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Trial registered on ANZCTR

Registration number

ACTRN12623000756628

Ethics application status

Approved

Date submitted

20/04/2023

Date registered

11/07/2023

Date last updated

11/07/2023

Date data sharing statement initially provided

11/07/2023

Type of registration

Retrospectively registered

Titles & IDs

Public title

Adapting medical weight loss methods to the management of nonalcoholic fatty liver disease: A randomised control trial evaluating the effects of a very low energy diet on hepatic and metabolic outcomes in individuals with nonalcoholic fatty liver disease

Scientific title

The comparative effects of a very low energy diet and the mediterranean diet on hepatic and metabolic outcomes in nonalcoholic fatty liver disease: A randomised controlled trial.

Secondary ID [1]

None

Universal Trial Number (UTN)

Trial acronym

DARWIN

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Nonalcoholic fatty liver disease

Condition category

Condition code

Oral and Gastrointestinal

Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

The intervention is a 12 week 800kcal ketogenic very low energy diet which utilises two optifast meal replacement products per day and one very low carbohydrate meal. The carbohydrate composition of the diet is defined at <=60g of carbohydrates per day. Participants are provided with a recipe book and examples of meals include: mexican beef mince, shredded poached chicken, zucchini enchiladas. Participants undergo face to face education (15-20 minutes duration) about the diet with the trial dietician prior to commencement. Optifast meal replacement products are provided to the participants alongside recipe suggestions for their daily meal.

Prior to randomisation all participants will undergo a baseline assessment of their fatty liver disease including an MRI performed by a radiographer (approximately 30 minute duration) and interpreted by a radiologist to quantify their liver fat fraction, and an ultrasound guided liver biopsy under local anaesthetic performed by a radiologist (approximately 30 minutes duration) to assess for underlying steatohepatitis and liver fibrosis.

Phone support is offered from the dietician at 2, 4 and 9 weeks with a face to face review at 6 weeks. Compliance to the diets will be monitored using a food diary app (easy diet diary) and the intervention group will have ketone levels checked (3-hydroxybutyrate) to assess whether ketosis was achieved.

At the end of the diet participants will enter a 12 week weight maintenance phase and be instructed by a dietician to follow an ad libitum calorie controlled diet in order to maintain any weight loss achieved by the dietary intervention. Each participant’s maximum calorie intake is calculated individually (using Schofield equation which incorporates weight, gender, age and reported physical activity levels) and full energy requirements (for weight maintenance) are used to determine dietary prescription. Participants in the intervention arm are no longer provided with meal replacements. Serving sizes are reinforced and support to resume intake within real world setting is provided. To facilitate and record adherence a food diary app is used.
The intervention group will also be commenced on low dose semaglutide (0.5mg via subcutaneous injection once weekly for 12 weeks) to assist with weight maintenance during this phase. This will be self administered by participants after education from the trial team.

End of intervention assessments including a repeat MRI and liver biopsy will occur at week 24.
A final follow up will occur at week 48 to assess for any enduring effects of the intervention.

Intervention code [1]

Treatment: Other

Comparator / control treatment

The control group undergo a 12 week isocaloric mediterranean diet.
Participants undergo face to face education (15 - 20 minutes duration) about the diet with the trial dietician prior to commencement. Essential component of the mediterranean diet are provided to the participants including olive oil and tinned fish, alongside a two weekly rotating meal plan. Participants in the Mediterranean diet arm are provided with a recipe book and some examples of meals included are: Lentil soup, baked risoni with lamb and salad, chicken soup with egg and lemon
Phone support is offered from the dietician at 2, 4 and 9 weeks with a face to face review at 6 weeks. Compliance to the diet will be monitored using a food diary app (easy diet diary) to calculate a Mediterranean Diet Adherence Score (MEDAS).

At the end of the diet participants will enter a 12 week weight maintenance phase and be instructed by a dietician to follow a calorie controlled diet in line with Mediterranean diet principles in order to maintain any weight loss achieved by the dietary intervention. Each participant’s maximum calorie intake is calculated individually (using Schofield equation which incorporates weight, gender, age and reported physical activity levels) and full energy requirements (for weight maintenance) are used to determine dietary prescription. Food products will no longer be provided. Serving sizes are reinforced and support to resume intake within real world setting is provided. To facilitate and record adherence a food diary app is used (easy diet diary).

End of intervention assessments including a repeat MRI and liver biopsy will occur at week 24.
A final follow up will occur at week 48 to assess for any enduring effects of the intervention.

Control group

Active

Outcomes

Primary outcome [1]

Change in intra-hepatic lipid content on MRI

Timepoint [1]

Week 12 post-intervention commencement

Secondary outcome [1]

Change in intra-hepatic lipid content on MRI

Timepoint [1]

Week 24 and 48 post-intervention commencement

Secondary outcome [2]

Change in liver histology on liver biopsy
- NAFLD activity score

Timepoint [2]

Week 24 post-intervention commencement

Secondary outcome [3]

Body weight (kg) measured on the same digital scales without shoes or excess clothing

Timepoint [3]

Week 12, 24, 48 post-intervention commencement

Secondary outcome [4]

Body composition (DXA scan)
- body fat percentage

Timepoint [4]

Week 12, 24, 48 post-intervention commencement

Secondary outcome [5]

Liver enzymes on blood samples (ALT, AST, GGT, ALP, Bilirubin, Albumin)

Timepoint [5]

Week 12, 24, 48 post-intervention commencement

Secondary outcome [6]

Lipid profile assessed on blood samples

Timepoint [6]

Week 12, 24, 48 post-intervention commencement

Secondary outcome [7]

Physical activity
- wearable activity monitor

Timepoint [7]

7 day monitoring period which will occur at baseline pre-intervention commencement (Week 0) and again at Week 6, 12, 24 and 48 post-intervention commencement

Secondary outcome [8]

Inflammatory marker profile on blood samples

Timepoint [8]

Pre-intervention commencement (Week 0) , week 6, 12, 24, 48 post-intervention

Secondary outcome [9]

Dietary Inflammatory Index scores

Timepoint [9]

Pre-intervention commencement (Week 0) , week 6, 12, 24, 48 post-intervention

Secondary outcome [10]

Sustainability of diet assessed via qualitative, one-on-one, 30 minute online recorded interviews using Zoom with a member of the research team

Timepoint [10]

Week 12 post-intervention commencement

Secondary outcome [11]

Quality of life as assessed by questionnaire
- Nutrition quality of life (NQoL)

Timepoint [11]

Pre-intervention commencement (Week 0) , week 12, 24, 48 post-intervention commencement

Secondary outcome [12]

Faecal microbiome assessed via RNA shotgun analysis of stool samples

Timepoint [12]

Pre-intervention commencement (Week 0) , week 12, 24, 48 post-intervention commencement

Secondary outcome [13]

Change in liver stiffness measurement assessed by Fibroscan

Timepoint [13]

Week 12, 24, 48 post-intervention commencement

Secondary outcome [14]

Change in liver histology on liver biopsy
- Fibrosis stage

Timepoint [14]

Week 24 post-intervention commencement

Secondary outcome [15]

Body composition (DXA scan)
- lean mass percentage

Timepoint [15]

Week 12, 24, 48 post-intervention commencement

Secondary outcome [16]

Waist circumference assessed using a non-elastic tape measure

Timepoint [16]

Week 12,24 and 48 post-intervention commencement

Secondary outcome [17]

Blood pressure assessed using sphygmomanometer

Timepoint [17]

Week 12, 24, 48 post-intervention commencement

Secondary outcome [18]

Fasting glucose assessed on blood samples

Timepoint [18]

week 12, 24, 48 post-intervention commencement

Secondary outcome [19]

Insulin resistance assessed via HOMA-IR score assessed from fasting blood samples

Timepoint [19]

Week 12, 24, 48 post-intervention commencement

Secondary outcome [20]

Impact of the diets on mood as assessed by questionnaire
- Depression anxiety stress scale (DASS 21)

Timepoint [20]

Pre-intervention commencement (Week 0), week 12,24,48 post-intervention commencement

Secondary outcome [21]

Quality of life assessed by questionnaire
- Diet related quality of life (DR-QoL)

Timepoint [21]

Pre-intervention commencement (Week 0) , week 12, 24, 48 post-intervention commencement

Secondary outcome [22]

Quality of life assessed by questionnaire
- Assessment of quality of life (AQoL)

Timepoint [22]

Pre-intervention commencement (Week 0) , week 12, 24, 48 post-intervention commencement

Secondary outcome [23]

Impact of the diets on mood as assessed by questionnaire
- Clinical impairment assessment (CIA)

Timepoint [23]

Pre-intervention commencement (Week 0), week 12,24,48 post-intervention commencement

Secondary outcome [24]

Impact of the diets on mood as assessed by questionnaire
- Eating disorder examination questionnaire (EDEQ)

Timepoint [24]

Pre-intervention commencement (Week 0), week 12,24,48 post-intervention commencement

Secondary outcome [25]

Impact of the diets on mood as assessed by questionnaire
- Primary goals for weight loss questionnaire (PGWLQ)

Timepoint [25]

Pre-intervention commencement (Week 0), week 12,24,48 post-intervention commencement

Eligibility

Key inclusion criteria

1. Individuals aged 18 – 70 who are able to provide consent
2. BMI 27kg/m2 to 35kg/m2
3. Elevated ALT and/or GGT
4. >= F1 fibrosis on liver biopsy
5. Liver fat on MRS >= 10%

Minimum age

18 Years

Maximum age

70 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

1. Alcohol >2 SD/day for men and >1 SD/day for women
2. Other liver disease, i.e. viral hepatitis, autoimmune liver disease, haemochromatosis
3. Decompensated cirrhosis or cirrhosis with Fibroscan > 25kPa
4. Other significant medical or psychological issue that would preclude a diet; such as cardiac disease, lung disease or malignancy
5. Antibiotics, probiotics, corticosteroids, hormonal therapies or methotrexate within three months of baseline data collection, or current use of a GLP-1 agonist or insulin
6. Already lost >5% body weight or previous bariatric surgery
7. Participation in another interventional trial, or participation in another interventional trial within the last 6 months

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)

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

1:1 randomisation with stratification for gender and type 2 diabetes mellitus (T2DM)

Masking / blinding

Who is / are masked / blinded?

Intervention assignment

Other design features

Phase

Not Applicable

Type of endpoint/s

Statistical methods / analysis

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

Actual

1/04/2021

Date of last participant enrolment

Anticipated

31/12/2023

Actual

Date of last data collection

Anticipated

31/12/2024

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

St Vincent's Hospital (Melbourne) Ltd - Fitzroy

Recruitment hospital [2]

St Vincent's Private Hospital - Fitzroy

Recruitment postcode(s) [1]

3065 - Fitzroy

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

St Vincent's Hospital Melbourne

Address [1]

41 Victoria Parade, Fitzroy VIC 3065

Country [1]

Australia

Primary sponsor type

Hospital

Name

St Vincent's Hospital Melboourne

Address

41 Victoria Parade, Fitzroy VIC 3065

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

St Vincent's Hospital Melbourne HREC

Ethics committee address [1]

41 Victoria Pde
Fitzroy 
Victoria
3065

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

15/03/2019

Ethics approval number [1]

277/18

Summary

Brief summary

In Australia, nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease, and results in significant healthcare burden from both liver and metabolic complications. NAFLD is defined by the presence of fat in the liver which can cause liver related morbidity and mortality through its progression to liver fibrosis, cirrhosis and increases the risk of developing liver cancer. It is strongly associated with obesity, insulin resistance and the metabolic syndrome, and weight loss is the mainstay of treatment. Weight loss can reduce the amount of fat in the liver, improve the level of liver fibrosis and improve individuals overall metabolic and cardiovascular risk. Current treatment guidelines advise dietary energy restriction, with many recommending a Mediterranean Diet (MD) which has been shown to improve liver fat and reduce the risk of developing T2DM. Despite this current treatment practices are heterogenous, and weight loss is difficult to achieve and maintain.
We aim to examine whether the treatment strategies used in the medical management of obesity, such as the use of very low energy diets (VLED) and appetite suppressing (AS) medications, can be adapted to the management of NAFLD which is a related but separate disease entity. 
This study is a single centre, randomised control trial evaluating the effect of the VLED compared with the standard of care MD in overweight and obese individuals with NAFLD.
Participants will be randomised to a 12-week program of either:
1. VLED: a ketogenic 800kcal/day diet utilising meal replacement supplements
2. The standard of care MD: a predominantly plant based diet supplemented with monounsaturated fatty acids (MUFAs)
At the end of the 12 week diet, all participants will enter a weight maintenance phase where they will be instructed to follow a calorie controlled but ad-libitum diet in order to maintain their weight, with the VLED group also commenced on low dose Semaglutide as an adjunctive AS medication for 12 weeks.
We will compare the impact of these two programs on the severity of NAFLD (change in degree of liver fat on MRI and liver fibrosis on liver biopsy). Other outcome measures include the degree of weight loss and weight maintenance achieved, body composition, and impact on physical activity, mood and quality of life.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

A/Prof Marno Ryan

Address

St Vincent's Hospital Melbourne
35 Victoria Pde
Fitzroy
Victoria
3065

Country

Australia

Phone

+61392313580

Fax

Marno.Ryan@svha.org.au

Contact person for public queries

Name

Ann Farrell

Address

St Vincent's Hospital Melbourne
35 Victoria Pde
Fitzroy
Victoria
3065

Country

Australia

Phone

+61 392313598

Fax

darwinstudy@svha.org.au

Contact person for scientific queries

Name

Ann Farrell

Address

St Vincent's Hospital Melbourne
35 Victoria Pde
Fitzroy
Victoria
3065

Country

Australia

Phone

+61 392313598

Fax

darwinstudy@svha.org.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

What supporting documents are/will be available?

Doc. No.	Type	Email
18905	Study protocol	darwinstudy@svha.org.au
18906	Informed consent form	darwinstudy@svha.org.au
18907	Ethical approval	darwinstudy@svha.org.au
18908	Clinical study report	darwinstudy@svha.org.au

Results publications and other study-related documents

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No additional documents have been identified.

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