Can a ketone drink reduce the severity of symptoms of Parkinson’s disease?

ISRCTN	ISRCTN64294760
DOI	https://doi.org/10.1186/ISRCTN64294760
Integrated Research Application System (IRAS)	256914
Protocol serial number	DeltaG PD Symptoms, IRAS 256914
Sponsor	TdeltaS Ltd
Funder	TdeltaS Ltd

Submission date: 21/12/2018
Registration date: 31/12/2018
Last edited: 10/08/2020

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Nervous System Diseases

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world, affecting up to 3 in 100 people aged over 65 years. PD is characterised by the death of neurons (nerve cells) that release the chemical messenger dopamine. The death of these neurons contributes to the classic motor (movement) symptoms of PD, which include slow movement and tremors (shaking). It is also increasingly appreciated that PD causes a wide variety of other types of symptoms, including sleep problems, loss of smell, depression, apathy, and cognitive dysfunctions (problems with memory and thinking).
There is no cure for PD, although there are a number of available treatments. A non-pharmacological (non-drug) therapy that has shown promise is the ketogenic diet. The ketogenic diet tricks the body into thinking it’s in a state of starvation so that it produces molecules called ketone bodies. Ketone bodies represent a highly efficient source of fuel for the brain and serve several signaling functions that may counteract the progression and treat the symptoms of PD. Encouragingly, research on PD mice has shown that ketone bodies prevent the death of PD-sensitive dopamine-releasing neurons and also that they reduce the symptoms of PD. Furthermore, human patients who were on a strict ketogenic diet for 28 days experienced substantial improvements in their PD symptoms.
Unfortunately, ketogenic diets come with two major drawbacks. Firstly, they are extremely restrictive and difficult to keep to. Secondly, most of the fuel energy measured in calories comes from fat and may increase cardiovascular (heart and circulation) disease risk. A research team at the University of Oxford has recently invented a ketone body dietary supplement (DeltaG) that may be able to provide the pros of ketones without the cons of ketogenic diets. Results in healthy people has already demonstrated that DeltaG is a tolerable and safe way to increase ketone body levels and favorably alter energy metabolism. The main aim of this study is to investigate whether DeltaG can be used to reduce the symptoms of PD.

Who can participate?
Patients with Hoehn and Yahr stage 1 or 2 Parkinson’s disease who are taking L-dopa, who are between the ages of 40 and 80, and who are fluent in English.

What does this study involve?
Participants will be recruited by word of mouth, emails to departmental mailing lists, posters located in university departments, and an advertisement on the Oxford Parkinson’s Disease Centre’s webpage. Potential participants will be interviewed to determine eligibility and asked to give informed consent.
Participants accepted to the study will be randomly allocated to one of two groups. One group will receive a ketone ester drink (DeltaG) and the other will receive a placebo control (dummy) drink. Participants will be expected to drink their respective drinks four times every day for 1 month. During the trial, participants will undergo a series of motor, non-motor, and blood tests conducted at the John Radcliffe Hospital and in their own homes.

What are the potential benefits and risks of participating?
Participants will need to provide blood samples, wear a continuous activity monitor, and use a smartphone application. The risks are low. DeltaG has been proven to be safe in humans, but can gastrointestinal (stomach) upset in a small proportion of people because of its bitter taste. Participants may experience improvements in their motor symptoms, sleep, sense of smell, cognitive function, and even mood.

Where is the study run from?
The John Radcliffe Hospital, Oxford (UK)

When is the study starting and how long is it expected to run for?
October 2018 to January 2021

Who is funding the study?
TdeltaS Ltd., a spin-out company from the University of Oxford.

Who is the main contact?
1. Mr. Nicholas Norwitz (DPhil student)
nicholas.norwitz@dpag.ox.ac.uk
2. Prof. Michele Hu (Chief Investigator)
parkinsons.discovery@nhs.net

Contact information

Mr Nicholas Norwitz
Scientific

Sherrington Building
Sherrington Rd
Oxford
OX1 3PT
United Kingdom

ORCID ID	0000-0002-0826-9069
Phone	+44 (0) 7444 054375
Email	nicholas.norwitz@dpag.ox.ac.uk

Prof Michele Hu
Scientific

Department of Neurology, West Wing, Level 3
John Radcliffe Hospital, Headley Way
Oxford
OX3 9DU
United Kingdom

ORCID ID	0000-0001-6382-5841

Mr Nicholas Norwitz
Public

Sherrington Building
Sherrington Rd
Oxford
OX1 3PT
United Kingdom

ORCID ID	0000-0002-0826-9069
Phone	+44 (0) 7444 054375
Email	nicholas.norwitz@dpag.ox.ac.uk

Study information

Primary study design	Interventional
Study design	Longitudinal single-blind randomized placebo-controlled trial
Secondary study design	Randomised controlled trial
Participant information sheet	ISRCTN64294760_PIS_v1.14_11Mar20.pdf
Scientific title	Supplementation with a ketone ester drink to alleviate the symptoms of Parkinson’s disease
Study acronym	N/A
Study objectives	Ingestion of a ketone ester supplement (DeltaG) will improve the symptoms of Parkinson's disease.
Ethics approval(s)	Approved (13/05/2019), NHS Health Research Authority (Skipton House, 80 London Road, London, SE1 6LH, UK; +44 (0)20 7972 2545; hra.approval@nhs.net), ref: 19/SC/0138.
Health condition(s) or problem(s) studied	Parkinson's disease
Intervention	To ensure equal group sizes, participants will be block randomized to a ketone ester or placebo control group. Following a 2-week period during which baseline measurements will be taken (weeks -2 to 0), members of each group will be asked to ingest a drink containing either 25 ml of ketone ester (DeltaG) or an equal volume of a taste-matched control fluid four times daily for 1 month (weeks 0 to 4). Participants will also be followed for 2 weeks after the conclusion of the intervention to monitor for any lasting changes (weeks 4 to 6). Over the course of the entire 2-month period, participants will visit the study location on a fortnightly basis and undergo a series of non-invasive, minimally burdensome motor, nonmotor, and biological tests in order to monitor for changes in functional status and disease pathology. Participant compliance will also be assessed to inform future studies and to inform whether or not we will choose to extend the intervention period. Depending on the preliminary results and participants’ compliance, we may want to extend the intervention by a further 2 months to monitor for cumulative (or additional) positive effects of the ketone supplement.
Intervention type	Supplement
Primary outcome measure(s)	1. Overall symptom severity in the drug "off" state assessed using the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) at weeks 0 and 4 2. Daily activity and gait assessed using a continuous activity monitor (Axivity AX3) worn on the lower back by participants for 7 days before (weeks -2 to -1) and during (weeks 2 to 3) the intervention 3. Motor skills assessed using a smartphone application once a day 4. Olfaction assessed using the Sniffin’ Sticks 16-odor identification test at weeks 0, 4, and 6 5. Selective attention assessed using the Stroop color-word test at weeks 0, 4, and 6 6. Cognitive function assessed using the the Montreal Cognitive Assessment (MoCA) at weeks 0, 4, and 6 7. Fatigue assessed using the Fatigue Severity Scale (FSS) survey over the phone once per week during a randomly-timed compliance call 8. Quality of life of participant assessed using the PDQ-39 questionnaire at weeks 0, 4, and 6 9. Quality of life of participant's carer assessed using the PDQ-Carer questionnaire at weeks 0, 4, and 6 10. Parkinson's disease-related sleep disorder assessed using the REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) at week 0.
Key secondary outcome measure(s)	1. Blood uric acid measured in a fasted state at weeks 0, 2, 4, and 6 2. Blood glucose measured in a fasted state at weeks 0, 2, 4, and 6 3. Blood fructosamine measured in a fasted state at weeks 0, 2, 4, and 6 4. Blood insulin measured in a fasted state at weeks 0, 2, 4, and 6 5. Blood lipids measured in a fasted state at weeks 0, 2, 4, and 6 6. Blood C-reactive protein (CRP) measured in a fasted state at weeks 0, 2, 4, and 6 7. Blood inflammatory cytokines measured in a fasted state at weeks 0, 2, 4, and 6 8. Compliance assessed by calling patients at random once per week to ask them when they last consumed the study drink and to request that they blindly (we will mask the monitor) measure their own blood ketone levels by fingerstick 9. Participant subjective comments on their experiences taking the drink assessed using a consumer-style questionnaire at week 4 Uric acid is a major circulating antioxidant that tends to be depleted in the blood of patients with Parkinson’s disease. Participants’ glucose, fructosamine, insulin, and lipids levels will afford insight into the quality of their carbohydrate metabolism and relative cardiovascular risk. This is relevant because diabetes and heart disease are also age-related diseases and often present as comorbidities alongside Parkinson’s disease. CRP and inflammatory cytokines are markers of systemic inflammation, a phenomenon characteristic of, and involved in the development of, many age-related diseases.
Completion date	01/01/2021

Eligibility

Participant type(s)	Patient
Age group	Mixed
Sex	All
Target sample size at registration	20
Key inclusion criteria	1. Diagnosis of Parkinson's disease 2. Taking L-dopa 3. Hoehn and Yahr stages 1-2 4. Fluent in English 5. Capable of giving informed consent 6. Aged 40-80
Key exclusion criteria	1. Communication impairments 2. Any disorder that the Chief Investigator deems may bias the study results or put the participant at risk
Date of first enrolment	02/02/2019
Date of final enrolment	02/10/2020

Locations

Countries of recruitment

United Kingdom
England

Study participating centre

John Radcliffe Hospital

Headley Way, Headington
Oxford
OX3 9DU
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
IPD sharing plan	The demographic data and individual participants’ study results generated during and/or analyzed during the current study will be available upon request from Nicholas Norwitz (nicholas.norwitz@dpag.ox.ac.uk) after the study concludes and for 5 years. If participants formally consent to have their individual data shared at the commencement of the study, it may be shared with other research teams upon justifiable request and will remain anonymized by a study-specific identification number.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
HRA research summary			28/06/2023	No	No
Participant information sheet	version v1.14	11/03/2020	10/08/2020	No	Yes
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes
Protocol file	version v1.10	12/03/2020	10/08/2020	No	No

Additional files

ISRCTN64294760_PIS_v1.14_11Mar20.pdf: uploaded 10/08/2020
ISRCTN64294760_PROTOCOL_v1.10_12Mar20.pdf: uploaded 10/08/2020

Editorial Notes

10/08/2020: The following changes were made to the trial record:
1. The recruitment resumed.
2. The ethics approval was added.
3. The participant information sheet was uploaded as an additional file.
4. Uploaded protocol (not peer reviewed) Version 1.10 12 March 2020.
5. The target number of participants was changed from 48 to 20.
16/04/2020: Due to current public health guidance, recruitment for this study has been paused.
06/03/2020: The recruitment end date was changed from 02/02/2020 to 02/10/2020.
11/01/2019: Internal review.