Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000850976
Ethics application status
Approved
Date submitted
28/04/2020
Date registered
27/08/2020
Date last updated
21/04/2025
Date data sharing statement initially provided
27/08/2020
Date results provided
21/04/2025
Type of registration
Prospectively registered

Titles & IDs
Public title
A short-term ketogenic diet combined with short-term fasting before chemotherapy in treating patients with acute leukaemia: a randomised controlled trial.
Scientific title
A short-term ketogenic diet combined with short-term fasting before chemotherapy in treating patients with acute leukaemia: a randomised controlled trial.
Secondary ID [1] 301138 0
Nil known
Universal Trial Number (UTN)
U1111-1251-0734
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
acute myeloid leukemia 317250 0
chemotherapy toxicity 317251 0
second malignancies 317252 0
Condition category
Condition code
Diet and Nutrition 315384 315384 0 0
Other diet and nutrition disorders
Infection 315386 315386 0 0
Studies of infection and infectious agents
Cancer 316440 316440 0 0
Leukaemia - Acute leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The isocaloric KD (Section 10 and Appendix A for detailed description) will consist of 90% energy from fat, 5-7% from protein, and 3-5% from carbohydrate. The ketogenic diet intervention will be administered 3 times per day (breakfast, lunch, and dinner) beginning 2-6 days before scheduled chemotherapy. The number of days prior to chemotherapy is variable because the start of chemotherapy depends on whether the patient has been admitted, has a central line in place, has completed all required pre-chemotherapy testing, and is clear of any infections or secondary conditions that delay chemotherapy. Generally, most patients will consume the ketogenic diet for 4-5 days. A minimum of 48 h is generally necessary to enter ketosis. The subject will fast, that is eat and drink nothing except water for 16 hours before scheduled chemotherapy. The ketogenic diet will then be continued 3 times per day during chemotherapy (7 days for the first cycle and, optionally,5 days for subsequent cycles). The total duration of the dietary intervention is 9-15 days for the first cycle of treatment and up to 10 days for subsequent cycles. For participants 60 years of age and younger, a further 2-4 cycles of therapy will be administered, and for those over 60, a further 1-2 cycles will be administered. Each cycle of treatment is administered at a frequency of approximately 28 days. In patients deemed unfit for intensive chemotherapy, treatment will be venetoclax and azacytidine, consisting of continuous oral venetoclax combined with a 7-day course of daily subcutaneous azacytidine repeated every 28 days until disease progression or unacceptable toxicity. The usual treatment for ALL patients is hyper-CVAD, with part A receiving 4 days chemotherapy and Part B, 3 days, during which the KD will be given. Administration of the KD will be adjusted for other ALL regimens.
Upon randomisation to the intervention group, the study team will notify the dietetics department to start the patient in the ketogenic diet for the induction chemotherapy cycle. The hospital will administer the ketogenic diet that consist of a fixed menu including several different breakfast meals (e.g. scrambled eggs and bacon, avocado, and Hollandaise sauce) and several lunch/dinner meals (e.g. Keto mashed potato, poached fish and hollandaise sauce, avocado pulp). To increase meal variety and compliance, the study team will provide additional keto snacks to the patient (roasted nuts, keto chocolate, etc.), approved by the dietician. A list of approved keto snacks and recipes will be provided to the patient and their relatives in case they wish to bring food from home that is compliant with the intervention diet. The list and recipes will comply with the Food Safety protocols established by the hospital dietetics department. If food intake is insufficient or inadequate, the hospital dietician will offer 200 ml Ketocal drinks as a supplement. Each meal will supply a 4:1 ratio of fat: protein/CHO. The meals and snacks will be eaten ad-libitum and will provide approximately 2000 calories per day for female and 2500 calories per day for male participants. Participants dietary preferences will be considered, with the possibility to exclude certain meals and substitute them for the patient’s preference within the keto menu.
Intervention code [1] 317446 0
Treatment: Other
Comparator / control treatment
Control participants will receive meals according to The Nutrition standards for adult inpatients in NSW hospitals (2011) https://www.aci.health.nsw.gov.au/resources/nutrition/nutrition-food-in-hospitals/nutrition-standards-diets . Control participants will not fast.
Control group
Active

Outcomes
Primary outcome [1] 323634 0
The incidence of major infection [defined as pneumonia, bacteraemia, or fungaemia causing a blood stream infection (primary BSI), or pneumonia accompanied by bacteraemia or fungaemia (secondary BSI)] will be compared between the 2 groups. A diagnosis of pneumonia requires a compatible chest x-ray or computed tomography scan. A diagnosis of bacteraemia or fungaemia will be made on a positive blood culture. A diagnosis of bacteraemia as a result of frequent contaminants such as coagulase-negative Staphylococcus requires two positive blood cultures.
Timepoint [1] 323634 0
This outcome will be evaluated every 28 days from baseline (Day -5) to completion of all chemotherapy cycles and every 3 months thereafter for 24 months.
Secondary outcome [1] 382432 0
Time from commencement of chemotherapy (day 1) to absolute neutrophil count greater than or equal to 0.5 x 109/L for 3 consecutive days for each cycle of chemotherapy.
Timepoint [1] 382432 0
Daily full blood count with absolute neutrophil count until absolute neutrophil count greater than or equal to 0.5 x 109/L for 3 consecutive days for each chemotherapy cycle.
Secondary outcome [2] 382433 0
Assess oral mucositis using the National Cancer Institute's Common Terminology Criteria for Adverse Events.
Timepoint [2] 382433 0
Daily from commencement of chemotherapy for 28 days as a hospital inpatient for each cycle of chemotherapy and 3 monthly thereafter until final follow-up at 24 months.
Secondary outcome [3] 382434 0
Investigate changes in plasma glucose,
Timepoint [3] 382434 0
Measured daily from commencement of ketogenic diet (5 days before chemotherapy) to day 28 or discharge from hospital, whichever is later, for each chemotherapy cycle.
Secondary outcome [4] 383697 0
Investigate changes in plasma insulin.
Timepoint [4] 383697 0
Daily from commencement of ketogenic diet (5 days before chemotherapy) to day 28 or discharge from hospital, whichever is later, for each chemotherapy cycle.
Secondary outcome [5] 383698 0
Investigate changes in plasma insulin-like growth factor 1 (IGF-1).
Timepoint [5] 383698 0
Daily from commencement of ketogenic diet (5 days before chemotherapy) to day 28 or discharge from hospital, whichever is later, for each chemotherapy cycle.
Secondary outcome [6] 383699 0
Investigate changes in plasma IGF-1 binding proteins.
Timepoint [6] 383699 0
Daily from commencement of ketogenic diet (5 days before chemotherapy) to day 28 or discharge from hospital, whichever is later, for each chemotherapy cycle.
Secondary outcome [7] 383700 0
Quantification of genotoxic stress measured at a single cell level.
Timepoint [7] 383700 0
Daily blood tests from commencing chemotherapy until discharge for each chemotherapy cycle. Bone marrow biopsies as per standard of care, before and after the first cycle of chemotherapy and after each cycle of-chemotherapy thereafter.
Secondary outcome [8] 383701 0
Somatic DNA mutation rate in haematological cells.
Timepoint [8] 383701 0
Bone marrow biopsies as per standard of care, before and after the first cycle of chemotherapy and after each cycle of-chemotherapy thereafter.
Secondary outcome [9] 383702 0
Quantification of DNA damage response signaling proteins in peripheral blood mononuclear cells and bone marrow cells.
Timepoint [9] 383702 0
Daily blood tests from commencing chemotherapy until discharge. Bone marrow biopsies as per standard of care, before and after the first cycle of chemotherapy and after each cycle of-chemotherapy thereafter.
Secondary outcome [10] 383703 0
Mass spectrometry assessment of senescence-associated secretory phenotype in peripheral blood mononuclear cells and bone marrow cells.
Timepoint [10] 383703 0
Daily blood tests from commencing chemotherapy until discharge. Bone marrow biopsies as per standard of care, before and after the first cycle of chemotherapy and after each cycle of-chemotherapy thereafter.
Secondary outcome [11] 383704 0
Plasma cardiac troponin I measurements.
Timepoint [11] 383704 0
Daily blood tests from commencing each cycle of chemotherapy until discharge.
Secondary outcome [12] 383705 0
Changes in cardiac function as measured by echocardiography.
Timepoint [12] 383705 0
Baseline before chemotherapy and 24 months after completion of chemotherapy.
Secondary outcome [13] 383706 0
Assess changes in the peripheral blood mononuclear cell transcriptome.
Timepoint [13] 383706 0
Daily blood sample from commencing diet to day 28 or discharge, whichever is later for each cycle of chemotherapy.
Secondary outcome [14] 383707 0
Assess changes in the peripheral blood mononuclear cell proteome.
Timepoint [14] 383707 0
Daily blood sample from commencing diet to day 28 or discharge, whichever is later for each cycle of chemotherapy.
Secondary outcome [15] 383708 0
Assess changes in the plasma metabolomic “fingerprint”.
Timepoint [15] 383708 0
Daily plasma from commencing diet to day 28 or discharge, whichever is later for each cycle of chemotherapy.
Secondary outcome [16] 383709 0
Assess changes in the gut microbiome.
Timepoint [16] 383709 0
Daily plasma from commencing diet to day 28 or discharge, whichever is later for each cycle of chemotherapy.
Secondary outcome [17] 383710 0
Death
Timepoint [17] 383710 0
This outcome will be evaluated from commencing the diet until final follow-up at 24 months after completing final cycle of chemotherapy .
Secondary outcome [18] 383711 0
Assess diarrhoea using the National Cancer Institute's Common Terminology Criteria for Adverse Events.
Timepoint [18] 383711 0
Daily from commencement of chemotherapy for 28 days as a hospital inpatient for each cycle of chemotherapy and 3 monthly thereafter until final follow-up at 24 months.
Secondary outcome [19] 383721 0
Food Acceptability Questionnaire
Timepoint [19] 383721 0
Measured daily using validated questionnaires whilst on both the intervention and standard hospital diet.
Secondary outcome [20] 383723 0
Food craving Questionnaire
Timepoint [20] 383723 0
Measured using validated questionnaires whilst on the diet intervention and standard hospital diet.

Eligibility
Key inclusion criteria
Participants with acute myeloid or lymphoblastic leukaemia as defined by WHO criteria (Section 9.2).

Inclusion and Eligibility Criteria:
• Participant is willing and able to give informed consent for participation in the trial. Adult male or female participants 18 years of age and over who can understand study procedures, comply with them, and provide written informed consent before any study-specific procedure.
• Diagnosed with de novo acute myeloid leukaemia or acute lymphoblastic leukaemia. History of cytologically or histologically confirmed diagnosis of AML or ALL (except acute promyelocytic leukemia) according to the 2008 World Health Organization (WHO) classification (bone marrow [BM] or peripheral blood [PB] blast counts =20%).
• Participant is scheduled to undergo induction chemotherapy as an in-patient.
• Performance status (Eastern Cooperative Oncology Group; ECOG) of 0-2.
• Body mass index (BMI) above 18.5 kg/m^2 (normal and above) or 16-18.5 kg/m^2 (underweight) if considered safe by the treating physician and dietician.
• Adequate renal function (serum creatinine < 1.5 X UNL [upper normal limit] or creatinine clearance > 50 ml/min). Creatinine clearance or glomerular filtration rate greater or equal to 30 mL/min as estimated by the Cockroft-Gault (C-G) or other medically acceptable formulas, such as MDRD (Modification of Diet in Renal Disease) or CKD-EPI (the Chronic Kidney Disease Epidemiology Collaboration).
• Ability to complete patient booklet by themselves or with assistance.
• Ability and willingness to undergo short-term ketogenic diet combined with short-term fasting prior to and during chemotherapy.
• Individuals who are currently receiving prophylaxis antibiotics, prophylaxis antifungal medication and/or prophylaxis antiviral medication.
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion and Ineligibility Criteria:
• Pregnant and/or nursing women.
• Patients with type 1 diabetes or patients with type 2 diabetes receiving insulin.
• History of syncope with calorie restriction in the past or other medical comorbidity, which would make fasting potentially dangerous.
• History of severe heart failure.
• Psychiatric conditions that preclude adherence to study protocol. Known significant mental illness or other condition such as active alcohol or other substance abuse or addiction that, in the opinion of the investigator, predisposes the subject to high risk of noncompliance with the protocol.
• Inability to maintain adequate nutrition and/or patients receiving parenteral nutrition at admission.
• Primary carnitine deficiency, carnitine palmitoyl transferase I or II deficiency, carnitine translocase deficiency, beta-oxidation defects, medium-chain acyl dehydrogenase deficiency, long-chain acyl dehydrogenase deficiency, short-chain acyl dehydrogenase deficiency, long-chain 3-hydroxyacyl-CoA deficiency, medium-chain 3-hydroxyacyl-CoA deficiency, pyruvate carboxylase deficiency, and porphyria.
• Patients with dietary restrictions incompatible with the trial dietary regimens.
• Treated with any investigational therapy within 2 weeks of the first dose of study treatment.
• Total serum bilirubin >2.5 × upper limit of normal (ULN; except for subjects with Gilbert's Syndrome for whom direct bilirubin is <2.5 × ULN), or liver cirrhosis, or chronic liver disease Child-Pugh Class B or C.
• Refractory congestive heart failure unresponsive to medical treatment; active infection resistant to all antibiotics; or non-AML-associated pulmonary disease requiring >2 liters per minute (LPM) oxygen, or any other condition that puts the subject at an imminent risk of death.

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)
Method for generating the randomisation schedule / allocation sequence: simple computer-generated random numbers, via a web-based randomisation system.

The statistician will design the randomisation schedule and the study team will hold the allocation. Randomisation will occur after the patient has been determined to be eligible for the study and has consented to participate.

To account for a potentially higher drop-out rate in the intervention group due to the open-labelled nature of the study, participants will be randomised 40% to the control group and 60% to the intervention group.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computerised sequence generation
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
12.1. Statistical Analysis Plan (SAP)
The plan for the statistical analysis of the trial are outlined below. There is not a separate SAP document in use for the trial.

12.2. Description of Statistical Methods
The two-proportion z-test will be used to determine whether the difference between the proportions of serious infection and/or death is significant. The ?2 or Kruskal-Wallis test will be used to compare various pre-treatment characteristics; number of days on study and number of days with neutrophil counts less than 0.5 x 109/L; and rates of diarrhoea, mucositis, and infection in the sFKD and standard diet groups. Time to major infection and time to death will be compared using the log-rank test.
For the Food Acceptability Questionnaire items, the related samples Wilcoxon rank sum test assessed within group changes over time and the independent samples Mann-Whitney U test to compare the diet groups, both at baseline and after each cycle of chemotherapy. For Craving Questionnaire scores, paired comparison t tests will be calculated within each diet group to assess whether the mean changes from baseline to after each cycle of treatment are significantly different from zero. Between-subjects t tests will be calculated to determine differences between the diets after each cycle of chemotherapy.
Exploratory analyses using appropriate regression methods will also be used to further investigate the secondary endpoints above. This will help offset the loss of power associated with subgroup analyses. For time to neutrophil engraftment the 2 groups will be compared using the Student’s t-test for continuous variables, and categoric variables will be examined with the chi-square test. A linear regression model will be used to examine confounders on time to engraftment. A 2-sidedpvalue of <0.05 will be considered to be significant.
To assess for differences in toxicity rates between study groups, Fisher's exact tests will be used; the Fisher's exact test is more efficient than a chi-square test when cell counts are small. These tests give the exact P value, rather than an approximation, of the observed cell frequencies. P values < 0.05 will be significant. Odds ratios using logistic regression will be calculated to estimate the degree to which patient demographics and clinicopathologic characteristics determined hematologic toxicity.

12.3. Sample Size Determination
This is a phase-II comparative study powered at 80% to detect a 50% reduction in infection rate. The total sample size required is 167 patients (67 in each arm, with 67 enrolled in the control arm, and 100 enrolled in the intervention arm to account for the expected higher dropout rate). The baseline infection rate is assumed to be 40%. This translates into a 20% infection rate in the in the group of patients who received short-term ketogenic diet combined with short-term fasting before chemotherapy. The test statistic used is the two-sided Z-test with pooled variance. The significance level of the test was targeted at 0.10. The overall sample is adjusted with 10% lost-follow-up rate.

12.4. Analysis Populations
All randomised participants will be analysed on an intention to treat basis. The intent-to-treat population will include all enrolled participants who received at least one sFKD meal or control.

12.5. The Level of Statistical Significance
A statistically significant result is one where the observed p-value is less than or equal to 0.05.

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
5/10/2020
Actual
12/10/2022
Date of last participant enrolment
Anticipated
27/10/2023
Actual
13/11/2024
Date of last data collection
Anticipated
13/11/2026
Actual
Sample size
Target
167
Accrual to date
Final
21
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 16582 0
Nepean Hospital - Kingswood
Recruitment hospital [2] 16583 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 30146 0
2747 - Kingswood
Recruitment postcode(s) [2] 30147 0
2145 - Westmead
Recruitment postcode(s) [3] 30148 0
2145 - Constitution Hill
Recruitment postcode(s) [4] 30149 0
2145 - Girraween
Recruitment postcode(s) [5] 30150 0
2145 - Greystanes
Recruitment postcode(s) [6] 30151 0
2145 - Mays Hill
Recruitment postcode(s) [7] 30152 0
2145 - Pemulwuy
Recruitment postcode(s) [8] 30153 0
2145 - Pendle Hill
Recruitment postcode(s) [9] 30154 0
2145 - South Wentworthville
Recruitment postcode(s) [10] 30155 0
2145 - Wentworthville
Recruitment postcode(s) [11] 30156 0
2750 - Emu Heights
Recruitment postcode(s) [12] 30157 0
2750 - Jamisontown
Recruitment postcode(s) [13] 30158 0
2750 - Emu Plains
Recruitment postcode(s) [14] 30159 0
2750 - Penrith
Recruitment postcode(s) [15] 30160 0
2750 - Penrith Plaza
Recruitment postcode(s) [16] 30161 0
2750 - Penrith South
Recruitment postcode(s) [17] 30162 0
2750 - Leonay
Recruitment postcode(s) [18] 30163 0
2747 - Caddens
Recruitment postcode(s) [19] 30164 0
2747 - Cambridge Gardens
Recruitment postcode(s) [20] 30165 0
2747 - Cambridge Park
Recruitment postcode(s) [21] 30166 0
2747 - Claremont Meadows
Recruitment postcode(s) [22] 30167 0
2747 - Jordan Springs
Recruitment postcode(s) [23] 30168 0
2747 - Llandilo
Recruitment postcode(s) [24] 30169 0
2747 - Shanes Park
Recruitment postcode(s) [25] 30170 0
2747 - Werrington
Recruitment postcode(s) [26] 30171 0
2747 - Werrington Downs
Recruitment postcode(s) [27] 30172 0
2747 - Werrington County

Funding & Sponsors
Funding source category [1] 305579 0
Government body
Name [1] 305579 0
NHMRC Investigator Grant Scheme
Country [1] 305579 0
Australia
Funding source category [2] 305580 0
University
Name [2] 305580 0
The University of Sydney, Sydney Medical School, Nepean Clinical School
Country [2] 305580 0
Australia
Funding source category [3] 305581 0
Hospital
Name [3] 305581 0
Nepean Hospital
Country [3] 305581 0
Australia
Primary sponsor type
Government body
Name
Nepean Blue Mountains Local Health District
Address
PO Box 63
Penrith, NSW, 2750
Country
Australia
Secondary sponsor category [1] 305994 0
None
Name [1] 305994 0
Address [1] 305994 0
Country [1] 305994 0
Other collaborator category [1] 281298 0
University
Name [1] 281298 0
The University of Sydney
Address [1] 281298 0
Camperdown NSW 2006
Country [1] 281298 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305881 0
Nepean Blue Mountains Hospital Local Health District HREC
Ethics committee address [1] 305881 0
Ethics committee country [1] 305881 0
Australia
Date submitted for ethics approval [1] 305881 0
13/05/2020
Approval date [1] 305881 0
09/02/2023
Ethics approval number [1] 305881 0

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

Contacts
Principal investigator
Name 101918 0
A/Prof Stephen Fuller
Address 101918 0
THE UNIVERSITY OF SYDNEY NEPEAN CLINICAL SCHOOL FACULTY OF MEDICINE AND HEALTH THE UNIVERSITY OF SYDNEY Level 3, 62 Derby Street, Kingswood, NSW, 2747
Country 101918 0
Australia
Phone 101918 0
+61247343732
Fax 101918 0
+61247341819
Email 101918 0
[email protected]
Contact person for public queries
Name 101919 0
Stephen Fuller
Address 101919 0
THE UNIVERSITY OF SYDNEY NEPEAN CLINICAL SCHOOL FACULTY OF MEDICINE AND HEALTH THE UNIVERSITY OF SYDNEY Level 3, 62 Derby Street, Kingswood, NSW, 2747
Country 101919 0
Australia
Phone 101919 0
+61247343732
Fax 101919 0
+61247341819
Email 101919 0
[email protected]
Contact person for scientific queries
Name 101920 0
Luigi Fontana
Address 101920 0
Charles Perkins Centre, Level 5 West, D17, Education and Research Hub, The Charles Perkins Centre, The University of Sydney, NSW, 2006
Country 101920 0
Australia
Phone 101920 0
+61286277499
Fax 101920 0
Email 101920 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
Yes
Will there be any conditions when requesting access to individual participant data?
Persons/groups eligible to request access:
• Only researchers who provide a methodologically sound proposal

Conditions for requesting access:
• -

What individual participant data might be shared?
• All of the individual participant data collected during the trial, after de-identification

What types of analyses could be done with individual participant data?
• Only to achieve the aims in the approved proposal

When can requests for individual participant data be made (start and end dates)?
From:
Beginning 3 months and ending 5 years following main results publication

To:
-

Where can requests to access individual participant data be made, or data be obtained directly?
• These data will be made available by emailing the Principal Investigator, [email protected]

Are there extra considerations when requesting access to individual participant data?
No


What supporting documents are/will be available?




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.