ANZCTR - Registration

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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 information initially provided

30/08/2019

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]

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

Condition category

Condition code

Neurological

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]

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]

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]

Change from baseline to week 6 and 12 (week 12 is primary endpoint).

Primary outcome [2]

Change in function (points).
- Assessment (study partner only) using the AD Cooperative Study - Activities of Daily Living (ADCS-ADL) inventory.

Timepoint [2]

Change from baseline to week 6 and 12 (week 12 is primary endpoint).

Primary outcome [3]

Change in quality of life (points).
- Assessment (study partner only) using the Quality of Life in AD (QOL-AD) questionnaire.

Timepoint [3]

Change from baseline to week 6 and 12 (week 12 is primary endpoint).

Secondary outcome [1]

Change in weight (kg), shoes off, using a standard scale (same scale every visit).

Timepoint [1]