Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000765527p
Ethics application status
Submitted, not yet approved
Date submitted
10/06/2024
Date registered
24/06/2024
Date last updated
24/06/2024
Date data sharing statement initially provided
24/06/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Evaluating the biological activity of a single dose of encapsulated oral semaglutide in healthy adults over a period of one week.
Scientific title
Evaluating the biological activity of a single dose of encapsulated oral semaglutide in healthy adults over a period of one week.
Secondary ID [1] 312309 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Blood glucose control 334066 0
Insulin levels 334122 0
Condition category
Condition code
Metabolic and Endocrine 330732 330732 0 0
Normal metabolism and endocrine development and function

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Semaglutide is a long-acting GLP-1 analogue used in the treatment of patients with type 2 diabetes (T2D). It has shown to improve glycaemic control and result in meaningful weight loss. The drug has a well described safety profile including a low risk of hypoglycaemia.
This short duration pilot study will evaluate the biological activity of a single dose of 4mg of oral Semaglutide in Diabetology’s Axcess formulation.

The primary aim of the study is to determine whether, compared to a placebo, orally delivered encapsulated semaglutide is associated with a difference in plasma blood glucose levels during an intravenous glucose tolerance test (IVGTT). The secondary aims are to 1) explore changes in plasma insulin during an IVGTT, and 2) to explore the duration of action over a span of 7 days (Day 0 – Day 6).

The study is a single-arm, open label, pharmacodynamic study conducted under controlled conditions in clinical research setting in 8 healthy participants in Western Australia.

All assessments and drug administration will be carried out by an experienced clinical diabetes research nurse and supervised by the principal investigator (practising paediatric endocrinologist). The encapsulated oral semaglutide capsule used in this study, Oraglutide, has been developed by Diabetology Ltd under GMP PICS guidelines, and has been approved and released for use in this study. Oraglutide is an enteric-coated capsule which contains 4mg of GLP-1 receptor agonist semaglutide with “generally regarded as safe” (GRAS) substances (namely 70.6mg sodium chenodeoxycholate, 33.33mg propyl gallate, 1.08mg fumed silica, 9.69mg sodium starch, and 5mg sodium salt). The capsule is to be kept refrigerated at -2 to -8 degrees Celsius prior to use. Oraglutide comes in 4mg semaglutide capsules and will be administered once on day 0 of the study.


Screening visit: Will occur within 2 weeks of placebo. Prospective participants will have their medical history assessed and have 8mLs of blood drawn to confirm inclusion criteria. Eligible participants will be informed that their General Practitioner’s will be notified of their enrolment in the study

Visit Day -2: An intravenous glucose tolerance test (IVTT) will be performed in the morning of Day -2 with the participant having fasted for 10h, except for water. During this time, they are also to abstain from cigarettes, alcohol, caffeine, and vigorous exercise. All participants will receive one placebo capsule (capsule containing excipients only, i.e. formulation ingredients minus the semaglutide (active ingredient)) with a glass of 100mL water. The IVGTT testing will be conducted by an experienced clinical research nurse, two hours after placebo and before any food is consumed. It will involve an intravenous administration of 0.5g/kg of intravenous glucose (50% sterile solution); to a maximum dose of 35g. Blood samples (32mls of blood) for serum total insulin and plasma glucose levels will be collected at 5min and 0min pre-glucose IV administration, and 5-, 15-, 25-, 35-, 45-, and 60 min post-glucose IV administration. The IV glucose is administered over 3mins. Subjects will be provided with a questionnaire (adverse event log) on Day-2 to be used for recording any potential study-related effects (e.g.: nausea, vomiting, diarrhoea, headache, vision irregularities, hunger, loss of appetite). The clinician will review this record at each subsequent visit to determine whether any of these signs are treatment related, and to ascertain the history of treatment emergent and concomitant medicines.

Visit Day 0: The IVTT procedure for Day 0 will be performed at approximately the same time as Day -2 and the placebo will be replaced with a once off Oraglutide capsule (containing the same excipients as the placebo but with 4mg of Semaglutide (active ingredient)). The clinician will review the adverse event log to determine whether any of these signs are treatment related.

Visit Days 1, 4 and 6: The IVTT procedure will also be performed on Days 1, 4, and 6 at approximately the same time as on days -2 and 0. No capsules will be administered on these days. The clinician will review the adverse event log at each visit.

Study participation is voluntary, and participants may withdraw at any time. Those who withdraw from the study after commencing on oral semaglutide, will be followed-up for adverse events and concomitant medications for the full week after taking the semaglutide. Should any treatment-emergent adverse events be reported, this will also be included in the DSMB report.
Participants who withdraw from the study will need to be replaced, as the study is powered for a sample size of 8 with completed data.

Both placebo and Oraglutide capsules will be administered during the clinic visit. The clinical diabetes research nurse will ensure that participants ingest the whole capsule at their respective visit.




Intervention code [1] 328784 0
Treatment: Drugs
Comparator / control treatment
Participants will act as their own control 2 weeks prior to the administration of 4mg of semaglutide.
The placebo capsule will contain the same excipient ingredients as the Oraglutide (in other words, the only missing ingredient in the capsule will be the 4mg of semaglutide)
Control group
Placebo

Outcomes
Primary outcome [1] 338494 0
The primary endpoint of the study will be glucose area under the curve as assessed over a one-hour intravenous glucose tolerance test (BGL-AUC0-60).
Timepoint [1] 338494 0
The primary comparison of interest will be between Day 0 (encapsulated semaglutide) and Day -2 (Placebo). Secondary exploratory analysis comparing Day -2 to Day 1, Day 4 and Day 6 will be conducted.
For each day, the timepoints of interest will be at time of ingestion of capsule (Placebo or oraglutide), and 5, 15, 25, 35, 45, and 60mins after ingestion.
Secondary outcome [1] 436147 0
The secondary endpoint of the study will be insulin area under the curve as assessed over a one-hour intravenous glucose tolerance test (Ins-AUC0-60).
Timepoint [1] 436147 0
The primary comparison of interest will be between Day 0 (encapsulated semaglutide) and Day -2 (Placebo). Secondary exploratory analysis comparing Day -2 to Day 1, Day 4 and Day 6 will be conducted.
For each day, the timepoints of interest will be at time of ingestion of capsule (Placebo or oraglutide), and 5, 15, 25, 35, 45, 60mins after ingestion.

Eligibility
Key inclusion criteria
• Adequate renal function defined as a GFR greater or equal 30 mL/min/1.73m2.
• Female patients of childbearing potential must have a negative serum pregnancy test at screening and practice effective birth control for the duration of the trial.
• Male patients must agree to practice effective contraceptive methods during the course of the study.
• Are able and willing to sign an informed consent to participate in the study.
• Able and willing to adhere to the study requirements, specifically: follow the study visit and assessment schedules, take the study medications as indicated.
Minimum age
18 Years
Maximum age
60 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
• Type 1 diabetes
• Type 2 diabetes
• Diabetes attributable to other secondary causes (e.g., genetic syndromes, secondary pancreatic diabetes, diabetes due to endocrinopathies, drug- or chemical-induced, and post-organ transplant).
• Treatment involving GLP-1 receptor agonists within 3 months prior to Visit 1.
• Have a history of acute or chronic pancreatitis.
• Have a known clinically significant gastric emptying abnormality (e.g., severe diabetic gastroparesis or gastric outlet obstruction).
• Have undergone or plan to have bariatric surgery during the course of the study.
• Have uncontrolled hypertension defined as SBP/DBP greater or equal to 160/100 mmHg.
• Have a history of cardiac disease.
• Have an estimated GFR < 30 mL/min/1.73m2
• Any condition that is currently being treated or may be treated with systemic corticosteroids or biologics during the course of the study; topical, intra-nasal and inhaled corticosteroids are allowed.
• Any current or history of any condition that may affect the patient’s participation in the study.
• Any current or history of any condition that in the opinion of the investigator participation in the study may increase the risk to the patient.
• Female patients that are pregnant or are breastfeeding or plan to breastfeed during the course of the study.
• Laboratory abnormalities at screening including:
o C-peptide < 0.4 ng/mL
o Abnormal serum thyrotropin (TSH) levels below the lower limit of normal or >1.5X the upper limit of normal; a single repeat test is allowable.
o Elevated liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) >3X the upper limit of normal; a single repeat test is allowable.
o Very high fasting triglyceride levels (>600 mg/dL); a single repeat test is allowable.
• Any relevant abnormality that would interfere with the study assessments.
• History of or current active liver disease (other than non-alcoholic hepatic steatosis), primary biliary cirrhosis, or active symptomatic gallbladder disease.
• Positive results for human immunodeficiency virus (HIV) antibodies, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C virus ribonucleic acid (RNA).
• Active or history of neoplastic disease (except for adequately treated non-invasive basal cell and/or squamous cell carcinoma or carcinoma in situ of the cervix) within the past 5 years prior to Baseline.
• Use of the following medications:
o Thyroid preparations or thyroxine (except in subjects on stable replacement therapy) within 6 weeks prior to screening.
o systemic (oral, intravenous, intramuscular) glucocorticoid therapy (in the last 12 months) or may require them for more than 2 weeks during the study period. Intra-articular and/or topical corticosteroids are not considered systemic.
o Any medications known to modify glucose metabolism or to decrease the ability to recover from hypoglycemia such as oral, parenteral, and immunosuppressive or immunomodulating agents. Inhaled nasal steroids are permissible.
• Involvement in a weight loss program and is not in the maintenance phase, or subject has started weight loss medication (e.g., orlistat or liraglutide) within 3 months prior to screening.
• Subject is a user of recreational or illicit drugs or has had a recent history (within 1 year of screening) of drug or alcohol abuse or dependence. (Note: Alcohol abuse includes heavy alcohol intake as defined by >3 drinks per day or >14 drinks per week or binge drinking) at screening. Occasional intermittent use of cannabinoid products will be allowed provided that no cannabinoid products have been used during the 1 week prior to each visit.
• A history of gastrointestinal disorders (e.g., hypochlorhydria) or gastroparesis with the potential to interfere with drug absorption.
• Any condition or other factor (at the Investigator's discretion) that is deemed unsuitable for subject enrolment into the study.
• Enrolled in another clinical trial involving an investigational product within 30 days of the screening visit.
• Is not able to understand and sign the informed consent of the study.

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
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Crossover
Other design features
Phase
Phase 0
Type of endpoint/s
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis
General Considerations:
Descriptive statistics will be produced for relevant demographic and clinical characteristics of the study sample; means (with standard deviations), medians (with interquartile ranges), or count/percentages will be presented as appropriate.
Means (with standard deviations) and medians (with interquartile ranges) will be presented BGL-AUC0-60 and Ins-AUC0-60 at each study day (-1,0,3,6).
To meet the primary aim of the study, a paired t-test comparing placebo (-1) and drug delivery day (day 0) will be conducted for BGL-AUC0-60; the mean difference and 95% confidence intervals will be presented.
To explore the duration of action of BGL-AUC0-60 and Ins-AUC0-60, one-way repeated measures ANOVA will be conducted. Planned pairwise comparisons between baseline (-1) and later study days (0, 3, and 6) will be conducted using Dunnet’s method to control for multiple comparisons.
Sample Size
Based on the results collected in animal studies of encapsulated oral semaglutide and blood glucose, this study is being powered to detect an effect size of 1.2. With alpha set at 0.05, a total of 8 participants, who complete all study visits, will be required to provide at least 80% power to detect this effect.
Study Power and Significance
A p-value of <0.05 will be considered statistically significant.
Statistical plan deviations:
Any deviations to the original statistical plan will be reported to relevant ethics committees as an amendment to the scientific protocol and in the manuscript.
Selection of participants for analyses:
Data from all participants who have completed their 6-days post treatment IVGTTs will be included in the study.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
24/06/2024
Actual
Date of last participant enrolment
Anticipated
24/06/2025
Actual
Date of last data collection
Anticipated
14/07/2025
Actual
Sample size
Target
8
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 26668 0
Perth Children's Hospital - Nedlands
Recruitment postcode(s) [1] 42708 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 316702 0
Hospital
Name [1] 316702 0
Perth Children's Hospital
Country [1] 316702 0
Australia
Funding source category [2] 316705 0
Government body
Name [2] 316705 0
Child and Adolescent Health Service
Country [2] 316705 0
Australia
Primary sponsor type
Individual
Name
Professor Timothy W Jones
Address
Country
Australia
Secondary sponsor category [1] 318904 0
Government body
Name [1] 318904 0
Child and Adolescent Health Service
Address [1] 318904 0
Country [1] 318904 0
Australia

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 315482 0
South Metropolitan Health Service Human Research Ethics Committee
Ethics committee address [1] 315482 0
Ethics committee country [1] 315482 0
Australia
Date submitted for ethics approval [1] 315482 0
30/04/2024
Approval date [1] 315482 0
Ethics approval number [1] 315482 0

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

Contacts
Principal investigator
Name 134830 0
Prof Timothy W Jones
Address 134830 0
Perth Children's Hospital, 15 Hospital Avenue, Nedlands, WA 6009
Country 134830 0
Australia
Phone 134830 0
+61 08 6456 5033
Fax 134830 0
Email 134830 0
[email protected]
Contact person for public queries
Name 134831 0
Prof Timothy W Jones
Address 134831 0
Perth Children's Hospital, 15 Hospital Avenue, Nedlands, WA 6009
Country 134831 0
Australia
Phone 134831 0
+61 08 6456 5033
Fax 134831 0
Email 134831 0
[email protected]
Contact person for scientific queries
Name 134832 0
Timothy W Jones
Address 134832 0
Perth Children's Hospital, 15 Hospital Avenue, Nedlands, WA 6009
Country 134832 0
Australia
Phone 134832 0
+61 08 6456 5033
Fax 134832 0
Email 134832 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
On de-identified aggregate data will be published and made available to the public


What supporting documents are/will be available?

Current supporting documents:
Doc. No.TypeCitationLinkEmailOther DetailsAttachment
23866Study protocol  [email protected] 387943-(Uploaded-10-06-2024-15-12-17)-4929_232492_RGS6856_Scientific Protocol V2.0 .pdf


Updated to:
Doc. No.TypeCitationLinkEmailOther DetailsAttachment
23866[Marked for deletion] Study protocol  [email protected] 387943-(Uploaded-16-08-2024-19-44-07)-236361_RGS6856_Scientific Protocol V3.0_26Jun2024 .pdf
24110[Marked for deletion] Ethical approval  [email protected] 387943-(Uploaded-16-08-2024-19-43-02)-RGS6856_SMH HREC LOA_01 Jul 2024.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.