Clinical trial NCT04584346: Acute Effects of Medium Chain Triglyceride (MCT) Nutritional Ketosis on Parkinson's Disease (PD) Symptoms and Biomarkers (MCT-PD)
Official title: Acute Effects of Medium Chain Triglyceride (MCT) Nutritional Ketosis on Parkinson s Disease (PD) Symptoms and Biomarkers (MCT-PD)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Parkinson's Disease
Keywords: MCT Medium Chain Triglyceride
Ketogenic Diet
Nutritional Ketosis
Parkinson's Biomarkers
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2020-10-14
Enrollment: 21
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Background:

The ketogenic diet uses fats as a person's major energy source rather than carbohydrates. There is increasing interest in using this diet to treat neurodegenerative disorders like Parkinson's disease. Researchers want to learn more about the ketogenic diet before recommending this diet in clinical practice.

Objective:

To study the effects of a ketogenic diet for someone with PD.

Eligibility:

People over age 50 with mild to moderate PD.

Design:

Participants will be screened with surveys and a 10-foot walking test. They will have a medical history, physical exam, and blood test.

Participants will be contacted twice in a 1-week period to discuss what they ate over the last 24 hours. They will log data about their daily exercise and activities using an online fitness tracking app.

Participants will stay at NIH Clinical Center for 1 week. They will be put into 1 of 2 groups. One group will follow a ketogenic diet and take MCT oil. The other group will follow a low-fat diet. Their body measurements will be taken. They will meet with a physical therapist and nutritionist.

Participants will have daily respiratory and glucose monitoring. They will have cognitive tests and complete surveys. They will have walking, motor function, and reaction time/finger tapping tests. They will have heart and nerve function tests. They will have electrocardiograms and electroencephalograms. Blood will be taken twice daily.

Participants will follow the ketogenic diet at home for 2 weeks. They will log their activities using the fitness tracking app. Then they will have a follow-up visit at NIH.

Participation in the trial will last for 4 weeks.

Detailed description: Study Description:

While three pilot studies of ketogenic diet (KD) in PD have shown either reduction in motor scores (UPDRS) or improved cognition (memory/fluency), 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, 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.

Eligibility criteria: * 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, 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 throughout study duration
9. Adhering to Usual Diet (SAD) at baseline, as per investigator determination

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.

Primary outcomes:
measure: Feasibiilty of Ketogenic Diet - Retention (Co-primary Endpoint)
timeFrame: Week 3
measure: Feasibility of Ketogenic Diet - Adherence (Co-primary Endpoint)
timeFrame: Week 3
measure: Feasibility of Ketogenic Diet - Acceptability (Co-primary Endpoint)
timeFrame: Week 3
Secondary outcomes:
measure: Timed Up and Go (TUG)
timeFrame: Day 7
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Institute of Neurological Disorders and Stroke (NINDS)
name: Debra J Ehrlich, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chaudhuri KR, Martinez-Martin P, Brown RG, Sethi K, Stocchi F, Odin P, Ondo W, Abe K, Macphee G, Macmahon D, Barone P, Rabey M, Forbes A, Breen K, Tluk S, Naidu Y, Olanow W, Williams AJ, Thomas S, Rye D, Tsuboi Y, Hand A, Schapira AH. The metric properties of a novel non-motor symptoms scale for Parkinson's disease: Results from an international pilot study. Mov Disord. 2007 Oct 15;22(13):1901-11. doi: 10.1002/mds.21596.
citation: Colla E. Linking the Endoplasmic Reticulum to Parkinson's Disease and Alpha-Synucleinopathy. Front Neurosci. 2019 May 29;13:560. doi: 10.3389/fnins.2019.00560. eCollection 2019.
citation: Chen MJ, Russo-Neustadt AA. Running exercise-induced up-regulation of hippocampal brain-derived neurotrophic factor is CREB-dependent. Hippocampus. 2009 Oct;19(10):962-72. doi: 10.1002/hipo.20579.