Efficacy and safety of oral semaglutide versus placebo both in combination with metformin and/or basal insulin in children and adolescents with type 2 diabetes

Despite the increased prevalence and the potential short-term and long-term
risks associated with early onset of T2D, optimal regimens to treat children
and adolescents with T2D are not established. Treatment approaches are often
extrapolated from those used for adults. For many years, metformin was the only
globally approved non-insulin treatment for children and adolescents with T2D.

There is an unmet medical need for effective therapies that preserve or
sustainably improve beta-cell function in young patients with T2D.
Insulins are approved for the treatment of paediatric T2D; however, insulins
are associated with hypoglycaemia and weight gain and are therefore subject to
considerable clinical inertia, i.e. the failure to in a timely manner initiate
insulin or intensify the dose.

GLP-1 RAs have therefore been suggested as another treatment option when
glycaemic control is not achieved with metformin and insulin alone.
Recently, the GLP-1 RA liraglutide (Victoza®) was approved in the US and EU for
use in patients 10 years and older with T2D. To date, no studies in children or
adolescents with T2D have evaluated whether improvements in beta-cell function
(and other parameters central to the pathophysiology of diabetes) gained while
on treatment with GLP-1 RAs in clinical trials persist after treatment
cessation.

This study has been transitioned to CTIS with ID 2023-506923-27-00 check the CTIS register for the current data.

Primary objective
To confirm superiority of oral semaglutide at the maximum tolerated dose* (3
mg, 7 mg or 14 mg) versus placebo on glycaemic control in children and
adolescents (age 10 to <18 years) with type 2 diabetes on a background
treatment of metformin or basal insulin or both.


Secondary objectives
To assess and compare the efficacy of oral semaglutide at the maximum tolerated
dose (3 mg, 7 mg or 14 mg) versus placebo on a background treatment of
metformin or basal insulin or both on:
• Other parameters of glycaemic control
• Parameters of body composition
• Growth parameters
• Cardio-metabolic parameters
To assess and compare the safety and tolerability of oral semaglutide at the
maximum tolerated dose (3 mg, 7 mg or 14 mg) versus placebo on a background
treatment of metformin or basal insulin or both.

This is a randomised, double-blind, placebo-controlled, parallel-group,
multi-national, and multi-centre clinical trial that includes a 52-week
treatment period followed by a 12-week off-trial product follow-up period in
subjects aged 10 to <18 years (at randomisation) with T2D diagnosed according
to the most recent ADA criteria1. Subjects will be randomised in a 1:1 manner
to receive either oral semaglutide or oral semaglutide placebo (hereafter
referred to as placebo) once daily in addition to background treatment with
metformin or basal insulin or both, in addition to diet and exercise for 52
weeks. Randomisation will be stratified by sex (male or female) and by age (<14
years of age or >=14 years of age). The stratification is done to ensure an even
distribution of males vs. females and age groups across treatment groups.

The trial consists of a 2-week screening period during which time all screening
parameters must be assessed. If eligible according to the inclusion and
exclusion criteria, subjects are to be randomised to either oral semaglutide or
placebo treatment for 52 weeks. All subjects will be dose-escalated to an
individual maximum tolerated dose. For the duration of the trial, subjects
should be on stable background treatment with either metformin, basal insulin
or a combination of both, all in addition to diet and exercise. After the
52-week treatment period, all subjects will continue in a 12-week follow-up
period with visits at week 57 and week 64 (end-of-trial visit). The maximum
duration of the trial including the 2-week screening and the 12-week follow-up
period will be up to 66 weeks (2+52+12 weeks), with an additional 2 weeks if
the visit window is fully used.

Subjects will, after a 2-week screening period, be randomised in a 1:1 manner
to receive either oral semaglutide or placebo. All subjects will follow a dose
escalation regimen to an individualised maximum tolerated dose.

As a safety precaution, dose-escalation in the paediatric subjects will be
approached cautiously depending on pre-defined criteria for glycaemic control
and the subjects' tolerability to trial product. Subjects will receive a
starting dose of 3 mg for 4 weeks and then the dose will be escalated with
minimum 4-week intervals to 7 mg and then to 14 mg.

The dose will only be escalated if the pre-defined criteria for glycaemic
control are met: mean of three fasting self-measured plasma glucose (SMPG)
measurements > 6.1 mmol/L [>110 mg/dL] taken on three consecutive days prior
the visit and the individual subject*s tolerability for the trial product.

The end-of-treatment visit will be at week 52. After the 52-week treatment
period, all subjects will continue a 12-week off-trial product follow-up period
with visits at week 57 and week 64 (end-of-trial visit).

Data from the oral semaglutide clinical development programme in adults with
T2D has not revealed any safety issues that outweigh the benefits.

As the trial population will consist of children and adolescents with T2D, an
external independent Data Monitoring Committee (DMC) will monitor unblinded
subject safety data on an ongoing basis.

Assessment of diabetes control and adherence to standard of care treatment will
be provided throughout the trial. It is therefore concluded that the potential
benefits from participating in the trial outweigh the risks for oral
semaglutide as well as placebo treated subjects.