per-protocol analysis of a randomised controlled trial. BMJ Open 
2017;7(12):e017194. PMID 29282259. 
Mena I, Cotzias GC. Protein intake and treatment of Parkinson’s disease with levodopa. N Engl J Med 
1975;292(4):181-184. 
Moazami-Goudarzi M, Sarnthein J, Michels L, Moukhtieva R, Jeanmonod D. Enhanced frontal low and 
highfrequency power and synchronization in the resting EEG of parkinsonian patients. Neuroimage 
2008;41:985-997. 
Mohorko N, Cernelic-Bizjak M, Polar-Vatovec T, Grom G, Kenig S, Petelin A, Jenko-Praznikar Z. 
Weight loss, improved physical performance, cognitive function, eating behavior, and metabolic profile in 
a 12-week ketogenic diet in obese adults. Nutr Res 2019;62:64-77. PMID 30803508. 
Mooradian AD, Haas MJ, Wong NCW. The effect of select nutrients on serum high-density lipoprotein 
cholesterol and apolipoprotein A-I levels. Endocrine Reviews 2006;27(1):2-16. 
Nakabeppu Y, Tsuchimoto D, Yamaguchi H, Sakumi K. Oxidative damage in nucleic acids and 
Parkinson’s disease. J Neurosci Res 2007;85(5). PMID 17279544. 
Neth BJ, Mintz A, Whitlow C, Jung Y, Sai KS, Register TC, Kellar D, Lockhart SN, Hoscheidt S et al. 
Modified ketogenic diet is associated with improved cerebrospinal fluid biomarker profile, cerebral 
perfusion, and cerebral ketone body uptake in older adults at risk for Alzheimer’s disease: a pilot study. 
Neurobiology of Aging 2020;86:54-63. PMID 31757576. 
Niethammer M, Tang CC, LeWitt PA, Rezai AR, Leehey MA, Ojemann SG, Flaherty AQ, Eskandar EN, 
et al. Long-term follow-up of a randomized AAV2-GAD gene therapy trial for Parkinson’s disease. JCI 
Insight 2017;2(7):e90133. PMID 28405611. 
Nigel J, Sagar HJ, Cooper JA. Cognitive components of reaction time in Parkinson’s disease. Jnl Neurol, 
Neurosurgy, Psych 1992;55:658-664. 
Nilsson J., Panizza M., Hallett M. Principles of digital sampling of a physiologic signal. 
Electroencephalogr. Clin. Neurophysiol. Potentials Sect. 1993;89:349–358. 
Nocera JR, Stegemöller EL, Malaty IA, Okun MS, Marsiske M, Hass CJ, and National Parkinson 
Foundation Quality Improvement Initiative Investigators. Using the Timed Up & Go test in a clinical 
setting to predict falling in Parkinson’s Disease. Arch Phys Med Rehabil 2013;94(7):1300-1305. PMID 
23473700. 
Nutt JG, Woodward WR, Hammerstad JP, Carter JH, Anderson JL. The “on-off” phenomenon in 
Parkinson’s disease. Relation to levodopa absorption and transport. N Engl J Med 1984;310(8):483-488. 
Ota M, Matsuo J, Ishida I, Takano H, Yokoi Y, Hori H, et al. Effects of a medium-chain triglyceride-
based ketogenic formula on cognitive function in patients with mild-to-moderate Alzheimer’s disease. 
Neurosci Lett 2019;18;690:232-236. PMID 30367958. 

70 
Abbreviated Title: Tolerability and efficacy of ketogenic diet in Parkinson’s Disease  
 
Version Date: 04/19/2021 
 
Protocol version date 04/19/2021 
Paoli A, Mancin L, Bianco A, Thomas E, Mota J F, Piccini F. Ketogenic diet and microbiota: friends or 
enemies? Genes (Basel) 2019; 31311141. 
Perez-Guisado J, Munoz-Serrano A, Alonso-Moraga A. Spanish ketogenic Mediterranean diet: a healthy 
cardiovascular diet for weight loss. Nutrition Journal 2008;7(30).  
Phillips MCL, Murtagh DKJ, Gilbertson LJ, Asztely FJS, Lynch CDP. Low-fat versus ketogenic diet in 
Parkinson’s disease: a pilot randomized controlled trial. Mov Disord 2018;33(8):1306-1314. PMID 
30098269. 
Pincus JH, Barry K. Influence of dietary protein on motor fluctuations in Parkinson’s disease. Arch 
Neurol 1987;44(3):270-272. PMID 3827678. 
Pinto A, Bonucci A, Maggi E, Corsi M, Businaro R. Anti-oxidant and anti-inflammatory activity of 
ketogenic diet: new perspectives for neuroprotection in Alzheimer’s disease. Antioxidants (Basel) 
2019;7(5). PMID 29710809. 
Pirez N, Wachowiak M. In vivo modulation of sensory input to the olfactory bulb by tonic 
and activity-dependent presynaptic inhibition of receptor neurons. J Neurosci. 2008;28(25): 6360–6371. 
Rahmani F, Saghazadeh A, Rahmani M, Teixeira AL, Rezaei N, Aghamollaii V, Ardebili HE. Plasma 
levels of brain-derived neurotrophic factor in patients with Parkinson disease: a systematic review and 
meta-analysis. Brain Res 2019;1704:127-136. PMID 30296429.  
Reger MA, Henderson ST, Hale C, Cholerton B, Baker LD, Watson GS, et al. Effects of beta-
hydroxybutyrate on cognition in memory-impaired adults. Neurobiol Aging 2004;25(3):311-314. PMID 
15123336. 
Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le Moan N, Grueter CA, Lim H, et al. 
Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous histone decateylase inhibitor. 
Science 2013;339(6116):211-214. PMID 23223453. 
Soveri A, Lehtonen M, Karlsson LC, Lukasik K, Antfolk J, Laine M. Test-retest reliability of five 
frequently used executive tasks in healthy adults. Appl Neuropsychol Adult 2018;25(2):155-165. PMID 
28001452. 
Stoet, G. A full documentation of the Stroop experiment. URL: 
https://www.psytoolkit.org/lessons/stroop_code_explained.html 
Stoet, G. N-Back task. URL: 
https://www.psytoolkit.org/experiment-library/nback.html 
Swann NC, de Hemptinne C, Thompson MC, Miocinovic S, Miller AM, Gilron R, et al. Elevated 
synchrony in Parkinson’s disease detected with electroencephalography. Ann Neurol 2015;78:742-750. 
Swanson CR, Li K, Unger TL, Gallagher MD, Van Deerlin VM, Agarwal P, Leverenz J, et al. Lower 
plasma apolipoprotein A1 levels are found in Parkinson’s disease and associate with apolipoprotein A1 g 
Taylor MK, Sullivan DK, Mahnken JD, Burns JM, Swerdlow RH. Feasibility and efficacy data from a 
ketogenic diet intervention in Alzheimer’s disease. Alzheimer’s & Dementia: Translational Research & 
Clinical Interventions 2018;4:28-36. 
Tagliabue A, Bertoli S, Trentani C, Borrelli P, Veggiotti P. Effects of the ketogenic diet on nutritional 
status, resting energy expenditure, and substrate oxidation in patients with medically refractory epilepsy: 
a 6-month prospective observational study. Clin Nutr 2012;31(2):256-249. PMID 22019282. 
Tendler D, Lin S, Yancy WS Jr, Mavropoulos J, Sylvestre P, Rockey DC, Westman EC. The effect of a 
low-carbohydrate, ketogenic diet on nonalcoholic fatty liver disease: a pilot study. Dig Dis Sci 
2007;52(2):589-593. PMID 17219068. 
Tholstrup T, Ehnholm C, Jauhiainen M, Petersen M, Hoy CE, Lund P, Sandstrom B. Effects of medium-
chain fatty acids and oleic acid on blood lipids, lipoproteins, glucose, insulin and lipid transfer protein 
activities. Am J Clin Nutr 2004;79(4):564-569. PMID 15051598. 
Traul KA, Driedger A, Ingle DL, Nakhasi D. Review of the toxicologic properties of medium-chain 
triglycerides. Food Chem Toxicol 2000;38(1):79-98. PMID 10685018. 

71 
Abbreviated Title: Tolerability and efficacy of ketogenic diet in Parkinson’s Disease  
 
Version Date: 04/19/2021 
 
Protocol version date 04/19/2021 
Tholstrup T, Ehnholm C, Jauhiainen M, Petersen M, Høy CE, Lund P, Sandström B. Effects of medium-
chain fatty acids and oleic acid on blood lipids, lipoproteins, glucose, insulin, and lipid transfer protein 
activities. Am J Clin Nutr 2004;79(4):584-589. PMID 15051598. 
Umemura A, Oeda T, Yamamoto K, Tomita S, Kohsaka M, Park K, Sugiyama H, Sawada H. Baseline 
plasma C-reactive protein concentrations and motor prognosis in Parkinson Disease. PLoS One 2015; 
10(8):e0136722. PMID 26308525. 
Utianski RL, Caviness JN, van Straaten ECW, Beach TG, Dugger BN, Shill HA, Driver-Dunckley ED, 
Sabbagh MN, Adler SCH, Hentz JG. Graph theory network function in Parkinson’s disease assessed with 
electroencephalography. Clinical Neurophysiology 2016;127:2228-2236. 
Vanitallie TB, Nonas C, Di Rocco A, Boyar K, Hyams K, Heymsfield SB. Treatment of Parkinson 
disease with diet-induced hyperketonemia: a feasibility study. Neurology 2005;64(4):728-730. PMID 
15728303. 
Van Uem JMT, Walgaard S, Ainsworth E, Hasmann SE, Heger T, Nussbaum S, et al. Quantitative 
Timed-Up-and-Go parameters in relation to cognitive parameters and health-related quality of life in 
mild-to-moderate Parkinson’s Disease. PLOS One 2016;11(4):e0151997. 
Van Wijk BCM, Beudel M, Jha A, Oswal A, Foltynie T, Hariz MI, Limousin P, Zrinzo L, Aziz TZ, et al. 
Subthalamic nucleus phase-amplitude coupling correlates with motor impairment in Parkinson’s disease. 
Clin Neurophys 2016;127(4):2010-2019.  
Vial F, McGurrin P, Osterholt T, Ehrlich D, Haubenberger D, Hallett M. Tremoroton, a new free online 
platform for tremor analysis. Clin Neurophysiol Pract 2020;5:30-34. PMID 31956739. 
Vial F, Kassavetis P, Merchant S, Haubenberger D, Hallett M. How to do an electrophysiological study of 
tremor. Clin Neurophysiol Pract 2019;28;4:134-142. PMID 31886436. 
Wan R, Weigand LA, Bateman R, Griffioen K, Mendelowitz D, Mattson MP. Evidence that BDNF 
regulates heart rate by a mechanism involving increased brainstem parasympathetic neuron excitability. J 
Neurochem 2014;129(4):573-580. PMID 24475741.  
Wang S, Yuan YH, Chen NH, Wang HB. The mechanisms of NLRP3 inflammasome/pyroptosis 
activation and their role in Parkinson’s disease. Int Immunopharmacol 2019;67. PMID 30594776. 
Wilding, IR, Hardy JG, Davis SS, Melia CD, Evans DF, Short AH, et al. Characterisation of the in vivo 
behavior of a controlled-release formulation of levodopa (Sinemet CR). Clin Neuropharmacol 
1991;14(4):305-321. PMID 1913698. 
Yokochi F, Nakamura R, Narabayashi H. Reaction time of patients with Parkinson’s disease, with 
reference to asymmetry of neurological signs. Jnl Neurol, Neurosurg, Psych 1985;48:702-705. 
Youm YH, Nguyen KY, Grant RW, et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 
inflammasome-mediated inflammatory disease. Nat Med 2015;21(3). PMID 25686106. 
Zappia M, Montesanti R, Colao R, Quattrone A. Usefulness of movement time in the assessment of 
Parkinson’s disease. Journal of Neurology 1994;241:543-550. 
Zheng B, Liao Z, Locascio JJ et al. PGC-1alpha, a potential therapeutic target for early intervention in 
Parkinson’s disease. Sci Transl Med 2010;2(52). PMID 20926834. 
Meta-analyses comparing low-carb diets of less than 130g carbohydrate per day to low-fat diets of less 
than 35% fat of total calories. Public Health Collaboration United Kingdom (PHCuk.org). URL 
<https://phcuk.org/wp-content/uploads/2018/02/Meta-Analyses-Comparing-Low-Carb-To-Low-Fat-
Diets-26.02.2018.pdf>\ 
 
Non-motor symptom severity scale (NMSS): URL 
https://www.movementdisorders.org/MDS/MDS-Rating-Scales/Non-Motor-Symptoms-Scale-for-
Parkinsons-Disease-NMSS.htm