Can a ketone drink increase ATP in the brains of patients with Parkinson's disease?
| ISRCTN | ISRCTN10531043 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN10531043 |
| Secondary identifying numbers | DeltaG PD ATP |
- Submission date
- 04/12/2018
- Registration date
- 07/12/2018
- Last edited
- 12/01/2021
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Nervous System Diseases
Plain English summary of protocol
Background and study aims
Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world, affecting 2-3% of individuals >65. It is biologically defined by the death of brain neurons that release the chemical messenger dopamine and is symptomatically characterized by a variety of motor and nonmotor issues.
It is thought that PD is caused, in part, by problems in energy metabolism. Specifically, there is a decrease in the production of ATP (adenosine triphosphate) within the brain’s dopamine-releasing neurons. ATP can be thought of as the energy currency of all cells, and the brain’s dopamine-releasing neurons are among the most energetically demanding cells in the human body. Therefore, this decrease in ATP production contributes to an energy crisis that ultimately leads to dopamine-releasing neuron cell death in patients with PD.
While there is no cure for PD, evidence suggests that altering the brain’s energy metabolism by providing neurons with a highly efficient source of fuel called ketone bodies can increase ATP levels and help to alleviate the symptoms of PD. Encouragingly, work in cell and animal models of PD has shown that ketone bodies do, in fact, prevent the death of dopamine-releasing neurons and also protect against the symptoms of PD.
Historically, the only way to meaningfully increase ketone body levels in humans has been through starvation or pseudo-starvation “ketogenic” diets. During starvation, or while on a ketogenic diet, there is a deficiency of glucose. Because the brain normally relies on glucose for fuel, evolution equipped humans with the ability to produce a highly efficient backup fuel—ketone bodies. In the absence of dietary carbohydrates, the liver produces ketone bodies from fat to fuel the brain. These ketone bodies alter brain metabolism in a manner that may protect neurons. Interestingly, human patients who adhered to a ketogenic diet for 28-days experienced impressive improvements in their PD symptoms. Unfortunately, starvation and ketogenic diets come with major drawbacks. The former is obviously not sustainable. The latter is also difficult to sustain because ketogenic diets are composed of >80% fat calories and are difficult with which to comply. Furthermore, ketogenic diets may confer cardiovascular risk.
The Clarke group at the University of Oxford has invented a ketone body dietary supplement (DeltaG) that may provide the pros of ketones without the cons of starvation or ketogenic diets. Data in healthy humans has already demonstrated that DeltaG is a tolerable and safe way to increase ketone body levels and favorably alter energy metabolism. The aim of this study is to investigate whether DeltaG can be used to increase ATP levels in the brains of patients with PD and, thereby, perhaps help to rescue PD-sensitive dopamine-releasing neurons from energy crisis and subsequent cell death.
Who can participate?
Patients with Hoehn and Yahr stage 1 or 2 Parkinson’s disease who are between the ages of 40 and 80, who are fluent in English, and who have no metal implants in their bodies.
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 undergo magnetic resonance imaging at the John Radcliffe Hospital in Oxford to measure the ATP levels in their brains before, and one hour after, consuming 350mg/kg of the Clarke group’s ketone supplement (DeltaG). In addition to the scan, participants will be asked to provide two blood samples taken from a venous cannula inserted into one of their arms to investigate how the ketone supplement affect the levels of circulating metabolites.
What are the potential benefits and risks of participating?
There are not expected to be direct benefits for participants, although the results of the research could inform therapeutic interventions for patients with Parkinson’s disease. The risks to participants are minimal. Perhaps the only notable risk is that it has been reported that the ketone supplement (DeltaG) can cause diarrhea, abdominal distension, and nausea. However, these gastrointestinal side effects are both rare and mild. DeltaG has generally regarded as safe (GRAS) certification from the FDA, is commercially available in the United States as a sports supplement, and prior work by the Clarke group has demonstrated that chronic ingestion of DeltaG at much higher doses is safe and generally well-tolerated.
Where is the study run from?
The John Radcliffe Hospital in Headington, Oxford, OX3 9DU, United Kingdom.
When is the study starting and how long is it expected to run for?
October 2018 to December 2019.
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)
michele.hu@ndcn.ox.ac.uk
Contact information
Scientific
Sherrington Building
Sherrington Rd
Oxford
OX1 3PT
United Kingdom
 ORCID ID |
0000-0002-0826-9069 |
|---|---|
| Phone | +44 (0) 7444 054375 |
| nicholas.norwitz@dpag.ox.ac.uk |
Scientific
Department of Neurology, West Wing, Level 3
John Radcliffe Hospital, Headley Way
Oxford
OX3 9DU
United Kingdom
| ORCID ID |
0000-0001-6382-5841 |
|---|
Public
Sherrington Building
Sherrington Rd
Oxford
OX1 3PT
United Kingdom
| ORCID ID |
0000-0002-0826-9069 |
|---|---|
| Phone | +44 (0)7444 054375 |
| nicholas.norwitz@dpag.ox.ac.uk |
Study information
| Study design | Single-centre non-randomised study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Non randomised study |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | ISRCTN10531043_PIS_V1.5_04Dec2018.pdf |
| Scientific title | Supplementation with a ketone ester drink to increase cerebral ATP in the brains of patients with Parkinson's disease as measured by magnetic resonance spectroscopy |
| Study objectives | Ingestion of a ketone ester supplement (DeltaG) will increase ATP levels in the brains of patients with Parkinson’s disease. |
| Ethics approval(s) | Approved 11/03/2019, South Central - Oxford A Research Ethics Committee (Bristol Research Ethics Committee Centre, Whitefriars, Level 3 Block B, Lewins Mead, Bristol, BS1 2NT, UK; Tel: +44 (0)207 104 8041; Email: nrescommittee.southcentral-oxforda@nhs.net), REC ref: 19/SC/0033 |
| Health condition(s) or problem(s) studied | Parkinson’s disease |
| Intervention | 12 patients with Parkinson’s disease will undergo 31-phosphorus magnetic resonance spectroscopy (31-P MRS) imaging in order to determine their baseline cerebral ATP levels. They will also have a set of bloods drawn at this timepoint to determine their glucose, lactate, insulin, free fatty acid, and beta-hydroxybutyrate baselines. Participants will then consume 350mg/kg of ketone ester supplement (DeltaG) and, one hour later, repeat the 31-P MRS and blood measurements. |
| Intervention type | Supplement |
| Primary outcome measure | Cerebral ATP levels measured by 31-P MRS before and one hour after ingestion of the ketone supplement |
| Secondary outcome measures | Glucose, insulin, free fatty acid, and beta-hydroxybutyrate levels measured by standard laboratory blood assays before and one hour after ingestion of the ketone supplement |
| Overall study start date | 01/10/2018 |
| Completion date | 01/12/2019 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Mixed |
| Sex | Both |
| Target number of participants | 12 |
| Total final enrolment | 10 |
| Key inclusion criteria | 1. Diagnosis of Parkinson's disease 2. Hoehn and Yahr stages 1-2 3. Fluent in English 4. Capable of giving informed consent 5. Aged 40-80 |
| Key exclusion criteria | 1. Communication impairments 2. Contraindications for undergoing magnetic resonance imaging (metal implants, claustrophobia) 3. Any disorder that the Principal Investigator deems may bias the study results or put the participant at risk |
| Date of first enrolment | 01/02/2019 |
| Date of final enrolment | 01/09/2019 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
Oxford
OX3 9DU
United Kingdom
Sponsor information
Industry
30 Upper High Street
Thame
OX9 3EZ
United Kingdom
| Website | http://tdeltas.com |
|---|
Funders
Funder type
Industry
No information available
Results and Publications
| Intention to publish date | 01/07/2021 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Not expected to be made available |
| Publication and dissemination plan | At the end of the study, the results will be presented at regional, national, and international meetings and published in medical journals. All published results and information will be anonymized. |
| IPD sharing plan | To adhere to the privacy protection requirements of our ethics board, participant level data will only be available to the research team and regulation institutions upon request to the sponsor. All participant level data will be stored in password-protected computers and facilities with restricted access. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Participant information sheet | version V1.5 | 04/12/2018 | 07/12/2018 | No | Yes |
| Protocol file | version V1.2 | 04/12/2018 | 07/12/2018 | No | No |
| Participant information sheet | version v1.10 | 12/03/2019 | 10/08/2020 | No | Yes |
| Protocol file | version v1.21 | 06/02/2019 | 10/08/2020 | No | No |
| Basic results | 12/01/2021 | 12/01/2021 | No | No | |
| HRA research summary | 28/06/2023 | No | No |
Additional files
- ISRCTN10531043_PIS_V1.5_04Dec2018.pdf
- Uploaded 07/12/2018
- ISRCTN10531043_Protocol_V1.2_04Dec2018.pdf
- Uploaded 07/12/2018
- ISRCTN10531043_PROTOCOL_v1.21_06Feb19.pdf
- uploaded 10/08/2020
- ISRCTN10531043_PIS_v1.10_12Mar19.pdf
- uploaded 10/08/2020
- ISRCTN10531043_Basic_results_12Jan2021.pdf
- uploaded 12/01/2021
Editorial Notes
12/01/2021: The basic results of this trial have been uploaded as an additional file.
10/08/2020: The following changes were made to the trial record:
1. The latest participant information sheet was uploaded as an additional file.
2. Uploaded updated protocol (not peer reviewed) Version 1.21 06 February 2019.
04/10/2019: The total final enrolment was added.
12/07/2019: Ethics approval details added.
07/12/2018: The participant information sheet has been uploaded.
07/12/2018: Uploaded protocol version 1.2 (not peer reviewed)
