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Trial registered on ANZCTR


Registration number
ACTRN12619000931178p
Ethics application status
Submitted, not yet approved
Date submitted
22/06/2019
Date registered
4/07/2019
Date last updated
4/07/2019
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] 298502 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
TWO BIRDS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Obesity 313401 0
Type 2 Diabetes 313402 0
Non-alcoholic fatty liver disease 313413 0
Hypertension 313414 0
Hyperlipidaemia 313415 0
Condition category
Condition code
Metabolic and Endocrine 311834 311834 0 0
Diabetes
Diet and Nutrition 311835 311835 0 0
Obesity
Oral and Gastrointestinal 311849 311849 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Cardiovascular 311926 311926 0 0
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] 314820 0
Treatment: Drugs
Intervention code [2] 314821 0
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] 320508 0
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] 320508 0
8 months post enrolment
Secondary outcome [1] 371842 0
Weight (measured in kg) on a SECA mBCA 515 Medical Body Composition Analyser
Timepoint [1] 371842 0
Baseline, 3, 5, and 8 months post-enrolment
Secondary outcome [2] 371843 0
Composite secondary outcome of serum total cholesterol and/or triglycerides on routine blood tests
Timepoint [2] 371843 0
Baseline, 3, 5, and 8 months post-enrolment
Secondary outcome [3] 371844 0
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] 371844 0
Baseline and 8 months post-enrolment
Secondary outcome [4] 371845 0
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] 371845 0
Baseline and 8 months post-enrolment
Secondary outcome [5] 372139 0
Systolic and diastolic blood pressure using a Welch Allyn sphygmomanometer
Timepoint [5] 372139 0
Baseline, 3, 5, and 8 months post-enrolment
Secondary outcome [6] 372140 0
Secondary outcome in changes in sleepiness using the Epworth Sleepiness Scale
Timepoint [6] 372140 0
Baseline and 8 months post-enrolment
Secondary outcome [7] 372141 0
Secondary composite outcome in eating behaviours using Food Intake Survey and the Weight and Lifestyle Inventory (WALI).
Timepoint [7] 372141 0
Baseline and 8 months post-enrolment
Secondary outcome [8] 372142 0
Change in physical function using the EQ-5D-5L questionnaire.
Timepoint [8] 372142 0
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
Gender
Both males and females
Can healthy volunteers participate?
No
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
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 14056 0
Blacktown Hospital - Blacktown
Recruitment postcode(s) [1] 26846 0
2148 - Blacktown

Funding & Sponsors
Funding source category [1] 303047 0
Commercial sector/Industry
Name [1] 303047 0
Nestle Health Science
Address [1] 303047 0
Head Office, Rhodes & NSW Sales Office
Nestlé Australia Ltd
Building D, 1 Homebush Bay Drive
Rhodes NSW 2138
Country [1] 303047 0
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] 303108 0
Other Collaborative groups
Name [1] 303108 0
Western Sydney Diabetes
Address [1] 303108 0
Administration and Education Building
Marcel Cres
Blacktown Hospital
Blacktown, NSW 2148
Country [1] 303108 0
Australia

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 303598 0
WSLHD HREC
Ethics committee address [1] 303598 0
WSLHD Research & Education Network
Westmead Hospital
Cnr Hawkesbury & Darcy Rds
Westmead NSW 2145
Ethics committee country [1] 303598 0
Australia
Date submitted for ethics approval [1] 303598 0
14/06/2019
Approval date [1] 303598 0
Ethics approval number [1] 303598 0

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 94206 0
Dr Ramy Bishay
Address 94206 0
Metabolic and Weight Loss Program
Department of Diabetes and Endocrinology
Clinical School Building, Western Sydney Univeristy
Blacktown Hospital, Marcel Cres
Blacktown, NSW 2148
Country 94206 0
Australia
Phone 94206 0
+61 410366737
Fax 94206 0
Email 94206 0
ramy.bishay@health.nsw.gov.au
Contact person for public queries
Name 94207 0
Dr Ramy Bishay
Address 94207 0
Metabolic and Weight Loss Program
Department of Diabetes and Endocrinology
Clinical School Building, Western Sydney Univeristy
Blacktown Hospital, Marcel Cres
Blacktown, NSW 2148
Country 94207 0
Australia
Phone 94207 0
+61 410366737
Fax 94207 0
Email 94207 0
ramy.bishay@health.nsw.gov.au
Contact person for scientific queries
Name 94208 0
Dr Ramy Bishay
Address 94208 0
Metabolic and Weight Loss Program
Department of Diabetes and Endocrinology
Clinical School Building, Western Sydney Univeristy
Blacktown Hospital, Marcel Cres
Blacktown, NSW 2148
Country 94208 0
Australia
Phone 94208 0
+61 410366737
Fax 94208 0
Email 94208 0
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?
Study protocol
Informed consent form
How or where can supporting documents be obtained?
Type [1] 2437 0
Study protocol
Citation [1] 2437 0
Link [1] 2437 0
Email [1] 2437 0
Other [1] 2437 0
Type [2] 2438 0
Informed consent form
Citation [2] 2438 0
Link [2] 2438 0
Email [2] 2438 0
Other [2] 2438 0
Summary results
No Results