ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12619000931178

Ethics application status

Approved

Date submitted

22/06/2019

Date registered

4/07/2019

Date last updated

3/11/2020

Date data sharing statement initially provided

4/07/2019

Type of registration

Prospectively registered

Titles & IDs

Public title

TWO BIRDS - Intensive lifestyle and medication to help improve diabetes and fatty liver disease through weight loss

Scientific title

TWO BIRDS - Targeting Weight loss in Obese diabetes patients with Both Intensive dietary modification with or without glucagon-like peptide 1 Receptor analogues to improve Diabetes and Steatosis/steatohepatitis

Secondary ID [1]

Nil Known

Universal Trial Number (UTN)

Trial acronym

TWO BIRDS

Linked study record

Health condition

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

Obesity

Type 2 Diabetes

Non-alcoholic fatty liver disease

Hypertension

Hyperlipidaemia

Condition category

Condition code

Metabolic and Endocrine

Diabetes

Diet and Nutrition

Obesity

Oral and Gastrointestinal

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

Cardiovascular

Hypertension

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

The study will be overseen by the clinician-investigator (RB) who will review all patients for suitability, consenting and medical review as per our protocol.

The intervention arm will receive industry-funded Optifast® program: 5-months of complete VLCD (820 KCal/day,) using Optifast® Phase 1: 3-4 meal replacements per day (months 1-3); Phase 2: 2 meal replacements plus one self-prepared healthy meal (month 4); Phase 3: 1 meal replacement + 2 self-prepared healthy meals (month 5); Phase 4: maintenance diet (months 6-8).

The clinic/study dietitian will deliver the program in a weekly to fortnightly group VLCD initiation and support format held face-to-face at the university clinics metabolic clinic campus. This is already delivered as part of standard of care in our program.

Optifast meal replacements will consist of an assortment of bars, shakes (made in water), desserts and soups. All meal replacements have nutritionally equivalent composition of carbohydrates, fat and protein and are nutritionally interchangeable between the different forms (e.g., bars = soups = desserts = shakes). The meal replacements come in a variety of flavours (bars: chocolate, cereal, cappucino); shakes: strawberry, vanilla, banana, chai, coffee, caramel; soups: tomato, vegetable, chicken; desserts - chocolate, vanilla).

As per our protocol (see attached), patients will be initiated on varying intensities of meal replacements throughout phases 1 to 3 and provided with a detailed participant handbook which includes meal plans and a list of allowable fluids, fruits, vegetables, fats and proteins during each stage of the program as per standard of care. This information is based on published material provided by Nestle Health Science support material and the Baker Heart and Diabetes Institute handbook available online (https://baker.edu.au/-/media/documents/fact-sheets/Baker-Institute-factsheet-VLED-program.ashx?la=en). Additional foods allowed in the intervention (e.g., fruit, salads, tuna, yoghurt) are purchased and prepared by the patient at their own cost as part of their routine grocery shopping (however meal replacements are provided free of charge). Patients are asked in group sessions to note the number of meal replacements to the study clinician and dietitian and adherence will be monitored at each clinic visit through interview.

The maintenance diet phase will be delivered in line with the Australian Healthy Eating Guideline (available online: https://www.eatforhealth.gov.au/guidelines/australian-guide-healthy-eating). Adherence will be determined on the WALI questionnaire and Food Intake Survey performed at the end of the study.

PLUS patients will be given education by the study diabetes educator to teach self-administration of GLP-1 RA (dulaglutide 1.5 mg subcutaneously weekly, Trulicity®). This medication is TGA and PBS approved for the treatment of type 2 diabetes.

Trulicity is delivered as a single 1.5 mg weekly subcutaneous injection using a prefilled pen, administered to the abdomen or thighs once a week. The patient will be taught self-injection by the clinic/study diabetes educator. Note, this is standard of care for prescribing these PBS subsidised and TGA approved medications.

Adherence to the GLP-1 RA therapy will be monitored from the prescription record kept by the partner pharmacy and delivered to the study coordinator on a monthly basis.

Intervention code [1]

Treatment: Drugs

Intervention code [2]

Treatment: Other

Comparator / control treatment

Comparator arm will receive: industry-funded Optifast® program: 5-months of complete VLCD (820 KCal/day,) using Optifast® Phase 1: 3-4 meal replacements per day (months 1-3); Phase 2: 2 meal replacements plus one self-prepared healthy meal (month 4); Phase 3: 1 meal replacement + 2 self-prepared healthy meals (month 5); Phase 4: maintenance diet (months 6-8)

Control group

Active

Outcomes

Primary outcome [1]

Diabetes remission (defined as an HbA1c < 6.5% on blood test) at the conclusion of the study period whilst off all diabetes therapies for 3-months OR HbA1c<6.0% whilst on metformin only

Timepoint [1]

8 months post enrolment

Secondary outcome [1]

Weight (measured in kg) on a SECA mBCA 515 Medical Body Composition Analyser

Timepoint [1]

Baseline, 3, 5, and 8 months post-enrolment

Secondary outcome [2]

Composite secondary outcome of serum total cholesterol and/or triglycerides on routine blood tests

Timepoint [2]

Baseline, 3, 5, and 8 months post-enrolment

Secondary outcome [3]

Composite secondary outcome of liver stiffness as assessed by a non-invasive measurements using a FibroScan®, blood tests (Enhanced Liver Fibrosis Score [ELF]) and clinical calculators (NAFLD fibrosis score and FIB-4 scores).

Timepoint [3]

Baseline and 8 months post-enrolment

Secondary outcome [4]

Composite secondary outcome of changes in depression and anxiety (Depression and Anxiety Severity Scale (DASS-21)), diabetes-related quality of life (Diabetes Distress Scale (DDS)), and quality of life (SF-36).

Timepoint [4]

Baseline and 8 months post-enrolment

Secondary outcome [5]

Systolic and diastolic blood pressure using a Welch Allyn sphygmomanometer

Timepoint [5]

Baseline, 3, 5, and 8 months post-enrolment

Secondary outcome [6]

Secondary outcome in changes in sleepiness using the Epworth Sleepiness Scale

Timepoint [6]

Baseline and 8 months post-enrolment

Secondary outcome [7]

Secondary composite outcome in eating behaviours using Food Intake Survey and the Weight and Lifestyle Inventory (WALI).

Timepoint [7]

Baseline and 8 months post-enrolment

Secondary outcome [8]

Change in physical function using the EQ-5D-5L questionnaire.

Timepoint [8]

Baseline and 8 months post-enrolment

Eligibility

Key inclusion criteria

1. BMI>35 kg/m2
2. Age 18-75 years of age
3. Have a diagnosis of type 2 diabetes mellitus with (HbA1c > 6.5%).
4. Have a diagnosis duration of T2D < 6 years
5. No clear contraindications to treatment with either very low calorie diets (VLCD) and/or glucagon-like peptide-1 (GLP-1) receptor analogues.

Minimum age

18 Years

Maximum age

75 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

Individuals with: Type 1 diabetes; pregnant or planning pregnancy; significant alcohol or drug abuse; severe/untreated mental health illnesses, including eating disorders; advanced cardiac, liver or renal disease; individuals taking sodium glucose co-transporter 2 receptor blockers and/or exenatide immediate release (Byetta ®) (will need to cease medications for at least 2 weeks prior to study commencement); individuals taking medications that affect weight within the past 1 month (e.g., corticosteroids, phentermine, topiramate, naltrexone, bupropion); contraindications to following VLCD (Vegan diet, lactose intolerance); recent history of pancreatitis or acute coronary event/revascularisation in the most recent 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)

This is an open-label trial as the study drug has no placebo comparator. Once participants meet eligibility criteria and are consented by the clinician and lead investigator, the participants will be sent to the RCT coordinator for randomisation using a commonly used computer algorithm previously used in RCTs. The data collected is part of routine clinical care and will be stored on a local health district PC. The statistician will have access to this data and will have no direct contact with either participants or clinicians during the enrolment period, and will be blinded to group assignment - saying either 'group 1' or 'group 2', ensuring that the allocation is random.

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

A random study list with blinded groups and a standard 50/50 allocation will be generated by the study statistician using the random generation commands in Stata version 15.

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

Univariate analysis (t-test or non-parametric) to determine significance of differences between groups at baseline. Repeat measures analysis of variance to assess outcomes longitudinally between treatment groups for both primary and secondary outcomes. Multivariable regression models for statistically significant associations on univariate analysis.

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

2/09/2019

Actual

4/02/2020

Date of last participant enrolment

Anticipated

22/12/2022

Actual

Date of last data collection

Anticipated

28/12/2023

Actual

Sample size

Target

200

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW

Recruitment hospital [1]

Blacktown Hospital - Blacktown

Recruitment postcode(s) [1]

2148 - Blacktown

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Nestle Health Science

Address [1]

Head Office, Rhodes & NSW Sales Office
Nestlé Australia Ltd
Building D, 1 Homebush Bay Drive
Rhodes NSW 2138

Country [1]

Australia

Primary sponsor type

Government body

Name

Western Sydney Local Health District

Address

5 Fleet St
North Parramatta NSW 2151

Country

Australia

Secondary sponsor category [1]

Other Collaborative groups

Name [1]

Western Sydney Diabetes

Address [1]

Administration and Education Building
Marcel Cres
Blacktown Hospital
Blacktown, NSW 2148

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

WSLHD HREC

Ethics committee address [1]

WSLHD Research & Education Network    
Westmead Hospital
Cnr Hawkesbury & Darcy Rds
Westmead NSW 2145

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

14/06/2019

Approval date [1]

03/10/2019

Ethics approval number [1]

2019/ETH08752

Summary

Brief summary

Obese people comprise 33% of Western Sydney and are 6x and 10x more likely to develop diabetes and non-alcoholic fatty liver disease (NAFLD), respectively, compared to normal weight individuals. This trend will lead to alarming rates of cardiovascular death, liver cirrhosis (scarring) and liver cancer. 

Weight loss can lead to diabetes remission and can be achieved successfully using very low calorie diets (VLCD), with rates close to 86% in adults. Additionally, a widely available and effective diabetes therapy – glucagon-like peptide-1 receptor analogues (GLP1-RA) – also assist with weight loss. Both treatments lead to significant weight loss, improve diabetes, and can reverse liver damage caused by NAFLD, yet the combination of these treatments has never been studied.

This is a pragmatic pilot study of patients attending the Metabolic and Weight Loss Program at Blacktown hospital to investigate the efficacy of VLCD +/- GLP1-RA in achieving diabetes control and reversal of liver injury. This will lead directly to practice change by senior clinicians involved in the study and improve patient care in the clinics at Blacktown hospital, and potentially further afield.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Ramy Bishay

Address

Metabolic and Weight Loss Program
Department of Diabetes and Endocrinology
Clinical School Building, Western Sydney Univeristy
Blacktown Hospital, Marcel Cres
Blacktown, NSW 2148

Country

Australia

Phone

+61 410366737

Fax

ramy.bishay@health.nsw.gov.au

Contact person for public queries

Name

Ramy Bishay

Address

Metabolic and Weight Loss Program
Department of Diabetes and Endocrinology
Clinical School Building, Western Sydney Univeristy
Blacktown Hospital, Marcel Cres
Blacktown, NSW 2148

Country

Australia

Phone

+61 410366737

Fax

ramy.bishay@health.nsw.gov.au

Contact person for scientific queries

Name

Ramy Bishay

Address

Metabolic and Weight Loss Program
Department of Diabetes and Endocrinology
Clinical School Building, Western Sydney Univeristy
Blacktown Hospital, Marcel Cres
Blacktown, NSW 2148

Country

Australia

Phone

+61 410366737

Fax

ramy.bishay@health.nsw.gov.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 data regarding the primary and secondary outcomes only will be shared at the completion of the study. Other demographic information (such as gender) may be shared in a deidentified manner.

When will data be available (start and end dates)?

Data will be available at the conclusion of the study analysis and de-identified. There is no prespecified end date.

Available to whom?

Public, research organisations and scientific bodies.

Available for what types of analyses?

Statistical and health economics.

How or where can data be obtained?

By written request to the clinician lead investigator only and following approval by the local Human Research Ethics committee. Requests can be obtained in writing to ramy.bishay@health.nsw.gov.au or by post to:

Metabolic and Weight Loss Program
Clinical School Building, Blacktown Clinical School
University of Western Sydney
Marcel Crescent, Blacktown Hospital
Blacktown, NSW 2148

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
2437	Study protocol					377787-(Uploaded-22-06-2019-17-56-35)-Study-related document.docx
2438	Informed consent form					377787-(Uploaded-22-06-2019-17-56-58)-Study-related document.doc

Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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No additional documents have been identified.

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