Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000764730
Ethics application status
Approved
Date submitted
28/04/2022
Date registered
27/05/2022
Date last updated
13/06/2023
Date data sharing statement initially provided
27/05/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Investigating the effect of oral insulin on glycaemia
Scientific title
The effect of oral insulin on subcutaneous insulin requirements and glycaemia in adolescents and young adults with Type 1 Diabetes (T1DM)
Secondary ID [1] 307006 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 1 Diabetes 326125 0
Condition category
Condition code
Metabolic and Endocrine 323450 323450 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The proposed pilot study aims to provide preliminary data of whether oral insulin is acceptable and can be used as an adjunct therapeutic intervention in individuals with Type 1 diabetes (T1D), and to use the information obtained to inform a future randomised controlled trial specifically designed to assess the efficacy of oral insulin as an adjunct to current insulin therapy.

The proposed pilot study is a prospective, 12-week, single-arm study in 10 adolescents/adults with T1D in Western Australia.

All assessments and drug administration will be carried out by an experience clinical diabetes research nurse and a paediatric endocrinologist. The study will be supervised by the principal investigator or associate investigator, both being practising paediatric endocrinologists. The oral insulin capsule used in this study, CapsulinTM, has been developed by Diabetology Ltd and is based on their patented Axcess delivery system. Capsulin is an enteric-coated capsule which contains unmodified human recombinant insulin with a mixture of well-characterized and “generally regarded as safe” (GRAS) substances which facilitate the transport of insulin through the intestinal wall and into the portal circulation. The capsule is stable at room temperature for 18 months.
Capsulin comes in 150 IU dose capsules, and will be provided to the participants in bottles
fitted with a tracking cap (Aardex) to monitor adherence to prescribed dose and time of dosing.

Participants will attend 5 clinic visits throughout the study:

(1) Visit 1 (week 0) - Participants will confirm their consent to the study, undergo baseline anthropometric, glycaemic and metabolic measurements, and participate in a 5-h meal challenge during which blood will be collected to test levels of gut hormones and glycaemic biomarkers. During this visit, participants will be provided with sufficient sensors for 2 weeks, have their pump set up, and those who are using the Medtronic 670G pump will be offered an additional continuous glucose monitor (CGM, Dexcom G6) to allow research staff to monitor the participants glucose levels in real-time. At the end of the meal challenge, participants will be educated on the appropriate timing of the oral insulin dosing (1 tablet of 150IU Capsulin taken once daily, half an hour before a main meal, for one week) and have a review of home hypoglycaemia management before leaving the clinic. To note that during the first three weeks from commencement of the oral insulin, participants will be followed in real-time using the follow-function of the closed loop system or Dexcom G6. Low alerts will be enabled on the phone which will permit immediate correction of hypoglycaemia. Adjustments will be made to the pump settings if required.
(2) Visit 2 (week 1) – Participants will have a clinical review of their total insulin dose, insulin sensitivity factors, insulin-carbohydrate ratios and CGM metrics. Assessment of Capsulin use and adverse events will be carried out through the review of the logbook and Aardex cap history. Participants will be provided with Capsulin for 5 weeks and will be instructed to commence intake of one tablet of 150IU Capsulin twice daily, half an hour before a main meal.
(3) Visit 3 (week 6) - Participants will have a clinical review of their total insulin dose, insulin sensitivity factors, insulin-carbohydrate ratios and CGM metrics. Assessment of Capsulin use and adverse events will be carried out through the review of the logbook and Aardex cap history. CGM data and pump settings will be downloaded. Participants will be provided with Capsulin for the remaining 6 weeks and will be advised to continue intake of 150IU Capsulin twice daily, half an hour before a main meal. By Week 3, participants will have weekly contact with the research staff for the monitoring and review of their CGM.
(4) Visit 4 (week 12) – Participants will undergo end-of-study anthropometric, glycaemic and metabolic measurements, and participate in a 5-h meal challenge during which blood will be collected to test levels of gut hormones and glycaemic biomarkers. CGM data and pump settings will be downloaded. Participants will be asked to report on appetite and impact on dietary intake, perceived weight loss and well-being.
(5) Visit 5 (week 14) – CGM data and pump settings will be downloaded to ensure that participants are back on baseline therapy.

For the 5-h meal challenge in visits 1 and 4, participants will have to attend the clinic after an overnight fast and have a subcutaneous bolus administered before consuming a standard meal. The standard meal will have a balance macronutrient composition (66% carbohydrate, 18% fat and 16% protein) and will need to be consumed within 20mins. No other oral intake (except for water) will be allowed during the monitoring period.

Study participation is voluntary, and participants may withdraw at any time. Participants will be asked to discontinue the study if they have had severe hypoglycaemia (seizure or coma or any episodes requiring glucagon) or severe diabetic ketoacidosis (venous pH <7.2) or have been non-compliant with the medication which in the judgement of the investigator increases risk for the participant.
Intervention code [1] 323459 0
Treatment: Drugs
Intervention code [2] 323460 0
Lifestyle
Intervention code [3] 323461 0
Prevention
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 331197 0
Composite outcome - Total insulin dose (units/kg/day) and proportion of basal and bolus insulin - assessed using pump data and insulin dose from Capsulin
Timepoint [1] 331197 0
At Visit 1 (baseline), Visit 2 (week 1 post-intervention commencement), Visit 3 (week 6 post-intervention commencement) and Visit 4 (week 12 post-intervention commencement)
Secondary outcome [1] 409145 0
Body Mass index z-scores - Height determined by stadiometer and weight determined using digital scales.
Timepoint [1] 409145 0
Visit 1 (Baseline) and Visit 4 (week 12 post-intervention commencement)
Secondary outcome [2] 409186 0
Metabolic biomarkers - Lipid profile. Assessed from venous blood
Timepoint [2] 409186 0
Visit 1 (Baseline) and Visit 4 (week 12 post-intervention commencement)
Secondary outcome [3] 409187 0
Metabolic biomarkers - Liver function test. Assessed from venous blood
Timepoint [3] 409187 0
Visit 1 (Baseline) and Visit 4 (week 12 post-intervention commencement)
Secondary outcome [4] 409188 0
Metabolic biomarkers - HbA1c. Assessed from venous blood
Timepoint [4] 409188 0
Visit 1 (Baseline) and Visit 4 (week 12 post-intervention commencement)
Secondary outcome [5] 409189 0
Gut hormone levels - Glucagon, Assessed from venous blood
Timepoint [5] 409189 0
Visit 1 (Baseline) and Visit 4 (week 12 post-intervention commencement)
Secondary outcome [6] 409190 0
Safety with the use of oral insulin - adverse events and severe adverse events (severe hypoglycaemia and diabetes ketoacidosis) assessed from self-reported log book and reported hospital admission
Timepoint [6] 409190 0
At Visit 1 (baseline), Visit 2 (week 1 post-intervention commencement), Visit 3 (week 6 post-intervention commencement) and Visit 4 (week 12 post-intervention commencement)
Secondary outcome [7] 409191 0
Recruitment rate - assessed by audit of study enrolment logs
Timepoint [7] 409191 0
Visit 1 (Baseline) and Visit 4 (week 12 post-intervention commencement)
Secondary outcome [8] 409192 0
Adherence to oral insulin medication - assessed using Aardex tracking data
Timepoint [8] 409192 0
At Visit 1 (baseline), Visit 2 (week 1 post-intervention commencement), Visit 3 (week 6 post-intervention commencement) and Visit 4 (week 12 post-intervention commencement)
Secondary outcome [9] 409194 0
Patient-reported outcome - experiences with oral insulin on appetite - captured in study-specific questionnaire
Timepoint [9] 409194 0
Visit 4 (week 12 post-intervention commencement)
Secondary outcome [10] 409199 0
Continuous Glucose Monitoring (CGM) metrics for glucose effectiveness (mean SG) - assessed using CGM data
Timepoint [10] 409199 0
At Visit 1 (baseline), Visit 2 (week 1 post-intervention commencement), Visit 3 (week 6 post-intervention commencement) and Visit 4 (week 12 post-intervention commencement)
Secondary outcome [11] 409819 0
Gut hormone levels - Glucagon-like polypeptide-1 (GLP-1). Assessed from venous blood
Timepoint [11] 409819 0
Visit 1 (Baseline) and Visit 4 (week 12 post-intervention commencement)
Secondary outcome [12] 409820 0
Gut hormone levels - glucose-dependent insulinotropic polypeptide (GIP). Assessed from venous blood
Timepoint [12] 409820 0
Visit 1 (Baseline) and Visit 4 (week 12 post-intervention commencement)
Secondary outcome [13] 409821 0
Retention rate - assessed by number of withdrawals
Timepoint [13] 409821 0
Visit 1 (Baseline) and Visit 4 (week 12 post-intervention commencement)
Secondary outcome [14] 409822 0
Patient-reported outcome - experiences with oral insulin on GI disturbances - captured in study-specific questionnaire
Timepoint [14] 409822 0
Visit 4 (week 12 post-intervention commencement)
Secondary outcome [15] 409823 0
Patient-reported outcome - experiences with oral insulin on Glycaemic outcomes (Time in range in euglycaemia, time in range in hypoglycaemia and time in range in hyperglycaemia)- captured in study-specific questionnaire
Timepoint [15] 409823 0
Visit 4 (week 12 post-intervention commencement)
Secondary outcome [16] 409824 0
Continuous Glucose Monitoring (CGM) metrics for percentage time in range (3.9 - 10 mmol/L) - assessed using CGM data
Timepoint [16] 409824 0
At Visit 1 (baseline), Visit 2 (week 1 post-intervention commencement), Visit 3 (week 6 post-intervention commencement) and Visit 4 (week 12 post-intervention commencement)
Secondary outcome [17] 409825 0
Continuous Glucose Monitoring (CGM) metrics for percentage time in hypoglycaemia (<3 and < 3.9mmol/L) - assessed using CGM data
Timepoint [17] 409825 0
At Visit 1 (baseline), Visit 2 (week 1 post-intervention commencement), Visit 3 (week 6 post-intervention commencement) and Visit 4 (week 12 post-intervention commencement)
Secondary outcome [18] 409826 0
Continuous Glucose Monitoring (CGM) metrics for percentage time in hyperglycaemia (>10 and >13.9mmol/L) - assessed using CGM data
Timepoint [18] 409826 0
At Visit 1 (baseline), Visit 2 (week 1 post-intervention commencement), Visit 3 (week 6 post-intervention commencement) and Visit 4 (week 12 post-intervention commencement)
Secondary outcome [19] 409827 0
Continuous Glucose Monitoring (CGM) metrics for glycaemic variability (coefficient of variation and standard deviation) - assessed using CGM data
Timepoint [19] 409827 0
At Visit 1 (baseline), Visit 2 (week 1 post-intervention commencement), Visit 3 (week 6 post-intervention commencement) and Visit 4 (week 12 post-intervention commencement)

Eligibility
Key inclusion criteria
1. T1D of at least 1 year duration,
2. C-peptide less than 0.1nmol/l (in the absence of hypoglycaemia)
3. Age 16 - 25 years
4. On Medtronic 670G/770G (using closed loop system for greater than or equal to 70% of the time in last 2 weeks and no plans to change the management during the study period.
5. HbA1c less than 7.5%
6. Ready to meet the requirements of the protocol.
7. Has the ability to download the insulin pump if on Medtronic 670G (Medtronic 770G users have automatic download)
8. English speaking, living in an area with internet and cellular phone coverage
Minimum age
16 Years
Maximum age
25 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Recent significant change in HbA1c exceeding 1.5% over the past 3 to 4 months.
2. Use of any non-insulin glucose-lowering agent.
3. Pregnancy, comorbidities: Renal dialysis/transplant or glomerular filtration rate <60ml/min/m2, malabsorption, coeliac disease, active liver disease, islet cell/pancreatic transplant

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised 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)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
This sample size was chosen based on providing estimates of the mean and variance of outcome measures to within a degree of precision acceptable to inform the power calculation for a definitive trial. Appropriate descriptive statistics (frequencies (%), mean (SD), median (IQR)) will be presented for all sociodemographic and clinical characteristics of the sample. Mean and standard deviation, along with their 95% confidence interval, will be presented for continuous/interval outcome measures of interest in each phase and for the paired difference between baseline and end of study. The SD for the primary outcome (change in average total daily insulin delivered subcutaneously) will be presented along with the upper value of a one-sided 80% confidence interval.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
30/05/2022
Actual
12/04/2023
Date of last participant enrolment
Anticipated
1/12/2023
Actual
Date of last data collection
Anticipated
1/03/2024
Actual
Sample size
Target
10
Accrual to date
2
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 22286 0
Perth Children's Hospital - Nedlands
Recruitment postcode(s) [1] 37448 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 311317 0
Hospital
Name [1] 311317 0
Perth Children's Hospital
Country [1] 311317 0
Australia
Funding source category [2] 311333 0
Government body
Name [2] 311333 0
Child and Adolescent Health Service
Country [2] 311333 0
Australia
Funding source category [3] 311334 0
Charities/Societies/Foundations
Name [3] 311334 0
Diabetes Research Western Australia
Country [3] 311334 0
Australia
Primary sponsor type
Government body
Name
Child and Adolescent Health Service
Address
15 Hospital Avenue
Nedlands
Western Australia 6009
Country
Australia
Secondary sponsor category [1] 312689 0
None
Name [1] 312689 0
Address [1] 312689 0
Country [1] 312689 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310820 0
Child and Adolescent Health Service HREC
Ethics committee address [1] 310820 0
15 Hospital Avenue
Nedlands
Western Australia 6009
Ethics committee country [1] 310820 0
Australia
Date submitted for ethics approval [1] 310820 0
21/09/2021
Approval date [1] 310820 0
16/03/2022
Ethics approval number [1] 310820 0
RGS5014

Summary
Brief summary
Subcutaneous insulin therapy in the form of insulin injections or insulin pump therapy has been the cornerstone of insulin delivery for people with Type 1 diabetes (T1D). Despite advancements in monitoring and improved delivery systems, most people with T1D are not able to achieve optimal glucose levels. This raises the need to look for alternative modes of insulin delivery which are non-invasive, likely to be less challenging and more acceptable in long-term. Apart from the mode of administration, oral insulin has the added advantage of replicating a near-physiological state with reduced levels of insulin in blood and thereby confers a ‘lower risk of hypoglycaemia’.. Many oral insulin preparations have been trialled, especially in the last two decades, although with limited success, especially due to the challenges in absorption of the oral medications. Improved oral drug delivery systems designed to address these barriers have provided a new horizon to explore this avenue further.
A multicentre 12-week clinical trial using oral insulin has recently demonstrated efficacy in adults with early-stage of Type 2 diabetes. Oral insulin caused a clinically meaningful reduction in glucose levels without hypoglycaemia. Hence, there is promise in exploring its potential in T1D. This proposed study is designed as the first step to explore the possibility of using oral insulin in T1D as an adjunct to current management.
The proposed pilot study is a 12-week single-arm observational study in 10 adolescents/adults with T1D in Western Australia. Oral insulin will be administered to participants on closed loop therapy and a range of clinical, metabolic and safety outcomes will be collected. The proposed study aims to provide preliminary data of whether oral insulin is acceptable and can be used as an adjunct therapeutic intervention in individuals with T1D, and to use the information obtained to inform a future randomised controlled trial specifically designed to assess the efficacy of oral insulin as an adjunct to current insulin therapy. The 12-week study will provide sufficient duration to review glycaemic outcomes that can be measured by HbA1c and metrics from continuous glucose monitoring (CGM).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 118978 0
Prof Timothy W Jones
Address 118978 0
Perth Children's Hospital
15 Hospital Avenue,
Nedlands
Western Australia 6009
Country 118978 0
Australia
Phone 118978 0
+61 864565033
Fax 118978 0
Email 118978 0
tim.jones@health.wa.gov.au
Contact person for public queries
Name 118979 0
Miss Julie Dart
Address 118979 0
Perth Children's Hospital
15 Hospital Avenue,
Nedlands
Western Australia 6009
Country 118979 0
Australia
Phone 118979 0
+61 864564608
Fax 118979 0
Email 118979 0
julie.dart@health.wa.gov.au
Contact person for scientific queries
Name 118980 0
Dr Mary Abraham
Address 118980 0
Perth Children's Hospital
15 Hospital Avenue,
Nedlands
Western Australia 6009
Country 118980 0
Australia
Phone 118980 0
+61 86456 5027
Fax 118980 0
Email 118980 0
mary.abraham@health.wa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
The outcomes of this research will be submitted for publication in peer reviewed journals and for presentation at scientific meetings. The project results will be disseminated to patients and families through the bi-monthly newsletter and parent evenings, and to the clinicians at the departmental meeting. Thus, no individual participant data will be shared.


What supporting documents are/will be available?

Current supporting documents:
Doc. No.TypeCitationLinkEmailOther DetailsAttachment
15892Study protocol  mary.abraham@health.wa.gov.au 383980-(Uploaded-28-04-2022-15-22-12)-Study-related document.pdf
15893Ethical approval  mary.abraham@health.wa.gov.au 383980-(Uploaded-28-04-2022-15-22-49)-Study-related document.pdf


Updated to:
Doc. No.TypeCitationLinkEmailOther DetailsAttachment
15892Study protocol  mary.abraham@health.wa.gov.au 383980-(Uploaded-28-04-2022-15-22-12)-Study-related document.pdf
15893Ethical approval  mary.abraham@health.wa.gov.au 383980-(Uploaded-28-04-2022-15-22-49)-Study-related document.pdf
23793Study protocol  mary.abraham@health.wa.gov.au 383980-(Uploaded-28-05-2024-18-10-35)-RGS5014 - Oral Insulin on Glycaemia Scientific Protocol V10 12.12.2023 .pdf
23794Ethical approval  mary.abraham@health.wa.gov.au 383980-(Uploaded-28-05-2024-18-12-03)-RGS5014_Amend 12.12.2024_Ethics approval.pdf

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.