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Trial registered on ANZCTR


Registration number
ACTRN12620000850976p
Ethics application status
Submitted, not yet approved
Date submitted
28/04/2020
Date registered
27/08/2020
Date last updated
27/08/2020
Date data sharing statement initially provided
27/08/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
A short-term ketogenic diet combined with 24-hour fasting and chemoprotection for patients with acute myeloid leukaemia
Scientific title
A phase II randomised controlled clinical trial in patients with acute myeloid leukaemia evaluating the effect on the incidence of major infection of a short-term ketogenic diet combined with 24-hour fasting compared to a standard hospital diet, before and during chemotherapy.
Secondary ID [1] 301138 0
None
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
Very high fat, very low carbohydrate (CHO) diet that drives the body to produce ketones. CHO free fluids and low joule drinks permitted. Protein controlled at a level that is sufficient to fight infections, heal wounds, maintain muscle mass and recover from cancer treatment as determined by the dietician. The amount of protein will vary from 5-7% of total energy. The ketogenic diet intervention will be administered 3 times per day (breakfast, lunch, and dinner) for 4 days, beginning 5 days before scheduled chemotherapy. The subject will fast, that is eat and drink nothing except water for 24 hours before scheduled chemotherapy. The ketogenic diet will then be continued 3 times per day during chemotherapy (7 days for the first cycle and then 5 days for subsequent cycles). The total duration of the dietary intervention is 12 days for the first cycle of treatment and 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.
A study dietitian will administer menus that consist of a choice of 5 breakfast meals (e.g. scrambled eggs and bacon, avocado, and Hollandaise sauce) combined with 2-3 x 200 ml Ketocal, and lunch/dinner meals consisting of 7 choices (e.g. Keto mashed potato, poached fish and hollandaise sauce, avocado pulp) combined with 1-3 x 200 ml Ketocal. Each meal will supply a 4:1 ratio of fat: protein/CHO. The meals will provide 2000 calories per day for female and 2500 calories per day for male participants.
In-hospital meals are provided to the participants by study team members. Prior to admission for the 2nd cycle of chemotherapy onwards, outpatient meals will be supplied to participant at their residence by study team members. A dietitian will review the participants daily face to face whilst in hospital and via telephone or telehealth as an outpatient.
Adherence to the intervention will be measured using a food diary. Food acceptability and food craving will be measured using validated questionnaires. The study dietitian will review participants each day and if required, adjust the diet for acceptability while maintaining 4:1 fat to protein and CHO ratio, and caloric intake.
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
• Participant is willing and able to give informed consent for participation in the trial.
• Male or Female, aged 18-75 years.
• Diagnosed with acute myeloid leukaemia.
• Scheduled to undergo at least 4 or more cycles of chemotherapy
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Body mass index (BMI) > 21 kg/m^2
• Weight loss < 5% of body weight in the last 6 months
• Adequate renal function (serum creatinine < 1.5 X UNL [upper normal limit] or creatinine clearance > 50 ml/min)
• 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
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Pregnant women.
• Nursing women.
• Diabetes mellitus undergoing therapy with insulin or oral agents
• History of low serum glucose (hypoglycaemia) or insulinoma
• History of syncope with calorie restriction in the past or other medical comorbidity, which would make fasting potentially dangerous
• History of significant cardiac disease, particularly uncompensated congestive heart failure New York Heart Association (NYHA) grade 2 or more or left ventricular ejection fraction (LVEF) < 40% on any prior assessment.
• Psychiatric conditions that preclude adherence to study protocol
• Patients receiving parenteral nutrition
• 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.

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)
Concealed allocation involving contacting the holder of the allocation schedule who is "off-site".
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
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 Chi square 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.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
5/10/2020
Actual
Date of last participant enrolment
Anticipated
27/10/2023
Actual
Date of last data collection
Anticipated
31/10/2025
Actual
Sample size
Target
134
Accrual to date
Final
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
Submitted, not yet 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
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 individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All of the individual participant data collected during the trial, after de-identification
When will data be available (start and end dates)?
Beginning 3 months and ending 5 years following main results publication
Available to whom?
Only researchers who provide a methodologically sound proposal
Available for what types of analyses?
Only to achieve the aims in the approved proposal
How or where can data be obtained?
These data will be made available by emailing the Principal Investigator, [email protected]


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
7808Study protocol  [email protected]
8200Informed consent form  [email protected]



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.