Effect of liraglutide for weight management in paediatric subjects with Prader-Willi Syndrome.
A randomised, placebo controlled, parallel group, multi-centre, multinational trial with a 16-week double-blind period and 36-week open-label period.

Prader-Willi syndrome (PWS) is a genetic disorder characterised by hypotonia
with poor sucking reflex, feeding difficulties, and poor weight gain during
infancy, hypogonadism, growth hormone insufficiency causing short stature, mild
to moderate mental retardation, early childhood-onset hyperphagia and obesity.

Obesity typically manifests in early childhood and is a major cause of
morbidity and mortality and is strongly associated with multiple comorbid
conditions, including cardiopulmonary compromise, type 2 diabetes mellitus
(T2DM), hypertension, etc. Food-seeking behaviour is common in patients with
PWS. Left unchecked and untreated, lack of appetite control can lead to morbid
obesity. Therefore improvement in weight control remains the most important
goal of any PWS treatment programme.
For treatment and prevention of obesity in PWS, low calorie and well-balanced
diets with rigorous supervision and restriction of food access combined with
regularly scheduled meals and physical activities are recommended. The
treatment of obesity in PWS is difficult and requires a comprehensive
multidisciplinary approach with establishment of rigid structures to limit food
intake and promote supervised physical activity. Bariatric surgery is not
recommended for children with PWS.

The role of pharmacotherapy in PWS is uncertain. No medication has shown
long-term effectiveness in controlling appetite.
Liraglutide is a once-daily glucagon-like peptide-1 (GLP-1) analogue.
Liraglutide has unique therapeutic potential for the treatment of obesity, due
to its combined effects not only on body weight but also on glycaemic control
and other weight-related comorbidities. Liraglutide regulates appetite by
increasing feelings of fullness and satiety, while lowering feelings of hunger
and prospective food consumption.

Currently, there are no approved weight management pharmacotherapies for
children and adolescents within Europe, and in the US the only medication
approved by the FDA for children * 12 years of age is orlistat. Therefore there
is an unmet medical need for anti-obesity medication as an adjunct to lifestyle
interventions in this patient population.

Primary objective
- To compare the efficacy of liraglutide versus placebo on weight loss in obese
paediatric subjects with PWS at 16 weeks and versus no treatment at 52 weeks.

Secondary objectives
- To compare the efficacy of liraglutide versus placebo on glycaemic control in
obese children and adolescents with PWS at 16 weeks and versus no treatment at
52 weeks.
- To estimate the liraglutide steady state exposure in obese children and
adolescents with PWS after 16 weeks of treatment.
- To compare the safety of liraglutide versus placebo in obese children and
adolescents with PWS at 16 weeks and versus no treatment at 52 weeks.

This is a multi-centre, multi-national, randomised, parallel group,
placebo-controlled trial with a 16 week double-blind period and a 36-week
open-label period. This trial consists of a part A and a part B. Part A of the
trial is conducted in obese adolescents (* 12 and < 18 years, Tanner stage 2*5)
with PWS. Part B of the trial is conducted in obese children (* 6 and * 12
years, Tanner stage 1) with PWS. Entry into part A and part B of the trial will
be sequential. After all subjects in part A have completed the 16-week
double-blind period, an independent external Data Monitoring Committee (DMC)
will review the PK data and safety data from part A. Based on result of the
safety and PK data of NN8022-4181 and part A of NN8022-4179, the recommendation
for part B - PWS children (aged 6 to < 12 years) with obesity is to initiate
treatment with liraglutide/placebo based on weight.
Subjects will be randomised 2:1 to receive liraglutide or liraglutide placebo.
Part A has four strata as subjects are stratified according to Tanner stage 2*3
and 4*5 and by presence/absence of dysglycaemia. Part B includes subjects with
Tanner 1 development and has two strata for presence/absence of dysglycaemia,
see section 11.
Dysglycaemia is defined as pre-diabetes with FPG * 5.6 * 6.9 mmol/L (* 100-125
mg/dl) and/or HbA1c 5.7 * 6.4 % (both inclusive). The HbA1c and FPG results
from V2 must be used.
At least 30% of subjects will be from areas with lifestyle and nutrition
comparable to that in the European Union (EU). All subjects and/or their
legally acceptable representative (LAR) will undergo counselling for weight
loss and must be prescribed a structured programme for diet and physical
activity throughout the trial (from randomisation to the end of the trial).
Placebo injections will be stopped at week 16, at the end of the double-blind
period.
Subjects treated with growth hormone therapy may enter the trial and will have
no change in treatment plan with growth hormone from randomisation to the end
of the open-label period (subjects on growth hormone will stay on, and subjects
off growth hormone will stay off during this period. Adjustments to doses of
growth hormone are permitted).

Liraglutide or liraglutide placebo will be administered by once-daily
subcutaneous (s.c.) injections either in the abdomen, thigh, or upper arm.
During the 16-week double-blind period, subjects randomised to receive
liraglutide placebo will receive placebo s.c. injections with injection volumes
equivalent to the corresponding liraglutide dose. Injections can be
administered at any time of day irrespective of meals. It is recommended that
the time of injection is consistent throughout the trial. At the end-of the
double-blind period, subjects randomised to receive placebo will stop
injections once the investigator and subject are un-blinded to treatment
allocation. During the 36-week open-label period, subjects in the liraglutide
group will continue to receive liraglutide treatment. The maximum duration of
treatment of a single subject, from first trial product administration to last
trial product administration will be 52 weeks, and the maximum dose will be 3.0
mg/day in part A and 2.4 or 3.0 mg/day in part B.


Dose escalation will be based on tolerability as assessed by the investigator.
In part A and in part B for children with a body weight * 45 kg, treatment is
planned to be initiated with liraglutide/placebo 0.6 mg daily for one week and
increase in weekly steps of 0.6 mg until a maximum tolerated dose (MTD) (as
judged by the investigator) or a dose of 3.0 mg liraglutide/placebo is reached.
For children with a body weight < 45 kg in part B, dosing will be initiated
with liraglutide/placebo 0.3 mg daily for one week and increased to 0.6 mg
after the first week, thereafter the dose is increased in weekly steps of 0.6
mg until a MTD (as judged by the investigator) or a dose of 2.4 mg
liraglutide/placebo is reached.

The trial product dose will be escalated only if the current dose is tolerated.
If a subject has tolerability issues with the higher dose level (as judged by
the investigator), it is allowed to lower to the previous dose level.
If a trial product dose is poorly tolerated, subjects are allowed to remain at
a dose level for a maximum of 2 weeks. This extended time of one additional
week is allowed at each dose level, i.e. the dose escalation process may take
up to 8 weeks in total. It is at the discretion of the investigator to judge
when the subject has reached MTD

The trial consists of 20 visits in 54 weeks, 10 during the screening and double
blind period of 16 weeks, 9 during the open label period of 36 weeks and one
follow-up visit after an additional 2 weeks.
At 5 visits a physical exam will be performed.
During the trial a diary consisting of a dosing diary, hypoglycaemia diary and
a menstrual calendar needs to be completed by the patient or parent/legal
representative.
At 3 visits questionnaires/interviews (hyperphagia, PHQ-9 and C-SSRS; PHQ and
C-SSRS only applicable for part A) need to be completed.
Since liraglutide is a blood glucose lowering agent (blood glucose-dependent)
for safety reasons patients will be instructed in the use of a blood glucose
meter (will be provided to them).
As with all medication side-effects can occur (gastro-intestinal side effects,
pancreatitis, dehydration and decrease kidney function, gallstone disease,
injection site reactions, allergic reactions, hypoglycaemia, increased heart
rate, dizziness, decrease in appetite, changed sense of taste and feeling weak
or tired). These have been described extensively in the patient information.

There might also be some discomfort due to a more frequent blood testing during
the trial. At 12 visits blood samples will be collected (approximately 150 mL
in total). Laboratory blood sampling may cause bruising and infection but the
risk of this occurring in the trial is not higher than for normal laboratory
blood sampling.