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Trial registered on ANZCTR


Registration number
ACTRN12614000836639
Ethics application status
Approved
Date submitted
28/07/2014
Date registered
6/08/2014
Date last updated
5/02/2020
Date data sharing statement initially provided
10/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A new combination therapy for the treatment of type 2 diabetes mellitus.
Scientific title
An open label trial of OZ101 as an add-on therapy for the treatment of type 2 diabetes mellitus in patients on sulphonylurea therapy.
Secondary ID [1] 284930 0
None
Universal Trial Number (UTN)
U1111-1158-9653
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 2 Diabetes Mellitus 292405 0
Condition category
Condition code
Metabolic and Endocrine 292723 292723 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
OZ101 tablets, primarily (94%) comprised of oligofructose molecules that is also present in fruits and vegetables, will be given orally to type 2 diabetes patients who are currently on sulphonylurea monotherapy or metformin plus sulphonylurea combination therapy. A total of 13.5 gr of OZ101 will be given to patients in arm 2 of the study. Each patient will take 3 tablets prior to or with each meal, with a total of 9 tablets per day, each tablet being 1.5 gr. A total of 27 gr of OZ101 will be given to patients in arm 3 of the study. Each patient will take 6 tablets prior to or with each meal, with a total of 18 tablets per day, each tablet being 1.5 gr. These tablets are readily dissolved in 200 ml of warm water, if patients prefer.

Patients will be given a diary to complete the number of tablets dispensed and unused amounts at a 4-weekly basis. A nurse or a pharmacist will verify the compliance at each 4-weekly visit.

Patients will be recruited who are exclusively being treated by second and third generation sulphonylurea monotherapy or metformin plus sulphonylurea combination therapy (preferably with glibenclamide, gliclazide, glimepiride and glipizide). A total of 30 patients will be randomized to three treatment arms based on two dosing regimens of OZ101 and a control.

Patients enrolled in arm 1 will continue to be treated with sulphonylurea-only or metformin plus sulphonylurea combination therapy. Patients enrolled in arm 2 will continue to be treated with sulphonylurea or metformin plus sulphonylurea combination therapy plus a dose of OZ101. Patients enrolled in arm 3 will continue to be treated with sulphonylurea or metformin plus sulphonylurea combination therapy plus 2 x dose of OZ101.

The study has been designed to compare changes in glycaemia in patients treated for 24 weeks with OZ101 plus sulphonylurea or plus metformin and sulphonylurea combination against sulphonylurea only or metformin and sulphonylurea combination.

The trial will be monitored by a credible Clinical Research Organisation and laboratory tests will be performed by a designated pathology laboratory that follows NATA, NHMRC, ICH-GCP guidelines.
Intervention code [1] 289757 0
Treatment: Drugs
Comparator / control treatment
This trial will assess the efficacy of addition of OZ101 to existing anti-diabetes sulphonylurea monotherapy or metformin and sulphonylurea combination therapy. Therefore, patients on sulphonylurea monotherapy or metformin and sulphonylurea combination therapy will be used as the control group.
Control group
Active

Outcomes
Primary outcome [1] 292567 0
Haemoglobin A1c
Timepoint [1] 292567 0
Measured at four time points:
At screening visit.
At baseline visit (4 weeks after screening visit).
At 12 weeks after intervention commencement.
At 24 weeks after intervention commencement.

HbA1c will be measured in whole blood as per instruction described at Roche modular E test.
Primary outcome [2] 292568 0
Fasting Blood Glucose
Timepoint [2] 292568 0
Measured at four time points:
At screening visit.
At baseline visit (4 weeks after screening visit).
At 12 weeks after intervention commencement.
At 24 weeks after intervention commencement.

Fasting blood glucose will be measured in FIOx tubes as per instruction described at Roche modular E test.
Secondary outcome [1] 309253 0
Post Prandial Glucose levels
Timepoint [1] 309253 0
Measured at four time points:
At screening visit.
At baseline visit (4 weeks after screening visit).
At 12 weeks after intervention commencement.
At 24 weeks after intervention commencement.

Post Prandial blood glucose will be measured in FIOx tubes as per instruction described at Roche modular E test.
Secondary outcome [2] 309254 0
7-point Self Managed Blood Glucose
Timepoint [2] 309254 0
Measured at four time points:
At screening visit.
At baseline visit (4 weeks after screening visit).
At 12 weeks after intervention commencement.
At 24 weeks after intervention commencement.

7-point self managed blood glucose, from capillary blood via finger pricking, will be measured using Roche AccuCheck Performa device as per manufacturer's instruction.
Secondary outcome [3] 309255 0
Body weight
Timepoint [3] 309255 0
Measured at four time points:
At screening visit.
At baseline visit (4 weeks after screening visit).
At 12 weeks after intervention commencement.
At 24 weeks after intervention commencement.

This will be measure at the investigator site using an accurate weighing station.
Secondary outcome [4] 309656 0
Safety aspects
Timepoint [4] 309656 0
Measured at four time points:
At screening visit.
At baseline visit (4 weeks after screening visit).
At 12 weeks after intervention commencement.
At 24 weeks after intervention commencement.

As a measure of safety aspects, the number and severity of hypoglycaemic episodes will be assessed. A diary will be given to patient to complete when hypoglycaemia occur. Patients will also instructed to measure their blood glucose levels, if practicable, during occurrence using their Roche AccuCheck Performa device.
Secondary outcome [5] 309733 0
Glycated circulating proteins
Timepoint [5] 309733 0
Measured at four time points:
At screening visit.
At baseline visit (4 weeks after screening visit).
At 12 weeks after intervention commencement.
At 24 weeks after intervention commencement.

Glycated circulating proteins (fructosamine) will be measured in serum as per instruction described at Roche modular E test.
Secondary outcome [6] 309734 0
beta-cell function
Timepoint [6] 309734 0
Measured at four time points:
At screening visit.
At baseline visit (4 weeks after screening visit).
At 12 weeks after intervention commencement.
At 24 weeks after intervention commencement.

Beta cell function will be measured using appropriate surrogate markers such as insulin collected in FIOx tubes as per instruction described at Roche modular E test.
Secondary outcome [7] 309735 0
Insulin Resistance
Timepoint [7] 309735 0
Measured at four time points:
At screening visit.
At baseline visit (4 weeks after screening visit).
At 12 weeks after intervention commencement.
At 24 weeks after intervention commencement.

Insulin resistance will be measured using appropriate surrogate markers such as insulin collected in FIOx tubes as per instruction described at Roche modular E test.
Secondary outcome [8] 309736 0
Adipose tissue function
Timepoint [8] 309736 0
Measured at four time points:
At screening visit.
At baseline visit (4 weeks after screening visit).
At 12 weeks after intervention commencement.
At 24 weeks after intervention commencement.

Adipose tissue function will be measured using appropriate surrogate markers such as adiponectin collected in gold top tubes as per instruction described at Roche modular E test.

Eligibility
Key inclusion criteria
I. Have given written informed consent prior to any study-specific procedures.
II. Are between the age of 25 and 65.
III. Diagnosed with T2DM, according to the acceptable criteria in their jurisdiction, for a minimum of 1 year and a maximum of 10 years.
IV. Patients who are on sulphonylurea monotherapy or metformin plus sulphonylurea combination therapy, either at maximum tolerated doses or below, at the time of entry into the trial and have been on sulphonylurea treatment for a period of not less than 6 months prior to entering into the trial, irrespective of duration of metformin intake.
V. The FGL is above 7 mmol/L with HbA1c between 7-10%, as at screening visit.
VI. Did not need any change and/or adjustment in sulphonylurea monotherapy or sulphonylurea plus metformin combination therapy during 12 weeks preceding visit 2 of the study to ensure that the maximal effect of sulphonylurea monotherapy or metformin plus sulphonylurea combination therapy has been observed.
VII. Patient has a BMI of between 25 and 40 kg/m2, as at screening visit.
VIII. No change has been occurred to concomitant medication within the past 12 weeks.
Minimum age
25 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
I. The Patient has been diagnosed with T2DM for less than 1 year OR more than 10 years.
II. The Patient has allergies to anti-diabetes drugs.
III. In the investigator’s opinion, the patient is likely to be non-compliant with the trial medication regimes.
IV. Patients are excluded if they have consumed excessive amounts of uncooked OF/inulin within 4 weeks prior to randomization or will consume excessive amounts of uncooked OF/inulin containing products during their participation in the trial.
A questionnaire listing the OF/inulin containing food products with daily intake limits will be provided to each enrolled patient. The patients who verify consumption of high amounts of these products above the daily intake limit will be excluded.
V. Patients who are taking probiotics supplements 4 weeks prior to randomization or who plans to take probiotic during the trial.
VI. Patients who have a previously known allergy to artichoke or chicory, onion, leek, and other OF/inulin containing products.
A comprehensive list of products containing OF/inulin will be provided to each patient for verification.
VII. Patients who are taking any other non-sulphonylurea oral or parenteral anti-diabetes medications, except metformin, such as, but not limited to, insulin, acarbose, voglibose, DPP4 inhibitors, SGLT-2 inhibitors, GLP-1 mimetics and pioglitazone.
VIII. Patients who are taking a combination of sulphonylurea and other anti-diabetes drugs, except metformin (e.g. pioglitazone or DPP-4 inhibitors) during the past 3 months of screening period.
IX. Patients who are taking warfarin.
X. Patients who plan to practice fasting (i.e. during the Holy month of Ramadan) during participation in the trial.
XI. Female patients of child-bearing potential who are pregnant or test positive for pregnancy at the time of enrolment based on a urine or serum pregnancy test.
XII. Female patients of child-bearing potential who do not agree to use a reliable method of birth control during the study.
XIII. Patients who are unable to participate in the study as judged by the study investigator.
XIV. Patients who have liver dysfunction OR other serious liver disease.
XV. Patients who have diabetes neuropathy or any other neurological conditions.
XVI. Patients who have diabetes nephropathy or any other renal diseases with eGFR<60ml/min and/or overt proteinuria.
XVII. Patients who have serious cardiovascular disease or acute cardiovascular events within the past 6 months.
XVIII. Patients who had heart failure.
XIX. Patients who have cancer.
XX. Patients who have inflammatory bowel disease.
XXI. Patients who have difficulties in managing bloating and passing winds.
XXII. Patients who are bed-ridden or otherwise non-ambulatory.
XXIII. Patients who suffer digestive dysfunction or unexplained nausea, who have irregular or unusual bowel movements.
XXIV. Patient’s with other medical conditions and consumption of other medications will be assessed and is under discretion of the investigator.
XXV. Patients who have prior arrangements to travel longer than 4 weeks during the clinical trial conduct will not be eligible to participate.
XXVI. Patients with concomitant systemic diseases or a recent history of medical conditions which, in the opinion of the site investigator or sponsor medical monitor, would render patients at increased medical risk if they would participate in this study or would interfere with interpretation of the results of the study.

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)
Active and control groups will be efficiently balanced in respect to baseline FGL and diabetes duration. Randomization of patients into the treatment groups will be performed according to the following criteria.

At the time of visit, patients or the investigators will not be aware of their assignment into the treatment arms. A web-based computer program with appropriate algorithm will be employed to allocate patient into the study arms. After receiving all required information the randomisation program will allocate patients to an appropriate arm and will assign a three digit subject number with a three letter country code (i.e. AUS101).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation will be employed using a randomisation table created by computer software. The randomisation program will be linked to the database and will use the entered data to equally distribute subject into each treatment arms as described below. For stratification purpose, patients baseline fasting blood glucose levels and duration of diabetes will be used.

Stratification will be performed according to:

1) Screening Fasting Blood Glucose < 10 mmol/L & Duration of Diabetes < 5 yrs.

2) Screening Fasting Blood Glucose < 10 mmol/L & Duration of Diabetes = 5 yrs.

3) Screening Fasting Blood Glucose = 10 mmol/L & Duration of Diabetes < 5 yrs.

4) Screening Fasting Blood Glucose = 10 mmol/L & Duration of Diabetes = 5 yrs

Each site will be provided with four stratum, each stratum having the following information within a table at each column.

Column 1: ID (i.e. AUS101)
Column 2: Treatment (i.e. Sulphonylure or metformin plus sulphonlyurea + 13.5 gr OZ101)
Column 3: Name
Column 4: Specific Comments
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Both intention to treat and per protocol analyses will be conducted. The changes in FGL, HbA1c from the baseline to 12 (interim analysis) and 24 (final analysis) weeks after commencement of intervention will be compared between the three treatment groups using standard statistical techniques. The change in the levels of individual study parameters and their 95% confidence intervals will be computed. The significance of difference in the changes in average levels of the study parameters in two active study groups compared to the control group will be evaluated using the analysis of variance techniques. The trajectories of study parameters combining the baseline and follow-up data will be compared between the treatment groups using generalized estimating equation approach, as appropriate.

The repeated measures (3-days per week) of self-monitored blood glucose will be compared between the three groups using appropriate repeated-measure regression technique(s). Profile plots of the FGL, HbA1c, body weight and SMBG longitudinally over the 24 weeks of study will be presented.

The frequencies and rates of hypoglycaemia in the three treatment groups will be presented, and will be compared using appropriate statistical techniques. All adverse and serious adverse events will be reported for individual patients, and also by overall frequencies by treatment groups, following the FDA guideline on adverse event reporting.

The following assumption were used to calculate sample size.
Alpha 0.025 (to allow for multiple analysis).
Power 80%.
Two sided test.
Allow for 20% drop-out.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
2/04/2018
Actual
15/07/2018
Date of last participant enrolment
Anticipated
28/12/2018
Actual
31/01/2019
Date of last data collection
Anticipated
30/08/2019
Actual
14/09/2019
Sample size
Target
30
Accrual to date
Final
30
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment postcode(s) [1] 10219 0
2155 - Kellyville
Recruitment outside Australia
Country [1] 7124 0
India
State/province [1] 7124 0
Kalyan Nagar, Bangalore

Funding & Sponsors
Funding source category [1] 289561 0
Commercial sector/Industry
Name [1] 289561 0
OzStar Therapeutics Pty Ltd
Country [1] 289561 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
OzStar Therapeutic Pty Ltd
Address
9 Gardenia Place, Castle Hill, NSW, 2154
Country
Australia
Secondary sponsor category [1] 288243 0
None
Name [1] 288243 0
Address [1] 288243 0
Country [1] 288243 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291300 0
Bellberry Limited
Ethics committee address [1] 291300 0
Ethics committee country [1] 291300 0
Australia
Date submitted for ethics approval [1] 291300 0
06/08/2014
Approval date [1] 291300 0
15/07/2015
Ethics approval number [1] 291300 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 49738 0
Dr Shahnam Ajdari
Address 49738 0
Health Centre Point Pty Ltd, Kellyville Plaza - Shop 3, 90 Wrights Road, Kellyville, NSW 2155.
Country 49738 0
Australia
Phone 49738 0
+6128883 0800, +6128883 0811
Fax 49738 0
+6128883 0822
Email 49738 0
healthcentrepoint@gmail.com
Contact person for public queries
Name 49739 0
Nassim Jaberi
Address 49739 0
Health Centre Point Pty Ltd, Kellyville Plaza - Shop 3, 90 Wrights Road, Kellyville, NSW 2155.
Country 49739 0
Australia
Phone 49739 0
+6128883 0800, +6128883 0811
Fax 49739 0
+6128883 0822
Email 49739 0
jaberi_nassim@yahoo.com
Contact person for scientific queries
Name 49740 0
Nick Gorgani
Address 49740 0
OzStar Therapeutics Pty Ltd. P. O. Box 375, St Leonards, NSW 1590.
Country 49740 0
Australia
Phone 49740 0
+61466318921
Fax 49740 0
+61280728916
Email 49740 0
nick_gorgani@ozstartherapeutics.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
As per the patient information sheet and consent form individual patient data will not be available.


What supporting documents are/will be available?

No Supporting Document Provided



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.