Alzheimer's Disease, Frontotemporal Dementia (FTD), Primary Progressive Non-fluent Aphasia
Conditions
Keywords
medium chain triglyceride, MCT, coconut oil, MRI, PET, ketones
Brief summary
The purpose of this study is to determine safety, tolerability, and pharmacokinetics/dynamics of a ketogenic dietary supplement containing medium chain triglycerides (MCTs) in patients with Alzheimer disease (AD). Novel imaging and laboratory biomarkers in response to this intervention will also be explored. In addition, a sub-study was added to the UBC-approved protocol on November 29, 2016, prior to enrollment of the first FTD participant in April 2017. The FTD sub-study was designed as a pilot study to evaluate the safety and tolerability of MCT supplementation in participants with nonfluent/agrammatic variant primary progressive aphasia (nfvPPA).
Interventions
DIETARY_SUPPLEMENTKetogenic medium chain triglyceride drink (MCT drink)
10 days supplementation with the MCT drink. Participants in dose group 1 will be assigned to 10 g per day, those in dose group 2 will be assigned 20 g per day, those in dose group 3 will be assigned 30 g per day, those in dose group 4 will be assigned 40 g per day, and those in dose group 5 will be assigned 50 g per day. The drink will be taken in the morning and evening. Participants will be enrolled 8 per group in ascending order.
DIETARY_SUPPLEMENTPlacebo
10 days supplementation with the placebo drink. Participants in dose group 1 will be assigned to 10 g per day, those in dose group 2 will be assigned 20 g per day, those in dose group 3 will be assigned 30 g per day, those in dose group 4 will be assigned 40 g per day, and those in dose group 5 will be assigned 50 g per day. The drink will be taken in the morning and evening. Participants will be enrolled 8 per group in ascending order.
Sponsors
University of British Columbia
Université de Sherbrooke
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
FTD-nfvPPA substudy: crossover pilot design
Eligibility
Sex/Gender
ALL
Age
20 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of mild-moderate Alzheimer disease (AD) * Mini-Mental State Examination (MMSE) 16-26 * Study partner available who has frequent contact with the participant * Good visual and auditory acuity for neuropsychological testing * Education including completion of at least six grades * Must read and speak English fluently * Antidepressants permitted, if stable for 4 weeks prior to screening (and participant is not currently depressed and does not have a history of major depression within the past 1 year) * Cholinesterase inhibitors permitted, if stable for 12 weeks prior to screening
Exclusion criteria
* Any significant neurologic disease other than AD * History of Diabetes Mellitus type I or II * Any contraindications to MRI or PET studies * Major depression, bipolar disorder as described within the past 1 year. * History of schizophrenia * History of alcohol or substance abuse or dependence within the past 2 years * Any significant systemic illness or unstable medical condition, which could lead to difficulty complying with the protocol * Current use of specific psychoactive medications * Investigational amyloid lowering therapies are prohibited two months prior to screening and for the duration of the trial. Other investigational agents are prohibited one month prior to screening and for the duration of the trial. * History of brain cancer For FTD-nfvPPA substudy Inclusion Criteria 1. Dx of nonfluent/agrammatic variant primary progressive aphasia 2. Older than 19 years 3. Stability of permitted medications for 4 weeks. In particular, subjects may: d. Take stable doses of antidepressants (if they are not currently depressed or do not have a history of major depression within the past 1 year). e. Washout from psychoactive medication for at least 4 weeks prior to screening. f. Cholinesterase inhibitors are allowable if stable for 12 weeks prior to the screening visit. 4. Study partner is available who has frequent contact with the subject (e.g. an average of 8 hours per week or more), and can accompany the subject to all clinic visits for the duration of the protocol. 5. Females are not pregnant, lactating, or of childbearing potential (i.e. women must be two years post-menopausal or surgically sterile). 6. PET scan consistent with FTD (showing frontal hypoperfusion +/- temporal hypoperfusion) 7. MRI consistent with FTD/PNFA 8. Education including completion of at least six grades 9. Must read and speak English fluently
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with adverse events, serious adverse events | From baseline to day 10 of intervention | — |
| Plasma ketone concentrations in response to ascending dose of MCT | Day 10 of intervention at 0.5, 1, 1.5, 2, 3, 4, 4.5, 5, 5.5, and 6 hours post MCT dose | Plasma ketone concentrations of betahydroxybutyrate (BHB) and acetoacetate (AcAc) will be measured in response to MCT dosing from 10-50 grams daily. |
| Safety and tolerability of SCCF-3012 | Baseline to Month 6 | Incidence of treatment-emergent adverse events, serious adverse events, and laboratory parameter changes during 3 months of continuous SCCF-3012 dosing at 30 g/day (15 g BID) in participants with nonfluent/agrammatic variant primary progressive aphasia (nfvPPA). Adverse events tabulated by severity (mild/moderate/severe) and relatedness to study intervention (unlikely/possible/probable/likely). Tolerability assessed by the proportion of participants able to complete 3 months of continuous dosing at the target dose without intervention-related discontinuation. |
| Pharmacodynamic ketone response | Baseline, Month 3, Month 6 (each at pre-dose, 1 hour, and 4 hours post-dose) | Plasma β-hydroxybutyrate (BHB) concentration in FTD-nfvPPA participants at pre-dose, 1 hour, and 4 hours following ingestion of the study drink, measured at the end of each 3-month phase. Primary pharmacodynamic endpoint is the 4-hour post-dose plasma BHB at the end of the MCT phase. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area under the plasma concentration versus time curve (AUC) of MCT | Day 10 of intervention at 0.5, 1, 1.5, 2, 3, 4, 4.5, 5, 5.5, and 6 hours post MCT dose | To determine the MCT plasma concentration at stated time points in response to MCT dosing from 10-50 grams daily. |
| Change in language function (WAB-R Part 1) | Baseline, Month 3, Month 6 | For FTD-nfvPPA, Western Aphasia Battery-Revised Part I Aphasia Quotient (AQ; range 0-100, higher = better language function). Administered by a blinded examiner. Within-subject change analyzed as end-of-MCT-phase AQ minus end-of-placebo-phase AQ. |
| Change in global functional status (FTLD-CDR-SB) | Baseline, Month 3, Month 6 | Frontotemporal Lobar Degeneration Clinical Dementia Rating Sum of Boxes (FTLD-CDR-SB), extended from the standard CDR with language and behaviour modules. Range 0-24, with higher scores indicating greater impairment. Within-subject change analyzed as end-of-MCT-phase minus end-of-placebo-phase. |
| Global clinical impression of change (CGIC) | Month 3, Month 6 | Clinician Global Impression of Change (7-point scale: 1 = very much improved to 7 = very much worse), rated by a study clinician blinded to treatment allocation. At each follow-up visit, rating reflects change relative to the immediately preceding assessment (3-month phase) and is attributable to the treatment received during that phase. |
Countries
Canada
Contacts
PRINCIPAL_INVESTIGATORHaakon Nygaard, MD, PhD
University of British Columbia
PRINCIPAL_INVESTIGATORHoward Feldman, MD
University of California, San Diego
Outcome results
None listed