Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000058572
Ethics application status
Approved
Date submitted
8/12/2023
Date registered
25/01/2024
Date last updated
25/01/2024
Date data sharing statement initially provided
25/01/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
The Ketogenic Heart Failure Trial
Scientific title
Ketogenic Diet in Heart Failure with Reduced Ejection Fraction: A Pilot Randomised Controlled Trial (The KETO-HF Trial)
Secondary ID [1] 310219 0
Nil known
Universal Trial Number (UTN)
Trial acronym
KETO-HF
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Heart failure with reduced ejection fraction
 330905 0
Condition category
Condition code
Cardiovascular 327689 327689 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants (n= 60) will be randomly assigned to the intervention (n= 30) or control arm (n =30) in a 1:1 ratio.
The intervention group will undergo a normocaloric ketogenic dietary intervention diet (with very low carbohydrate [<10% total energy intake], high fat [~70% total energy intake, majority as mono or polyunsaturated fat, <15% as saturated fat] and moderate protein [~20%]). which will be delivered by a qualified dietician either in-person or via telehealth, depending on patient preference and other hospital restrictions.

All participants will have the following collected at baseline:
- Data collected on background medical history, current medications, cardiovascular risk
factors, alcohol intake, smoking and social history as well as LVEF as measured by the most recent cardiac imaging, Heart failure symptoms classified according to NYHA class I-IV,
- Measurement of height, weight, waist circumference and blood pressure
- Complete self-administered Kansas City Cardiomyopathy questionnaire.
- Self-reported dietary intake and exercise questionnaire.
- Fasting bloods taken for pathology including pro-BNP level, serum creatinine and
electrolytes, liver function, FBC, C-reactive protein (high sensitivity, if available), lipids
[TC, LDL, HDL, TG’s] and diabetic profiles (fasting blood glucose level, HbA1C, fasting
insulin)
- Echocardiography with a left ventricular ejection fraction (LVEF).

At the time of the baseline visit, all intervention participants will be instructed in the following:
- Instruction on keeping a blood glucose diary (if diabetic)
- Instruction on monitoring fluid balance by self-monitoring weight on home scales, monitoring for ankle swelling and shortness of breath
- Instruction on keeping a blood pressure diary if the participant owns a home monitor.
- Instruction on the use of a food diary and/or smart phone app to record carbohydrate intake per day (grams/day), ideally entered daily, but at least 3 days of the week.
- Instruction on performing urine ketone measurements at home on a 3-times per
week basis.

At 1 week, 1 month and 3 months & 4 months participants will have a telephone review with the study coordinator to:
- Obtain any history of syncope, pre-syncope (dizziness/faintness), low blood pressure, low
blood glucose, adverse events (see below) or other participant-identified concerns.
- Review a diary of blood glucose recordings in patients with diabetes mellitus to identify
hypoglycaemia (e.g. a low blood glucose of 4.0mmol/L or less)
- Review any home blood pressure recordings or any available in-clinic recordings at the
time of seeing their cardiologist/being seen in the heart failure clinic.
- Review of the food diary/smart phone app to assess carbohydrate intake.
- Record urinary ketone results measured by the participants at home.

Patients randomised to the dietary intervention group will undergo in person or telehealth one-on-one consultations with a qualified dietician who will administer the ketogenic diet. The dietary intervention will include oral and written advice on a ketogenic diet, delivered via an initial 45-minute consultation soon after baseline, followed by 20-minute follow-up consultations at 1 week, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months and 4 months (total of 8 dietician visits).
Dietary advice will comply with the following:
1. Restriction of carbohydrate to <30 grams carbohydrate/day (a very low carbohydrate intake i.e., <10% total daily intake).
2. Moderate protein intake (~28% total daily intake) and,
3. High healthy fat intake (>60% total daily intake) aiming for ~34% mono-unsaturated fat,
14% polyunsaturated fat and 12% saturated fat.

The food diary or smart phone app will be reviewed for compliance and advice provided. Patients will be asked to calculate grams per day of carbohydrates using a dietary app and/or asked to record grams per day in a smart phone app or via a food diary. Education of foods to consume in large amounts, moderate amounts and low amounts within the recommended diet will be provided both verbally and in written form.

All participants (intervention and control) will undergo a final in-person 4-month follow up:
- Clinical history obtained on adverse events, new medical diagnoses, worsening heart
failure episodes, urgent/unplanned doctor visits or pathology, emergency presentations,
heart failure hospitalizations, major cardiovascular events, current medications, alcohol
intake and smoking.
- Heart failure symptoms classified according to NYHA class I-IV.
- Measurement of weight, waist circumference, fluid status and blood pressure.
- Complete self-administered Kansas City Cardiomyopathy questionnaire.
- Self-reported dietary intake and exercise questionnaire.
- Fasting bloods taken for pathology including pro-BNP level, serum creatinine and electrolytes, liver function, FBC, C-reactive protein (high sensitivity, if available), lipids
[TC, LDL, HDL, TG’s] and diabetic profiles (fasting blood glucose level, HbA1C, fasting
insulin)
- Echocardiography with LVEF

Adherence to the study intervention will be measured by the percentage of consultations attended, with reasonable compliance defined as =>70% dietician attendance, as well as the proportion of participants who achieve ketosis as measured by the presence of urine ketones in =>70% of urine ketone measures at each time point. Adherence will secondarily be assessed by review of patient diary showing a self-reported carbohydrate intake of less than or equal to 30 grams/day.
Intervention code [1] 326610 0
Lifestyle
Intervention code [2] 327577 0
Behaviour
Comparator / control treatment
After randomisation, the patients randomised to the control group will receive standard guideline-directed and device therapy for their heart failure. This may include standard drug therapy including angiotensin-converting-enzyme inhibitors (ACE-I), angiotensin-receptor blocker (ARB) or sacubitril-valsartan (ARNI), beta-blockers, diuretics and mineralocorticoid receptor antagonists (MRAs).

Control participants will undergo a baseline assessment, as outlined above for the intervention arm. At 1 week, 1 month, 3 months, and 4 months participants will have a telephone review with the study coordinator to report any adverse events. Finally, control participants will attend an in-person follow-up at 4 months, as outlined above for the intervention arm.

All control participants will have a letter sent to their general practitioner (with the patients consent) discussing their involvement in the trial and conveying any clinically significant abnormalities detected at the baseline examination and/or blood investigations.
Control group
Active

Outcomes
Primary outcome [1] 336800 0
feasibility of a Ketogenic diet in patients with heart failure
Timepoint [1] 336800 0
Feasibility will be measured by compliance with a Ketogenic diet based on the presence of ketosis from urine ketones (at least 3 times a week), daily food diary/smart phone app reports and attendance at dietician visits baseline, 1 week, 1 month, 3 months, 4 months, 6 month and 12 months
Primary outcome [2] 336803 0
Safety of a Ketogenic diet
Timepoint [2] 336803 0
Safety will be measured through history, examination, and pathology to monitor for adverse events including symptomatic hypotension, syncope, hypokalaemia/hypoglycaemia requiring medical treatment and other important patient-reported side effects.

This data will be collected baseline visit, 1 week, 1 month, 3 months, 4 months, 6 month and 12 months follow up.
Secondary outcome [1] 430620 0
Major adverse cardiovascular between the groups
Timepoint [1] 430620 0
Hospitalisation data collected from medical records and participant questionnaires at 1 week, 1 month, 3 months, 4 months, 6months and 12 months follow up
Secondary outcome [2] 430621 0
Renal function between the groups
Timepoint [2] 430621 0
Blood tests performed at baseline and 4 month follow up
Secondary outcome [3] 430622 0
Occurrence of cardiovascular death
Timepoint [3] 430622 0
Hospitalisation data collected from medical records and participant questionnaires at 1 week, 1 month, 3 months, 4 months, 6months and 12 months follow up
Secondary outcome [4] 430623 0
Changes in pro-BNP levels
Timepoint [4] 430623 0
Blood tests performed at baseline and 4 month follow up
Secondary outcome [5] 430624 0
systolic and diastolic function measured on echocardiography
Timepoint [5] 430624 0
Echocardiogram performed at baseline and 4 month follow up
Secondary outcome [6] 430625 0
heart failure symptoms and signs
Timepoint [6] 430625 0
Blood tests performed at baseline, 1 week, 1 month, 3 months, 4 months, 6months and 12 months follow ups. Data will also be collected from participant questionnaires at these time points.

Eligibility
Key inclusion criteria
1. Age 18 years and older
2. HFrEF with a LVEF less than or equal to 40%
3. Willingness to try and adhere to a dietary intervention and to be randomised.
4. At least one enrolment enhancing criteria:
a. N Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP), pro-BNP =600 pg/mm in the preceding 12 months
b. Hospital admission for heart failure in the preceding 12 months (including admission at the time of diagnosis)
c. Current heart failure symptoms: NYHA Class II, III or IV
d. Type 2 Diabetes mellitus
e. Renal impairment eGFR<45ml/min
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Type 1 Diabetes Mellitus or Type II Diabetes Mellitus requiring insulin.
2. Women who are pregnant, breastfeeding or planning a pregnancy during the study period
3. Symptomatic hypotension or systolic blood pressure <90mmHg
4. Body mass index (BMI) <18.5 kg/m2
5. History of rare metabolic conditions:
a. Insulinoma
b. Primary carnitine deficiency
c. Carnitine palmitoyl transferase I or II deficiency
d. Carnitine translocase deficiency
e. Beta-oxidation defects
f. Medium-chain acyl dehydrogenase deficiency
g. Long-chain acyl dehydrogenase deficiency
h. Short-chain acyl dehydrogenase deficiency
i. Long-chain 3-hydroxyacyl-CoA deficiency
j. Medium-chain 3-hydroxyacyl-CoA deficiency
k. Pyruvate carboxylase deficiency
l. Porphyria

6. Non-English-speaking participants can be included if they are amenable to undergo the intervention and follow-up with the assistance of an interpreter.

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)
central randomisation by database/ computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table generated by a statistician
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/02/2024
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
60
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 25926 0
Westmead Hospital - Westmead
Recruitment hospital [2] 25927 0
Blacktown Hospital - Blacktown
Recruitment postcode(s) [1] 41761 0
2145 - Westmead
Recruitment postcode(s) [2] 41762 0
2148 - Blacktown

Funding & Sponsors
Funding source category [1] 314381 0
Government body
Name [1] 314381 0
Western Sydney Local Health District
Country [1] 314381 0
Australia
Funding source category [2] 315391 0
Government body
Name [2] 315391 0
The Heart Foundation
Country [2] 315391 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
The University of Sydney NSW 2006 Australia
Country
Australia
Secondary sponsor category [1] 317453 0
None
Name [1] 317453 0
Address [1] 317453 0
Country [1] 317453 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313474 0
Western Sydney Local Health District Human Research Ethics Committee
Ethics committee address [1] 313474 0
WSLHD Research and Education Network, Westmead Hospital, Hawkesbury Road, Westmead NSW 2145
Ethics committee country [1] 313474 0
Australia
Date submitted for ethics approval [1] 313474 0
10/05/2023
Approval date [1] 313474 0
02/08/2023
Ethics approval number [1] 313474 0

Summary
Brief summary
The failing heart has been found to shift to ketone bodies as a significant fuel source with resultant improvements in cardiac function. There is a strong theoretical rationale for ketosis in improving heart failure, yet clinical research of this therapeutic strategy in heart failure with reduced ejection fraction (HFrEF) is lacking. In fact, there are very few dietary trials in patients with heart failure, despite diet being a cornerstone of cardiovascular disease prevention and treatment.
This is an investigator-initiated, open-label, prospective randomised controlled pilot study, with two groups: control (no dietary intervention, n=30) and intervention: a normocaloric KD (N=30). This study has the pre-specified goal of exploring the cardiovascular effects of a KD in patients with heart failure to guide a larger clinical trial.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 128294 0
A/Prof Sarah Zaman
Address 128294 0
Westmead Applied Research Centre, Level 5, Block K, Entrance 10, Westmead Hospital, Hawkesbury Road, Westmead, NSW, 2145
Country 128294 0
Australia
Phone 128294 0
+61 414365523
Fax 128294 0
Email 128294 0
sarah.zaman@sydney.edu.au
Contact person for public queries
Name 128295 0
Ms Swetha Perera
Address 128295 0
Westmead Applied Research Centre, Level 5, Block K, Entrance 10, Westmead Hospital, Hawkesbury Road, Westmead, NSW, 2145
Country 128295 0
Australia
Phone 128295 0
+61 412449645
Fax 128295 0
Email 128295 0
swetha.perera@sydney.edu.au
Contact person for scientific queries
Name 128296 0
Ms Swetha Perera
Address 128296 0
Westmead Applied Research Centre, Level 5, Block K, Entrance 10, Westmead Hospital, Hawkesbury Road, Westmead, NSW, 2145
Country 128296 0
Australia
Phone 128296 0
+61 412449645
Fax 128296 0
Email 128296 0
swetha.perera@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified participant data of published results can be obtained by contacting the primary investigator (A/Prof. sarah zaman), with any reasonable requests for the purpose of research considered.
When will data be available (start and end dates)?
Analysis will be performed at the end of the study Dec 2027. Data will be available (15years from end of study).
Available to whom?
Published in medical journals and and the main findings disseminated to participants who enrolled in the study
Available for what types of analyses?
Any purpose, only to achieve the aims in the study protocol
How or where can data be obtained?
Results can be obtained by contacting the primary investigator, with any reasonable requests for the purpose of research considered.
Name: A/Prof. sarah zaman
Email: Sarah.Zaman@sydney.edu.au


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
No additional documents have been identified.