Clinical trial NCT05469997: Ketogenic Diet Interventions in Parkinson's Disease: Safeguarding the Gut Microbiome
Official title: Ketogenic Diet Interventions in Parkinson's Disease: Safeguarding the Gut Microbiome
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Parkinson Disease
Keywords: Parkinson's Disease
Gut Microbiome
Ketogenic Diet
Mediterranean Diet
Medium-Chain Triglyceride
Life-style Interventions
Lead sponsor: University of British Columbia
Sponsor class: OTHER
Collaborators: name: Weston Family Foundation
First posted: 2022-07-22
Enrollment: 50
Sex: ALL
Minimum age (years): 45
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: This safety study consists of two 8-week interventions (MeDi-MCT and MeDi-KD) in randomized order using a cross-over design, separated by an 8-week washout period. Participants will be randomized into either the MeDi-MCT or the MeDi-KD group for the first phase of the study. After 8-weeks of intervention, they will undergo an 8-week washout period where no interventions will be applied. Subsequently, the participants will commence the second phase of the study by receiving the other study intervention for 8 weeks.
Primary purpose: SUPPORTIVE_CARE

Brief summary: Parkinson's Disease (PD) is the second most common neurodegenerative disorder with common gut-related symptoms, which are attributed to alterations in the gut microbiome - the collection of microorganisms that live within the gut. Classical ketogenic diets (KD) have shown to be beneficial in PD and non-PD populations but are associated with alterations in the gut microbiome that are characteristic of a perturbed system. This study aims to investigate the safety of modified Mediterranean-ketogenic interventions that are thought to be safer alternatives to the classical KD, as it relates to the gut microbiome health in patients with PD. We hypothesize that the modified Mediterranean-ketogenic interventions will not be associated with any significant perturbation of the gut microbiome in PD patients.

Detailed description: Background:

Parkinson's disease (PD), the second most common and the most rapidly growing neurodegenerative disease worldwide \[1,2\]. Gut-related symptoms are common and often the initial symptoms, suggesting a possible intestinal origin of PD \[4\]. Over a dozen studies have demonstrated gut dysbiosis in PD with reduced diversity, increased pro-inflammatory capacity, and decreased Short-Chain Fatty Acids (SCFA) production as key characteristics \[5-10\] and persistently increased relative abundance of Akkermansia \[5-17\].

Emerging evidence suggests that both ketogenic \[18-23\] and Mediterranean diets \[24-30\] have beneficial and likely complementary effects in PD. Mediterranean diets (MeDi) are primarily but not exclusively plant-based \[24\]. Their promotion of high fiber content intake promotes the production of SCFA and are associated with improved gut microbiome health \[25\]. Ketogenic diets (KD) are high in fat, adequate in protein and very low in carbohydrates \[31\]. KD can provide ketone bodies (KB) \[32\] as an alternative fuel source to glucose, the utilization of which is perturbed in the PD brain \[33\]. Another method for inducing the state of ketosis is by consumption of ketogenic medium-chain triglycerides (MCTs) \[43\]. MCTs are converted to KBs, which can readily cross the blood-brain barrier and be used as an energy source \[43\]. Pilot trials in PD report improved Unified Parkinson's Disease Rating Scale (UPDRS) scores \[20\], cognitive performance \[21\] and non-motor symptoms \[22\] with KD interventions \[23\].

Several studies of classical KDs in non-PD populations have observed significant alterations in the gut microbiome, including an increase in Akkermansia \[47\] and a decrease in fecal SCFA levels \[50\].

By combining the principles of MeDi with ketogenic interventions, we hope to leverage the gut-health promoting aspects of the former with bioenergetics benefits of the latter, in a safe manner. To the best of our knowledge, no clinical trials have been performed into combined ketogenic and Medi-stye dietary interventions in PD yet.

Design:

A proof of concept, random order, cross-over study in participants with PD examining two 8-week interventions: (1) the Mediterranean ketogenic diet (MeDi-KD) and (2) the Mediterranean diet supplemented with medium-chain triglycerides (MeDi-MCT), separated by an 8-week washout period.

Hypothesis:

1. Neither the MeDi-MCT nor the MeDi-KD (pre-post comparison) will be significantly associated with measures of gut microbiome dysbiosis such as increased gut inflammation, impaired gut-barrier integrity, and reduced SCFA content.
2. Retention rates for both diets will be at least 75%.

Eligibility criteria: Inclusion Criteria:

* Age between 40-85 years
* PD diagnosis based on Movement Disorder Society (MDS) criteria \[52\]
* Hoehn \& Yahr score of 1 to 3
* On stable dopaminergic medication for at least one month

Exclusion Criteria:

* Atypical parkinsonism
* Medical or psychiatric conditions that would prevent full participation in the nutrition intervention
* Significant dysphagia
* Diabetes on insulin
* Anti-coagulation on warfarin
* Inflammatory bowel disease
* Dementia defined by Montreal Cognitive Assessment (MoCA) Scores of less than 21
* Inability to fill in electronic questionnaires or understand study instructions
* Use of immunomodulatory agents
* Probiotic use in the last 4 weeks (except for dietary sources such as yoghurt, kefir etc.), or antibiotic use in the last 3 months prior to the trial
* Use of MCT oil or on ketogenic diet in last 8 weeks prior to the trial
* Allergic to MCT oil, coconut oil, or coconut

Primary outcomes:
measure: Change from baseline and difference across interventions in measures of fecal and serum calprotectin, a biomarker for gut inflammation.
timeFrame: Preintervention 1 (Baseline 1)/ Post-intervention 1 (Week 8)/ Pre-intervention 2 (baseline 2; Week 16)/ Post-intervention 2 (Week 24)
measure: Changes from baseline and differences across interventions in other measures of gut health, namely short-chain fatty acid production, gut-barrier integrity, and microbial composition.
timeFrame: Preintervention 1 (Baseline 1)/ Post-intervention 1 (Week 8)/ Pre-intervention 2 (baseline 2; Week 16)/ Post-intervention 2 (Week 24)
Secondary outcomes:
measure: The number of participants who completed the study after successful enrollment relative to the total enrolled participants.
timeFrame: Post-intervention 1 (Week 8)/Post-intervention 2 (Week 24)
measure: Percent time spent in clinically relevant levels of ketosis ( equivalent to >0.5 mmol/L) by each participant throughout each intervention.
timeFrame: Post-intervention 1 (Week 8)/Post-intervention 2 (Week 24)
Other outcomes:
measure: Changes from baseline in motor and non-motor Parkinson's Disease symptoms after each intervention
timeFrame: Preintervention 1 (Baseline 1)/ Post-intervention 1 (Week 8)/ Pre-intervention 2 (baseline 2; Week 16)/ Post-intervention 2 (Week 24)
measure: Tracking changes from baseline in severity of Fatigue Symptoms after each intervention
timeFrame: Preintervention 1 (Baseline 1)/ Post-intervention 1 (Week 8)/ Pre-intervention 2 (baseline 2; Week 16)/ Post-intervention 2 (Week 24)
measure: Changes from baseline in apathy symptoms after each intervention
timeFrame: Preintervention 1 (Baseline 1)/ Post-intervention 1 (Week 8)/ Pre-intervention 2 (baseline 2; Week 16)/ Post-intervention 2 (Week 24)
measure: Changes from baseline in depressive symptoms after each intervention
timeFrame: Preintervention 1 (Baseline 1)/ Post-intervention 1 (Week 8)/ Pre-intervention 2 (baseline 2; Week 16)/ Post-intervention 2 (Week 24)
measure: Changes from baseline in Anxiety symptoms after each intervention
timeFrame: Preintervention 1 (Baseline 1)/ Post-intervention 1 (Week 8)/ Pre-intervention 2 (baseline 2; Week 16)/ Post-intervention 2 (Week 24)
measure: Tracking changes in the quality of life of the study participants after each intervention
timeFrame: Preintervention 1 (Baseline 1)/ Post-intervention 1 (Week 8)/ Pre-intervention 2 (baseline 2; Week 16)/ Post-intervention 2 (Week 24)
measure: Assessing changes in capacity for performing physical activities in the study participants after each intervention
timeFrame: Preintervention 1 (Baseline 1)/ Post-intervention 1 (Week 8)/ Pre-intervention 2 (baseline 2; Week 16)/ Post-intervention 2 (Week 24)
measure: Assessing changes in the the stool consistency of the study participants after each intervention
timeFrame: 24 weeks (weeks 1-24)
measure: Assessing the constipation and irritable bowl symptoms in the study participants
timeFrame: Preintervention 1 (Baseline 1)/ Post-intervention 1 (Week 8)/ Pre-intervention 2 (baseline 2; Week 16)/ Post-intervention 2 (Week 24)
measure: Determining the dietary habits of the study participants prior to beginning of the study
timeFrame: Preintervention 1 (Baseline 1)
measure: Tracking changes in the cognitive function of the study participants
timeFrame: Preintervention 1 (Baseline 1)/ Post-intervention 1 (Week 8)/ Pre-intervention 2 (baseline 2; Week 16)/ Post-intervention 2 (Week 24)
Locations:
city: Vancouver
country: Canada
facility: Djawad Mowafaghian Centre for Brain Health
state: British Columbia
Study officials:
affiliation: University of British Columbia
name: Silke Appel-Cresswell, MD
role: PRINCIPAL_INVESTIGATOR
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