Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000854639
Ethics application status
Approved
Date submitted
24/06/2023
Date registered
8/08/2023
Date last updated
8/08/2023
Date data sharing statement initially provided
8/08/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Nutritional intervention in bipolar disorder and schizophrenia
Scientific title
The effects of diet on metabolic and mental health outcome measures in bipolar disorder and schizophrenia: a randomized controlled clinical trial
Secondary ID [1] 309835 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Schizophrenia 330263 0
Bipolar disorder 330264 0
Condition category
Condition code
Mental Health 327131 327131 0 0
Schizophrenia
Mental Health 327132 327132 0 0
Other mental health disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention group ("the KD arm") will be asked to follow a well-formulated and nutritionally balanced ketogenic diet (75% fat, 20% protein and 5% carbohydrates) for 12 weeks (+2 weeks introduction "run-in" to the diet and +2 weeks cessation period), taking into account the participants food preferences, allergies and intolerances, food preparation abilities and financial circumstances. The definition of "ketogenic" is based on the ability of the diet to induce the physiological production of ketone bodies ("ketones") by the liver in response to the diminished carbohydrate intake. Such ability is a natural physiological response and as such varies in accordance to the participants' sex, underlying metabolic state and long-standing dietary habits.

During the 2-week run-in period, the participant will for the first five days be required to only change their breakfast meal. On day six, the participants will be required to change the lunch meal as well (at this point, they are on their specified diet both morning and lunch). On day eleven, the dinner meal will be required to be changed into the specified diet, resulting in a complete change of diet. Similarly, during the cessation period, the participant will start by changing one meal back to "normal" for 5 days, then 2 meals and after 11 days, the participant will be back to their previous dietary habits. If the participant decides to continue the diet after the study has ended, they will not be required to stop it after week 14. Support from a dietitian and a team member will be offered for up to 3 months.

The KD arm will therefore receive an individualised nutritional assessment and advice by a qualified dietician experienced in therapeutic KD that will maximise the efficacy and safety of the KD in each case. The assessment will occur as soon as possible following the randomisation into the treatment group and will last approximately 60 minutes.

Following the assessment, the participants in the KD arm will receive informational material in the form of a KD Handbook (designed specifically for this study) containing the principles of the diet; necessary information to understand different macro and micronutrients relevant to the diet; education around the most common side effects of being on a KD and how to manage them; a collection of illustrated, easy to follow recipes to help the participants' daily compliance with the diet;

Daily readings of peripheral blood ketone and blood glucose levels will be monitored in order to ensure safety of, and compliance with, the diet. The participants will be asked to text a picture of their digital device showing ketones and blood sugar levels; as an optional alternative, they may send a text with the results to the team or receive a phone call by a team member instead. With appropriate consent in place, family members and/or carers will be encouraged to support the participant with their food sourcing, meal preparation, and blood test monitoring.

If necessary, in view of poor adherence to the diet by a participant or at the participant's own request, additional education by a team member under strict supervision of the dietitian and senior psychiatrists in the team, will be delivered to the participants or to their families or carers to ensure adherence to the KD.
Intervention code [1] 326266 0
Treatment: Other
Comparator / control treatment
The control group ("the AGHE arm") will follow a diet in accordance to the principles of to the Australian Guide to Healthy Eating for 12 weeks (+2 weeks introduction to the diet and +2 weeks cessation period).

The AGHE is a structured dietary advice (45-65% carbohydrates, 20-35% fats and 10-35% protein) made available to all Australians by the Australian National Medical Health and Research Council and the Department of Health and Aged Care.
Adherence to this advice is poor among Australians who suffer with severe and enduring mental disorders, hence allocation to this Arm is considered an active intervention. The AGHE is a recommended, healthy diet that differs from the KD fundamentally because it does not induce a ketogenic physiological production response by the liver.

The AGHE arm will therefore also receive an individualised nutritional assessment and advice by a qualified dietician experienced in AGHE. The assessment will occur as soon as possible following the randomisation into the control group and will last approximately 60 minutes.

Following the assessment, the participants in the AGHE arm will receive informational material in the form of the AGHE Handbook (designed specifically for this study) containing the principles of the diet; necessary information to understand different macro and micronutrients relevant to the diet; education around the most common effects of dietary changes and how to manage them; a collection of illustrated, easy to follow receipts to help the participants' daily compliance with the diet;

During the 2-week run-in period, the participant will for the first five days be required to only change their breakfast meal. On day six, the participants will be required to change the lunch meal as well (at this point, they are on their specified diet both morning and lunch). On day eleven, the dinner meal will be required to be changed into the specified diet, resulting in a complete change of diet. Similarly, during the cessation period, the participant will start by changing one meal back to "normal" for 5 days, then 2 meals and after 11 days, the participant will be back to their previous dietary habits. If the participant decides to continue the diet after the study has ended, they will not be required to stop it after week 14. Support from a dietitian and a team member will be offered for up to 3 months.

Daily readings of peripheral blood ketone and blood glucose levels will be monitored in order to ensure safety of, and compliance with, the diet. The participants will be asked to text a picture of their digital device showing ketones and blood sugar levels; as an optional alternative, they may send a text with the results to the team or receive a phone call by a team member instead. With appropriate consent in place, family members and/or carers will be encouraged to support the participant with their food sourcing, meal preparation, and blood test monitoring.

If necessary, in view of poor adherence to the diet by a participant or at the participant's own request, additional education by a team member under strict supervision of the dietitian and senior psychiatrists in the team, will be delivered to the participants or to their families or carers to ensure adherence to the AGHE.
Control group
Active

Outcomes
Primary outcome [1] 335000 0
Change on the “Young Mania Rating Scale” (YMRS)
Timepoint [1] 335000 0
The outcome will be measured using the appropriate scales by a trained psychiatrist at the assessments in week 0 (baseline), week 8 and week 14 (end of trial).
Primary outcome [2] 335257 0
Change on the “Positive and Negative Syndrome Scale” (PANSS)
Timepoint [2] 335257 0
Changes will be assessed at baseline (week 0), week 8 and week 14 (end of trial).
Primary outcome [3] 335258 0
Change on the “Affect Liability Scale” (ALS-18)
Timepoint [3] 335258 0
Changes will be assessed at baseline (week 0), week 8 and week 14 (end of trial).
Secondary outcome [1] 422671 0
To investigate the effect of a ketogenic diet on measures of glucose
Timepoint [1] 422671 0
Glucose and ketone levels will be monitored by the participants from home. A "blood glucose plus beta-ketone monitoring system" and test strips will be supplied to participants to measure this every day (2 hours prior to dinner).
Secondary outcome [2] 422672 0
To investigate the effect of a ketogenic diet on the immune biomarkers (albumin, TNF-alpha, IL-12, IL6, CRP and fibrinogen). This will be assessed from blood samples.
Timepoint [2] 422672 0
Blood samples will be taken during the week 0 (baseline), week 8 and week 14 (end of trial) assessments.
Secondary outcome [3] 422673 0
To investigate the effect of a ketogenic diet on the microbiome using stool samples
Timepoint [3] 422673 0
The collection of stool is optional for participants. If opt in, they will need to provide a sample in week 0 and week 14.
Secondary outcome [4] 422674 0
To investigate the effect of a ketogenic diet on cortisol using hair samples.
Timepoint [4] 422674 0
This will be an optional measure for all participants at the week 0 and week 14 assessments.
Secondary outcome [5] 422675 0
To investigate the effect of a ketogenic diet on heart rate variability using wearable personal health devices i.e. an Empatica wristband or an Oura Ring - depending on availability of the sets and personal preference by the participants.
Timepoint [5] 422675 0
This will be optional for all participants at week 0 and week 10. The devices must be worn continuously for 7 days in week 0 and again in week 10.
Secondary outcome [6] 423354 0
Determine the safety and tolerability of the diets in psychotic patients.
Timepoint [6] 423354 0
This will be monitored continuously and cross-sectionally evaluated by an experienced psychiatrist during the assessments in week 0, 8 and 14. Items will include: objective measures of adherence to the diet; diary logs; evaluation of patient-reported side effects by clinical interview;
Secondary outcome [7] 423627 0
Changes of the “WHO Disability Assessment Schedule – 2 (WHODAS-2)”
Timepoint [7] 423627 0
Changes will be assessed at baseline (week 0), week 8 and week 14 (end of trial).
Secondary outcome [8] 423628 0
Changes on the “Beck Depression Inventory” (BDI) (primary outcome)
Timepoint [8] 423628 0
Changes will be assessed at baseline (week 0), week 8 and week 14 (end of trial).
Secondary outcome [9] 423629 0
To investigate the effect of a ketogenic diet on laboratory blood test measures of lipid metabolism (HDL, LDL, triglycerides, cholesterol)
Timepoint [9] 423629 0
Lipid metabolism will be measured during assessments in week 0 (baseline), week 8 and week 14 (end of trial).
Secondary outcome [10] 423630 0
To investigate the effect of a ketogenic diet on body weight using a scale.
Timepoint [10] 423630 0
Body weight will be measured during assessments in week 0 (baseline), week 8 and week 14 (end of trial).
Secondary outcome [11] 423631 0
To investigate the effect of a ketogenic diet on heart rate (HR) using a digital blood pressure monitor on the upper arm.
Timepoint [11] 423631 0
Heart rate will be measured during assessments in week 0 (baseline), week 8 and week 14 (end of trial).
Secondary outcome [12] 423632 0
To investigate the effect of a ketogenic diet on the neuroendocrine biomarkers (cortisol and DHEAS).
Timepoint [12] 423632 0
Blood samples will be taken during the week 0 (baseline), week 8 and week 14 (end of trial) assessments.
Secondary outcome [13] 423633 0
To investigate the effect of a ketogenic diet on the metabolic biomarkers (HDL, LDL, triglycerides, glucose, HbA1c, cholesterol and insulin) using a blood sample.
Timepoint [13] 423633 0
Blood samples will be taken during the week 0 (baseline), week 8 and week 14 (end of trial) assessments.
Secondary outcome [14] 423634 0
To investigate the effect of a ketogenic diet on level of activity using a wearable personal health devices i.e. an Empatica wristband or an Oura Ring - depending on availability of the sets and personal preference by the participants.
Timepoint [14] 423634 0
This will be optional for all participants at week 0 and week 10. The devices must be worn continuously for 7 days in week 0 and again in week 10.
Secondary outcome [15] 423635 0
To investigate the effect of a ketogenic diet on quality of sleep using wearable personal health devices i.e. an Empatica wristband or an Oura Ring - depending on availability of the sets and personal preference by the participants.
Timepoint [15] 423635 0
This will be optional for all participants at week 0 and week 10. The devices must be worn continuously for 7 days in week 0 and again in week 10.

Eligibility
Key inclusion criteria
1) Meet the DSM-4 diagnostic criteria for bipolar disorder or meet the DSM-5 diagnostic criteria for schizophrenia for at least 6 months, assessed using the MINI Neuropsychiatric Interview
2) Clinically stable is defined as 3 months with no relapses.
3) Able to provide informed consent to take part in the study.
4) Able to speak, read and understand English to a level whereby they can understand the participant information sheet (PIS).
5) Able to understand basic principles of the specific diet
6) Ability to complete an accurate diet and symptom diary as well as questionnaires required.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Pregnancy or breastfeeding (or those planning to become pregnant within 3 months)
2) Active substance misuse with alcohol or illicit drugs
3) Use of the ketogenic diet in the previous 2 months
4) Currently following a vegan diet
5) Admission to a hospital within the past 3 months
6) Current involvement in another research study (This feasibility study is of moderate intensity and requires daily monitoring and a significant dietary intervention requiring careful planning. As such it would not be appropriate for participants involved in other current research to take part due to the potentially high level of burden on them. Those involved in recent research that has ended by the time of recruitment to this study would be eligible, and will be made fully aware of the level of engagement required to allow them to make an informed decision)
7) Inability to complete week 0 assessments
8) Clinically significant liver or kidney disease
9) Clinically significant cardiovascular disease
10) Severe hyperlipidemia
11) Type 1 diabetes
12) History of eating disorder
13) BMI < 18.5kg
14) On medication that can cause ketosis
15) Not willing to change diet or unable to change diet due to medical reasons
16) No access to cooking facilities and ingredients to prepare recipes following the specific diet.

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 allocation will be concealed from the investigators using sealed opaque envelopes and will only be known by the research coordinator. Each subsequent entry to each strata will be sequentially followed, thereby creating a stratified, random allocation that is double-blinded.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The study will use stratified randomization. We will stratify by assuming eight groups based on the following criteria: diagnosis (schizophrenia or bipolar disorder), gender (male or female), and duration of illness (DOI) of more or less than five years.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The optimal sample size is calculated based on a statistical power of 90% and a significance level of 0.05 (two-tail). To calculate the sample size, we have estimated the incidence to be 75% in group 1 (individuals on the KD) and 40% in group 2 (individuals on the AGTHE diet). We aim for a 1:1 enrolment ratio.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
4/09/2023
Actual
Date of last participant enrolment
Anticipated
2/09/2024
Actual
Date of last data collection
Anticipated
31/12/2024
Actual
Sample size
Target
100
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 24867 0
Townsville University Hospital - Douglas
Recruitment postcode(s) [1] 40515 0
4814 - Douglas

Funding & Sponsors
Funding source category [1] 314018 0
Charities/Societies/Foundations
Name [1] 314018 0
Baszucki Family Foundation
Country [1] 314018 0
United States of America
Primary sponsor type
University
Name
James Cook University
Address
1 James Cook Drive, 4811 Douglas, Queensland
Country
Australia
Secondary sponsor category [1] 315908 0
Hospital
Name [1] 315908 0
Townsville University Hospital
Address [1] 315908 0
100 Angus Smith Drive, 4817 Douglas, Queensland
Country [1] 315908 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313155 0
Townsville Hospital and Health Service Human Research Ethics Committee
Ethics committee address [1] 313155 0
Ethics committee country [1] 313155 0
Australia
Date submitted for ethics approval [1] 313155 0
21/03/2022
Approval date [1] 313155 0
03/02/2023
Ethics approval number [1] 313155 0
HREC85408

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

Contacts
Principal investigator
Name 127186 0
Prof Zoltan Sarnyai
Address 127186 0
James Cook University, 1 James Cook Drive, Townsville, Queensland 4811
Country 127186 0
Australia
Phone 127186 0
+61 0747816992
Fax 127186 0
Email 127186 0
[email protected]
Contact person for public queries
Name 127187 0
Calogero Longhitano
Address 127187 0
JCU Clinical School
Townsville University Hospital
100 Angus Smith Drive
4811 Douglas, Townsville, Queensland
Australia
Country 127187 0
Australia
Phone 127187 0
+61 0744333000
Fax 127187 0
Email 127187 0
[email protected]
Contact person for scientific queries
Name 127188 0
Zoltan Sarnyai
Address 127188 0
James Cook University, 1 James Cook Drive, Townsville Queensland 4811
Country 127188 0
Australia
Phone 127188 0
+61 0747816992
Fax 127188 0
Email 127188 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
19366Study protocol    The study protocol will be submitted to a relevant... [More Details]



Results publications and other study-related documents

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