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Trial registered on ANZCTR


Registration number
ACTRN12616000613404
Ethics application status
Approved
Date submitted
8/04/2016
Date registered
11/05/2016
Date last updated
11/05/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
The effect of short term excess dietary fat, carbohydrate or energy on liver fat content in healthy women.
Scientific title
The impact of short term high fat, carbohydrate and energy diets on markers of non-alcoholic fatty liver disease (NAFLD) in healthy women.
Secondary ID [1] 286897 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Non-alcoholic fatty liver disease 295302 0
Condition category
Condition code
Diet and Nutrition 295570 295570 0 0
Other diet and nutrition disorders
Oral and Gastrointestinal 298464 298464 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study seeks to determine whether an excess energy diet with either a moderately high proportion of fat or a moderately high proportion of refined carbohydrate, or an isocaloric diet with either a moderately high proportion of fat or a moderately high proportion of carbohydrate (with an emphasis on refined carbohydrates) increases liver fat content in normal weight individuals with no liver disease.

This is a randomised cross-over dietary intervention trial with 2 arms. One arm will consume two different isocaloric diets and the other arm will consume two different hypercaloric diets. Each experimental diet will be consumed for 4 weeks. There will be a 6-week washout period between each of the two diets. All participants will be advised to continue with their usual physical activities.

To standardise baseline diet composition, all participants will be complete a 2-week standard diet based on current New Zealand dietary recommendations and results from the 2008/09 Adult Nutrition Survey (Table 1 in the Attachment). In summary the macronutrient ranges will be carbohydrate: 45-60%, protein: 15-25%, fat: 20-35% and this will also be based on the recommended servings of fruit, vegetables, wholegrains, protein foods and healthy fats.

A. Pre-intervention standardised diet
Participants will be asked to complete a 3-day weighed food record. The study dietitian (KS) will instruct participants how to correctly complete the 3-day weighed food record. The record of each participant will be analysed by the study dietitian (KS) using Kai-culator, a computer program developed by the Department of Human Nutrition, University of Otago, which allows New Zealand specific dietary analysis. If necessary, adjustments will be made to each study participant’s diet so their diet macronutrient composition is consistent with current NZ dietary recommendations (see Table 1 in the Attachment). The total daily calorie intake will remain the same. They will consume the standardised pre-intervention diet for 2 weeks.

B. Experimental diets
The macronutrient composition of each experimental diet was determined to be at the upper levels of intakes achievable by people in the longer term in everyday life (Table 2 in the Attachment).

Diets will be prescribed by the study dietitian (KS) and recommended foods will be those currently found in a typical NZ diet and that are readily accessible. Each participant will be instructed at the beginning of each new diet on the types of foods to consume to achieve the macronutrient distribution in the experimental diets. Changing the macronutrient proportions within each of these diets will be done by either adding extra portions or increasing the portion size of fat or carbohydrate foods. If this is within an isocaloric diet context the opposite macronutrient will be decreased to keep energy balanced. These changes will be personalised to the participant to fit within current dietary patterns and preferences.

Weekly 30 minute visits to the study dietitian (KS) will be scheduled during the 4-week experimental diet period to enhance compliance with the experimental diet. The study dietitian (KS) will also be readily contactable (via email, phone or txt) to answer any dietary questions and to provide further guidance as necessary. Other additional strategies that will be used to monitor dietary adherence will include 3-day weighed food records during each dietary phase and weekly monitoring of body weight.

For those in the hypercaloric diet arm, the dietitian will provide weight loss guidance atthe conclusion of the experimental diets until the participant returns to her usual pre-study weight.

Isocaloric (IC) Diets
Participants in the first arm of the study will consume two different isocaloric diets. Each of the two diets will be consumed for four weeks. The calorie intake of each individual will be calculated to maintain their current bodyweight and will take into account results from their 3-day weighed food record.

One isocaloric diet will have a relatively high percentage of energy (55-60%) from carbohydrate with most from refined carbohydrate sources (IC-HC). After a six week washout period participants will then consume an isocaloric diet with a moderately high proportion of energy (35-40%) from fat (IC-HF). For both isocaloric diets, the ratio of total fat to unsaturated fat will be 2.5:1, with the percentage of energy sourced from unsaturated fat being 10% for the relatively high carbohydrate diet and 15% for the moderately high fat diet.

Hypercaloric (HC) Diets
Participants in the second arm of the study will consume two different hypercaloric diets. The calorie intake of each individual will be calculated to be proportionally higher in energy to induce a 3-5% weight gain during each of the four week hypercaloric diet periods, This equates to an approximately 25-35% increase in energy based on each participants' 3-day weighed food record.

One hypercaloric diet will have a relatively high percentage of energy (55-60%) from carbohydrate with most from refined carbohydrate sources (HC-HC). After a six week washout period, participants will then consume a hypercaloric diet with a moderately high proportion of energy (35-40%) from fat (HC-HF). For both hypercaloric diets, the ratio of total fat to unsaturated fat will be 2.5:1, with the percentage of energy sourced from unsaturated fat being 10% for the relatively high carbohydrate diet and 15% for the moderately high fat diet.
Intervention code [1] 292513 0
Lifestyle
Intervention code [2] 294456 0
Prevention
Comparator / control treatment
This is a cross-over trial. Each participant will be her own control. This crossover design avoids problems of comparability of study and control groups with regard to confounding variables (e.g., age and sex). Within the isocaloric group and within the hypercaloric group, the high carbohydrate diet will be compared with the high fat diet. That is, the IC-HC diet will be compared with the IC-HF diet, and the HC-HC diet will be compared with the HC-HF diet.
Control group
Active

Outcomes
Primary outcome [1] 295765 0
Change in % of liver fat as measured by Hydrogen Magnetic Resonance Spectroscopy (H-MRS).
Timepoint [1] 295765 0
At the completion of each 4 week intervention diet.
Secondary outcome [1] 322073 0
Change in level of liver enzymes - alanine transaminase (ALT) measured from serum using Roche Diagnostics GmbH kits on a Roche Cobas C311 Chemistry Autoanalyser.
Timepoint [1] 322073 0
At the completion of each four week intervention diet.
Secondary outcome [2] 322075 0
Change in level of liver enzymes - aspartate transaminase (AST) measured from serum using Roche Diagnostics GmbH kits on a Roche Cobas C311 Chemistry Autoanalyser.
Timepoint [2] 322075 0
At the completion of each four week intervention diet.
Secondary outcome [3] 322076 0
Change in level of total cholesterol as measured by serum assay.
Timepoint [3] 322076 0
At the completion of each four week intervention diet.
Secondary outcome [4] 322829 0
Change in level of HDL cholesterol as measured by serum assay.
Timepoint [4] 322829 0
At the completion of each four week intervention diet.
Secondary outcome [5] 322830 0
Change in level of LDL cholesterol as measured by serum assay.
Timepoint [5] 322830 0
At the completion of each four week intervention diet.

Eligibility
Key inclusion criteria
* healthy non-smoking women aged 20-55 years
* normal weight (defined as body mass index (BMI) 20-25kg/m2)
* healthy liver (defined as normal liver enzymes and normal liver imaging (ultrasound))
* Dunedin (New Zealand) city residents
Minimum age
20 Years
Maximum age
55 Years
Sex
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
* any liver disease including NAFLD
* consume more than 14 standard units of alcohol per week
* diabetes or prediabetes
* pregnancy
* lactating
* postmenopausal
* taking recreational drugs or medication that potentially affects the liver
* dietary intolerances or food allergies
* contraindications to H-MRS radiological examination including claustrophobia

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Participants will be randomised into four groups after a 2-week standard diet. The study biostatistician will generate a list of the four treatment options (isocaloric or hypercaloric diet, high fat or high carbohydrate first) in a spreadsheet in a random order numbered one to twelve.

The treatment options will be transferred to the numbered brown envelopes (opaque with no windows) in the sequence order. This will be done at a separate site by a research assistant supervised by the study biostatistician.

Participants will be randomised by opening the numbered brown envelopes in sequence in the order of participants coming for their clinic visit. The participant will be assigned to the group specified in the envelope. This will specify which diet they start with, they will also cross over to the corresponding diet. e.g. if a participant starts with isocaloric high fat they will then crossover to isocaloric high carbohydrate.

The four treatment groups are:
* Isocaloric, high fat (IC-HF)
* Isocaloric, high carbohydrate (IC-HC)
* Hypercaloric, high fat (HC-HF)
* Hypercaloric, high carbohydrate (HC-HC)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software will be used generate a list of randomly ordered treatment options in a spreadsheet by the study biostatisician. There will be no stratification.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
STATA 13.1 will be used for statistical analyses. Linear mixed models will be used to compare the intervention diets. Dietary data will be analysed using Kai-culator, a computer program developed by the Department of Human Nutrition, University of Otago, which allows New Zealand specific dietary analysis.

Five participants will be required in each group (isocaloric group and hypercaloric group), that is, 10 participants in total. These sample size calculations were based on findings from the overfeeding study by Rosqvist F, et al (2014). We calculated what is required to provide 80% power when using a two-sided test at the 0.05 level to detect a difference in liver fat of 0.5% assuming a standard deviation of 0.25% and without making any assumptions about correlations between repeated measures, To allow for a 20% drop out, 12 participants will be recruited.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
10/05/2016
Date of last participant enrolment
Anticipated
31/05/2016
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
12
Accrual to date
Final
Recruitment outside Australia
Country [1] 7081 0
New Zealand
State/province [1] 7081 0
Otago

Funding & Sponsors
Funding source category [1] 291800 0
University
Name [1] 291800 0
Department of Medicine, University of Otago
Country [1] 291800 0
New Zealand
Primary sponsor type
University
Name
University of Otago
Address
PO Box 56
Dunedin 9054
Country
New Zealand
Secondary sponsor category [1] 292182 0
None
Name [1] 292182 0
Address [1] 292182 0
Country [1] 292182 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293316 0
UOHEC (Health) University of Otago Health Ethics Committee
Ethics committee address [1] 293316 0
University of Otago
362 Leith St
North Dunedin
Dunedin 9016
Ethics committee country [1] 293316 0
New Zealand
Date submitted for ethics approval [1] 293316 0
10/08/2015
Approval date [1] 293316 0
01/12/2015
Ethics approval number [1] 293316 0
15/107

Summary
Brief summary
Non-alcoholic fatty liver disease (NAFLD) affects up to 30% of adults. NAFLD can progress to end stage liver disease and increases the risk of cardiovascular disease, but little is known about the cause. Whether particular nutrients or simply too much energy in a person’s diet triggers fat to be stored in the liver is unknown.

The goal of this study is to examine the effect of four different experimental diets on liver fat and markers of NAFLD in normal weight individuals. In two of the four diets slightly more energy than needed will be eaten (hypercaloric). One of these diets will have a moderately high proportion of fat (HF) and the other diet will have a moderately high proportion of refined carbohydrates (HC). In this hypercaloric diet group diets will be prescribed to achieve a 3-5% bodyweight gain. For the other two diets, participants will consume their usual amount of energy to maintain their normal body weight (isocaloric), but one diet will have a moderately high proportion of fat (IF)and the other diet will have a moderately high proportion of refined carbohydrates (IC). Participants in each group (hypercaloric and isocaloric) will crossover between the moderately high fat and the moderately high refined carbohydrate diets with a six week washout period in between, acting as their own control. The difference in liver fat will be measured by Proton Magnetic Resonance Spectroscopy (H-MRS).

Trial website
Trial related presentations / publications
Public notes
Attachments [1] 827 827 0 0
/AnzctrAttachments/368742-Attachment_Intervention Description Tables 1 & 2.docx

Contacts
Principal investigator
Name 58026 0
Dr Kirsten Coppell
Address 58026 0
Edgar Diabetes & Obesity Research
Department of Medicine
Univeristy of Otago
PO Box 56
Dunedin 9054
Country 58026 0
New Zealand
Phone 58026 0
+64 3 470 9074
Fax 58026 0
Email 58026 0
[email protected]
Contact person for public queries
Name 58027 0
Kirsten Coppell
Address 58027 0
Edgar Diabetes & Obesity Research
Department of Medicine
University of Otago
PO Box 56
Dunedin 9054
Country 58027 0
New Zealand
Phone 58027 0
+64 3 470 9074
Fax 58027 0
Email 58027 0
[email protected]
Contact person for scientific queries
Name 58028 0
Kiri Sharp
Address 58028 0
Edgar Diabetes & Obesity Research
Department of Medicine
University of Otago
PO Box 56
Dunedin 9054
Country 58028 0
New Zealand
Phone 58028 0
+64 3 474 0999 ext 8514
Fax 58028 0
Email 58028 0
[email protected]

No information has been provided regarding IPD availability


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No Supporting Document Provided



Results publications and other study-related documents

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