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Trial registered on ANZCTR


Registration number
ACTRN12618001450202
Ethics application status
Approved
Date submitted
25/08/2018
Date registered
28/08/2018
Date last updated
16/07/2021
Date data sharing statement initially provided
10/07/2019
Date results provided
16/07/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
The Ketogenic Diet In Alzheimer's
Scientific title
The Ketogenic Diet In Alzheimer's: A Randomized Crossover Trial
Secondary ID [1] 295905 0
None
Universal Trial Number (UTN)
U1111-1216-9300
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Alzheimer's disease 309377 0
Condition category
Condition code
Neurological 308240 308240 0 0
Alzheimer's disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
We aim to recruit 25-30 volunteers from the Waikato and Bay of Plenty regions via presentations at Dementia Waikato meetings in Hamilton and at similar meetings in Rotorua and Tauranga, as well as via Waikato and Bay of Plenty geriatric services and letters of invite to GPs.

This will be a single-phase (all at once), parallel-group (1:1 randomization), 24-week (two 12-week phases, plus a 6-10 week washout) randomized crossover study in patients with mild AD. Patients will be randomized using a randomization generator, stratified by dementia severity rating scale (DSRS) score (DSRS below mean study DSRS, above mean) and body-mass index (BMI) (BMI below mean study BMI, BMI above mean).

There will be eight visits at Waikato Hospital: 1 screening visit, 1 training visit, then for each phase of the crossover, 1 baseline assessment visit (2 total), 1 assessment visits at week 6 after commencing the diet intervention (2 total), and 1 assessment visit at week 12 after commencing the diet intervention (2 total).

The 2-hour screening visit will include: (1) presentation of study and diet plans, (2) relevant demographic, medical, and social history, (3) Dementia Severity Rating Scale (DSRS), (4) Informed Consent questionnaire, (5) check for NINCDS-ADRDA criteria for all-cause dementia and probable AD, (6) Geriatric Depression score (short form), (7) Hachinski Ischemia score, (8) body mass index (BMI) calculations, and (9) assuming sufficient consent capacity, written informed consent from both the patient and their study partner.

The screening visit will occur 1-2 months before the start of the diet interventions. Patients will continue their usual, nonmodified diets as well as their usual medications from the screening visit to the start of the diet intervention.

The 45-minute training visit will include recommended calorie intake calculations, blood tests for APO-E4 status, training on how to use the blood glucose and ketone monitors, and a detailed explanation of how to use the diet plans. Patients will be given a blood glucose and ketone monitor at this visit, with which they will record their own levels every second night (at bedtime); this will not only demonstrate whether a patient is in physiological ketosis or not, it will also provide instant feedback to the patient as to how “well” they are doing.

The 60-minute baseline assessment visit, as well as those at weeks 6 and 12, will consist of:

(1) A cognitive assessment using the Addenbrookes Cognitive Examination (ACE-III) scale (New Zealand version A at baseline, version B at week 6, and version C at week 12).
(2) A functional assessment using the AD Cooperative Study - Activities of Daily Living (ADCS-ADL) inventory.
(3) A quality of life assessment using the Quality of Life in AD (QOL-AD) questionnaire.
(4) Body weight measurements.
(5) Blood tests for glycosylated haemoglobin (HbA1C), triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and total cholesterol.

For each assessment visit, each scale (ACE-III, ADCS-ADL, and QOL-AD) will be performed by the same diet-blinded clinician, on the same weekday, at the same time of day. It will be strictly forbidden for either patient or clinician to discuss any aspect of diet during the assessments. Patients will receive their randomized diet plan at the end of the baseline assessment visit.

The ketogenic plan will have full recipes for the 12-week phase. The usual diet plan will have optional recommended recipes and a copy of the NZ healthy eating guidelines. We will incorporate food from multiple ethnicities into each diet. Each plan will include space to tick the completion of each meal as well as record daily (bedtime) blood glucose and ketone levels and simple recipes. The usual diet with healthy recommendations plan will provide optional low-fat recipes on average per 1750 kcal per day composed of 42 g of fat (10 g saturated), 75 g of protein, 246 g net carbohydrate, and 33 g of fiber. The ketogenic plan will have recipes on average per 1,750 kcal per day composed of 152 g of fat (67 g saturated), 75 g of protein, 16 g net carbohydrate, and 11 g of fiber.

Regular support and education sessions will be provided via emails and videos - the lead investigator and nutrition specialist will send global e-mails to all patients every second day and film and post 10-minute videos on the study’s website every weekend for the 12 weeks of each phase of the study. Both diet approaches will be equally presented as potentially conferring health benefits, and both groups will be consistently reminded to eat until satiated.

Primary outcomes will be mean within-individual changes in cognition (ACE-III score), daily function (ADCS-ADL score), and quality of life (QOL-AD score) from baseline to week 12, analyzed using Wilcoxon signed-rank tests.

Secondary outcomes will consist of intra-individuals changes in metabolic parameters, including weight, BMI, HbA1C, triglycerides, HDL, LDL, and total cholesterol, also using Wilcoxon signed-rank tests.

We will analyze data two ways. First, we we will analyze using all randomized participants (intention to treat), with imputation for any missing data, to test for feasibility plus efficacy. Second, we may complete a case completer analysis (those who complete both phases) to test for efficacy alone.

There will be a 6-10-week washover period, with all participants returning to their normal pre-study diets, between the two 12-week diet interventions phases. According to the only previous study of a ketogenic diet in people with mild or moderate Alzheimer's by Taylor et al, a 4-week washout was sufficient for any cognitive improvements in that study to return to baseline, pre-diet intervention values. We choose 6-10 weeks to ensure that we have completely absolved any carryover effects from the first phase into the second phase. We will aim for 6-10 weeks to minimize any chance of a period effect; given practical considerations (the washout will be during local holidays), we cannot be specific about the exact length of the washout period at this stage.

If we have a sufficient number of Maori patients enrolled, a sub-group analysis comparing the effects of the two different diets on NZ European versus Maori participants would be considered. We may also consider a sub-analysis based on BMI (above mean BMI, below mean BMI) and APOE4 status (carriers, noncarriers).
Intervention code [1] 312229 0
Treatment: Other
Comparator / control treatment
The following changes were made prior to enrolment commencement:
Comparator remains modified ketogenic diet.
Control is now patient's usual diet, supplemented by optional low-fat and NZ healthy eating guidelines recipes.
Control group
Active

Outcomes
Primary outcome [1] 307203 0
Change in cognition (points).
- Assessment (patient) using the Addenbrookes Cognitive Examination (ACE-III) scale (New Zealand version A at baseline, version B at week 6, and version C at week 12).
Timepoint [1] 307203 0
Change from baseline to week 6 and 12 (week 12 is primary endpoint).
Primary outcome [2] 307204 0
Change in function (points).
- Assessment (study partner only) using the AD Cooperative Study - Activities of Daily Living (ADCS-ADL) inventory.
Timepoint [2] 307204 0
Change from baseline to week 6 and 12 (week 12 is primary endpoint).
Primary outcome [3] 307205 0
Change in quality of life (points).
- Assessment (study partner only) using the Quality of Life in AD (QOL-AD) questionnaire.
Timepoint [3] 307205 0
Change from baseline to week 6 and 12 (week 12 is primary endpoint).
Secondary outcome [1] 351117 0
Change in weight (kg), shoes off, using a standard scale (same scale every visit).
Timepoint [1] 351117 0
Change from baseline to week 6 and 12.
Secondary outcome [2] 351118 0
Change in body mass index (BMI) using a standard scale to check weight (same scale every visit) and a tape measure to check height (in cm) and then BMI will be calculated using an online BMI calculator.
Timepoint [2] 351118 0
Change from baseline to week 6 and 12.
Secondary outcome [3] 351119 0
Change in glycosylated hemoglobin (HbA1C) (mmol/mol) via serum assay.
Timepoint [3] 351119 0
Change from baseline to week 6 and 12.
Secondary outcome [4] 351120 0
Change in triglycerides (mmol/L) via serum assay.
Timepoint [4] 351120 0
Change from baseline to week 6 and 12.
Secondary outcome [5] 351121 0
Change in high-density lipoprotein (HDL) (mmol/L) via serum assay.
Timepoint [5] 351121 0
Change from baseline to week 6 and 12.
Secondary outcome [6] 351122 0
Change in low-density lipoprotein (LDL) (mmol/L) via serum assay.
Timepoint [6] 351122 0
Change from baseline to week 6 and 12.
Secondary outcome [7] 351123 0
Change in total cholesterol (mmol/L) via serum assay.
Timepoint [7] 351123 0
Change from baseline to week 6 and 12.
Secondary outcome [8] 351217 0
Blood glucose level (mmol/L) via serum assay.
Timepoint [8] 351217 0
Daily (bedtime) throughout the 12-week study.
Secondary outcome [9] 351218 0
Blood beta-hydroxybutyrate (ketone) level (mmol/L) via serum assay.
Timepoint [9] 351218 0
Daily (bedtime) throughout the 12-week study.

Eligibility
Key inclusion criteria
(1) Aged 50 to 90 years.
(2) Satisfies revised NINCDS-ADRDA criteria for probable AD.
(3) Mild dementia (DSRS <19) and sufficient consent capacity (passing grade on a modified AD Informed Consent questionnaire, defined as at least 70% of questions 1 to 10 correct and 100% of questions 11 to 14 correct on the first or second administration, with the word “medication” replaced with “diet”).
(3) BMI >18.5.
(4) An active study partner able and willing to follow either diet plan.
Minimum age
50 Years
Maximum age
90 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
(1) Inability to speak or understand English.
(2) Moderate or severe depression (short form Geriatric Depression score >8).
(3) Substantial concomitant cerebrovascular disease (Hachinski Ischemia score >4).
(4) Any change in dosage of an acetylcholinesterase inhibitor or memantine within 6 weeks before commencing the diets.
(5) A concurrent medical or psychiatric condition that in the opinion of the investigators would make it difficult to complete the study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The following change was made several months prior to enrolment commencement:

This is a single-phase study, so randomization will be conducted all at once, 1-2 days prior to the participants receiving their diet allocation, by the study's statistician.

The statistician, who is not affiliated with the study in any other way, will independently carry out randomization. The lead investigator, or any other study investigator, will not be involved in any way.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Patients will be randomized by the study statistician, stratifying by two variables - dementia severity rating scale (DSRS) score (above mean DSRS in study, below mean) and body mass index (BMI) (above mean BMI in study, below mean). There will thus be four blocks:
- High DSRS, high BMI.
- High DSRS, low BMI.
- Low DSRS, high BMI.
- Low DSRS, low BMI.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Our hospital Alzheimer's specialists consider an ACE-III change of 5 points to be clinically meaningful, and previous studies suggest a change in ADCS-ADL of 2 points, and a QOL-AD change of 3 points, are clinically meaningful. To obtain 90% power using a significance level of 0.05, we calculate that 18 patients (9 per diet group) will detect an ACE-III change of 5 +/- 10 points, or an ADCS-ADL change of 2 +/- 4 points, or a QOL-AD change of 3 +/- 6 points. Given that the single previous study of a ketogenic diet in Alzheimer's by Taylor et al 2018 showed a dropout rate of 27%, we aim to recruit 25-30 patients.

We will analyze data two ways. First, we we will analyze using all randomized participants (intention to treat), with imputation for any missing data, to test for feasibility plus efficacy. Second, we may complete a case completer analysis (those who complete both phases) to test for efficacy alone.

There will be a 6-10-week washover period, with all participants returning to their normal pre-study diets, between the two 12-week diet interventions phases. According to the only previous study of a ketogenic diet in people with mild or moderate Alzheimer's by Taylor et al, a 4-week washout was sufficient for any cognitive improvements in that study to return to baseline, pre-diet intervention values. We choose 6-10 weeks to ensure that we have completely absolved any carryover effects from the first phase into the second phase. We will aim for 6-10 weeks to minimize any chance of a period effect; given practical considerations (the washout will be during local holidays), we cannot be specific about the exact length of the washout period at this stage.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/05/2019
Actual
1/07/2019
Date of last participant enrolment
Anticipated
31/08/2019
Actual
21/08/2019
Date of last data collection
Anticipated
8/05/2020
Actual
8/05/2020
Sample size
Target
25
Accrual to date
Final
26
Recruitment outside Australia
Country [1] 20799 0
New Zealand
State/province [1] 20799 0
Waikato

Funding & Sponsors
Funding source category [1] 300496 0
Charities/Societies/Foundations
Name [1] 300496 0
Waikato Medical Research Foundation
Country [1] 300496 0
New Zealand
Primary sponsor type
Hospital
Name
Waikato Hospital Neurology Department
Address
Neurology Dept
Waikato Hospital
Pembroke Street
Hamilton 3204
New Zealand
Country
New Zealand
Secondary sponsor category [1] 299973 0
None
Name [1] 299973 0
NA
Address [1] 299973 0
NA
Country [1] 299973 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301294 0
Health and Disability Ethics Committee
Ethics committee address [1] 301294 0
Ethics committee country [1] 301294 0
New Zealand
Date submitted for ethics approval [1] 301294 0
23/08/2018
Approval date [1] 301294 0
05/11/2018
Ethics approval number [1] 301294 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 86526 0
Dr Matthew CL Phillips
Address 86526 0
Neurology Dept, Waikato Hospital, Pembroke St, Hamilton NZ 3204
Country 86526 0
New Zealand
Phone 86526 0
+64274057415
Fax 86526 0
Email 86526 0
Matthew.Phillips@waikatodhb.health.nz
Contact person for public queries
Name 86527 0
Matthew CL Phillips
Address 86527 0
Neurology Dept, Waikato Hospital, Pembroke St, Hamilton NZ 3204
Country 86527 0
New Zealand
Phone 86527 0
+64274057415
Fax 86527 0
Email 86527 0
Matthew.Phillips@waikatodhb.health.nz
Contact person for scientific queries
Name 86528 0
Matthew CL Phillips
Address 86528 0
Neurology Dept, Waikato Hospital, Pembroke St, Hamilton NZ 3204
Country 86528 0
New Zealand
Phone 86528 0
+64274057415
Fax 86528 0
Email 86528 0
Matthew.Phillips@waikatodhb.health.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Potentially any data requested, depends on intended use.
When will data be available (start and end dates)?
Immediately upon (same day of) publication with no end date.
Available to whom?
Medical professionals and researchers.
Available for what types of analyses?
Any statistical analysis.
How or where can data be obtained?
Emailing the corresponding author at Matthew.Phillips@waikatodhb.health.nz.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseRandomized crossover trial of a modified ketogenic diet in Alzheimer's disease.2021https://dx.doi.org/10.1186/s13195-021-00783-x
N.B. These documents automatically identified may not have been verified by the study sponsor.