This study has been transitioned to CTIS with ID 2023-506927-27-00 check the CTIS register for the current data. Primary objectiveThe primary objective of this study is to confirm non-inferiority of once-weekly somapacitan compared with once-daily…
ID
Source
Brief title
Condition
- Other condition
- Endocrine and glandular disorders NEC
Synonym
Health condition
groeistoornis
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Height velocity reported for each indication separately. From baseline (week 0)
to visit 7 (week 52) in cm/year
Secondary outcome
Key secondary endpoints
- Change in Height SDS reported for each indication separately. From baseline
(week 0) to visit 7 (week 52). Unit: -10 to +10
- Change in IGF-I SDS reported for each indication separately. From baseline
(week 0) to visit 7 (week 52). Unit: -10 to +10
- Change in fasting plasma glucose reported for each indication separately.
From screening (visit 1) to visit 7 (week 52) in mmol/L
- Change in fasting plasma glucose reported for each indication separately.
From screening (visit 1) to visit 15 (week 156) in mmol/L
- Weekly average somapacitan concentration (Cavg) based on population PK
analysis. From visit 3 (week 4) to visit 7 (week 52) in ng/mL
Background summary
Short stature
Short stature can be due to various aetiologies and the cause may be a primary
or secondary growth disorder, or idiopathic. Primary growth disorders are
intrinsic to the growth plate and include clinically defined syndromes and
factors that result in being born small for gestational age (SGA). Secondary
growth disorders are believed to change the milieu of the growth plate and
include growth hormone (GH) deficiency, disorders of the insulin-like growth
factor (IGF)-I axis including IGF-I deficiency or resistance, endocrine and
metabolic disorders, organ system disorders, malnutrition, psychosocial
disorders, and iatrogenic conditions. A combined approach of systematic
phenotyping, targeted genetic testing and whole-exome sequencing allows the
identification of the underlying cause of ISS in at least 33% of cases. The
majority, however, have no identified cause. The condition is very
heterogeneous and may be either familial or non-familial. While the list of
secondary growth disorders has hardly changed over the last decades, the number
of primary growth disorders has considerably increased due to the expanding use
of novel genetic techniques.
Treatment of short stature
GH increases growth by both a direct action on the growth plates as well as by
stimulating IGF-1 secretion, mainly in the liver. Human GH (hGH) also has
important effects on the metabolism of proteins, lipids and carbohydrates, not
only during childhood, but also throughout adult life. It is critically
important to maximize height with GH therapy before the onset of puberty. The
earlier GH is commenced, the more likely the child is to achieve a height that
is appropriate for the target height.
In children who have a deficiency of endogenous GH (GHD), the use of GH
replacement therapy stimulates linear growth and increases growth rate. In
1985, when biosynthetic GH became available on a large-scale, a large number of
clinical studies investigating the effect of GH in various indications
associated with short stature and normal GH secretion were initiated. In the
years that followed, recombinant human GH (rhGH) treatment was approved for use
in various other indications. It was first approved for treatment of children
with chronic renal insufficiency in 1993, Turner syndrome (TS) in 1990,
Prader-Willi syndrome (PWS) in 2000, short children born small for gestational
age (SGA) in 2001, children with idiopathic short stature (ISS) in 2003, and
children with Noonan syndrome (NS) in 2007. The rationale for this treatment is
based on the empirical observation of growth acceleration in response to GH
administration, rather than on a pathophysiological approach.
Study objective
This study has been transitioned to CTIS with ID 2023-506927-27-00 check the CTIS register for the current data.
Primary objective
The primary objective of this study is to confirm non-inferiority of
once-weekly somapacitan compared with once-daily Norditropin® in terms of
longitudinal growth measured by height velocity at week 52 in children with
each of the four indications SGA, TS, NS or ISS.
Key secondary objectives
The key secondary objectives of this study are to evaluate both other aspects
of longitudinal growth and to evaluate safety, including long-term safety, of
once-weekly somapacitan compared with once-daily Norditropin® in terms of
safety parameters measured by glucose metabolism in children with each of the
four indications SGA, TS, NS or ISS.
Furthermore, it is to evaluate the steady state pharmacokinetics of once-weekly
somapacitan in children with each of the four indications: SGA, TS, NS or ISS.
Study design
This is an interventional, multi-national, multi-centre, randomised,
open-labelled, active comparator, phase 3 basket study designed to compare the
effect and safety of once weekly dosing of somapacitan versus daily
Norditropin® after 52 weeks in GH treatment naïve children with short stature
in each of the indications SGA, TS, NS or ISS. The main treatment phase will be
followed by 104 weeks extension to further evaluate safety. The study includes
four sub-studies - one for each of the above listed indications.
The study consists of:
• an up to 3-week screening period (Up to 6 weeks for TS and NS)
• a 52-week intervention period
• a 104-week extension period
• a 30-day follow-up period
Intervention
SGA: Eligible participants will be randomised in a 2:1:1 manner to receive
either somapacitan 0.24 mg/kg/week (2 out of 4 participants), Norditropin®
0.035 mg/kg/day (1 out of 4) or Norditropin® 0.067 mg/kg/day (1 out of 4).
TS, NS and ISS: Eligible participants will be randomised in a 2:1 manner to
receive either somapacitan 0.24 mg/kg/week (2 out of 3 participants) or
Norditropin® 0.05 mg/kg/day (1 out of 3).
Treatments will be administered subcutaneously. The 52 weeks treatment period
will be followed by a 2-year 1-arm extension period with once-weekly dosing of
somapacitan 0.24 mg/kg/week to evaluate safety.
Study burden and risks
Benefit assessment
Information gained from this study will support the development of a growth
hormone product with clinical advantages over currently available products to
children with SGA, TS, NS and ISS.
For most of the participating children the administration of study intervention
during the study most likely reduces the treatment burden compared to current
available therapy as somapacitan is administered once weekly.
It is expected that many participating children will experience increased
height velocity compared to pre-study experience.
Both children receiving somapacitan and Norditropin® might benefit from the
increased attention during the participation of the study which might lead to
an increase in treatment adherence.
Overall benefit-risk conclusion
Overall, the safety profile of somapacitan is similar to the well-known safety
profile of daily growth hormone products e.g., Norditropin® and no new safety
concerns have been found during the conduct of the somapacitan study program.
There are well known risks associated with administration of injectable
medication as well as procedural risks as described in table *2 1. In this
study the risks associated with administration of trial product as well as the
risks associated with the study procedures are expected to be comparable to
what is seen in routine clinical practice.
More detailed information about the known and expected benefits and risks and
reasonably expected adverse events (AE) of somapacitan and Norditropin® may be
found in the respective IBs or any updates hereof.
Taking into account the measures taken to minimise risk and burden to children
participating in this study, the potential risks identified in association with
somapacitan are justified by the anticipated benefits that may be afforded to
children with SGA, TS, NS and ISS.
Flemingweg 8
Alphen aan den Rijn 2408AV
NL
Flemingweg 8
Alphen aan den Rijn 2408AV
NL
Listed location countries
Age
Inclusion criteria
1. Informed consent of parent or legally acceptable representative of
participant and child assent, as age appropriate must be obtained before any
study-related activities. Studyrelated activities are any procedures that are
carried out as part of the study, including activities to determine suitability
for the study.
2. No prior exposure to growth promoting therapy, including but not limited to
growth hormone, IGF-I and ghrelin analogues.
Applicable to children with SGA:
3. Born small for gestational age (birth length below -2 SDS OR birth weight
below -2 SDS OR both) (according to national standards).
4. Prepubertal children:
a) Boys:
• Age above or equal to 2 years and 26 weeks and below 11.0 years at screening.
• Testis volume below 4 mL
b) Girls:
• Age above or equal to 2 years and 26 weeks and below 10.0 years at screening.
• Tanner stage 1 for breast development: No palpable glandular breast tissue)
5. Impaired height defined as at least 2.5 standard deviations below the mean
height for chronological age and sex at screening according to the standards of
Centers for Disease Control and Prevention.
6. Impaired height velocity defined as annualised height velocity below the
50th percentile for chronological age and sex according to the standards of
Prader calculated over a time span of minimum 6 months and maximum 18 months
prior to screening.
7. Body Mass Index below the 95th percentile according to Centers for Disease
Control and Prevention, Body Mass Index-for-age growth charts.
Applicable to girls with TS:
8. Confirmed diagnosis of TS by 30-cell (or more) lymphocyte chromosomal
analysis.
9. Prepubertal girls:
• Age above or equal to 2 years and 26 weeks and below 10.0 years at screening.
• Tanner stage 1 for breast development: No palpable glandular breast tissue)
10. Impaired height defined as at least 2.0 standard deviations below the mean
height for chronological age and sex at screening according to the standards of
Centers for Disease Control and Prevention.
11. Historical height measured 6-18 months prior to screening.
12. Thyroid hormone replacement therapy should be adequate and stable for at
least 90 days prior to randomisation, if applicable.
Applicable to children with NS:
13. Clinical diagnosis of NS according to van der Burgt score list
14. Prepubertal children:
a) Boys:
• Age above or equal to 2 years and 26 weeks and below 11.0 years at screening.
• Testis volume below 4 mL
b) Girls:
• Age above or equal to 2 years and 26 weeks and below 10.0 years at screening.
• Tanner stage 1 for breast development: No palpable glandular breast tissue)
15. Impaired height defined as at least 2.0 standard deviations below the mean
height for chronological age and sex at screening according to the standards of
Centers for Disease Control and Prevention.
16. Historical height measured 6-18 months prior to screening.
17. Thyroid hormone replacement therapy should be adequate and stable for at
least 90 days prior to randomisation, if applicable.
Exclusion criteria
1. Known or suspected hypersensitivity to study intervention(s) or related
products.
2. Previous randomisation into same sub-study in this study.
3. Receipt of any investigational medicinal product within 3 months before
screening or participation in another clinical study at the time of
randomisation.
4. Children with suspected or confirmed growth hormone deficiency according to
local practice.
5. Children diagnosed with diabetes mellitus or screening values from the
central laboratory of
a. fasting plasma glucose above or equal to 126 mg/dL (7.0 mmol/L) or
b. HbA1c above or equal to 6.5%.
6. Current inflammatory diseases requiring systemic corticosteroid treatment
for longer than 2 consecutive weeks within the last 3 months prior to screening.
7. Children requiring inhaled glucocorticoid therapy at a dose greater than 400
µg/day of inhaled budesonide or equivalent (i.e., 250 µg/day for fluticasone
propionate) for longer than 4 consecutive weeks within the last 12 months prior
to screening.
8. Concomitant administration of other treatments that may have an effect on
growth, e.g., but not limited to methylphenidate for treatment of attention
deficit hyperactivity disorder (ADHD).
9. Diagnosis of attention deficit hyperactivity disorder (ADHD).
10. History or known presence of malignancy including intracranial tumours.
11. History or known presence of active Hepatitis B or Hepatitis C (exceptions
to this exclusion criterion is the presence of antibodies due to vaccination
against Hepatitis B).
12. Any disorder, which in the investigator*s opinion, might jeopardise
participant*s safety or compliance with the protocol.
13. The participant or the parent/legally acceptable representative is likely
to be non-compliant in respect to study conduct, as judged by the investigator.
14. Current treatment with sex hormones or aromatase inhibitors.
Applicable to children with SGA:
15. Any known or suspected clinically significant abnormality likely to affect
growth or the ability to evaluate growth with standing height measurements,
such as, but not limited to:
a. Known family history of skeletal dysplasia.
b. Significant spinal abnormalities including but not limited to scoliosis,
kyphosis and spina bifida variants.
c. Any other disorder/condition that can cause short stature such as, but not
limited to, psychosocial deprivation, nutritional disorders, chronic systemic
illness and chronic renal disease.
d. TS (including mosaicism). India: Please see local requirements in Appendix
11.
e. NS.
f. Hormonal deficiencies.
g. Children who are small due to malnutrition defined as -2 standard deviations
according to standards. 0¬-5 years: weight for height on World Health
Organisation Multicentre Growth Reference Study 2006. Above 5 years: World
Health Organisation 2007 Body Mass Index.
h. Known chromosomal aneuploidy or significant gene mutations causing medical
*syndromes* with short stature, including but not limited to Laron syndrome,
Prader-Willi syndrome, Russell-Silver Syndrome, skeletal dysplasias, abnormal
SHOX gene analysis or absence of GH receptors.
Applicable to children with TS:
16. Any known or suspected clinically significant abnormality likely to affect
growth or the ability to evaluate growth with standing height measurements,
such as, but not limited to:
a. Known family history of skeletal dysplasia.
b. Significant spinal abnormalities including but not limited to scoliosis,
kyphosis and spina bifida variants.
c. Any other disorder/condition that can cause short stature such as, but not
limited to, psychosocial deprivation, nutritional disorders, chronic systemic
illness and chronic renal disease.
d. NS.
e. Mosaicism below 10%.
f. TS with Y-chromosome mosaicism where gonadectomy has not been performed.
g. NYHA class II or above or requiring medication for any heart condition.
h. Coeliac disease where participant is not stable on gluten free diet for the
previous 12 months prior to screening.
Applicable to children with NS:
17. Any known or suspected clinically significant abnormality likely to affect
growth or the ability to evaluate growth with standing height measurements,
such as, but not limited to:
a. Known family history of skeletal dysplasia.
b. Significant spinal abnormalities including but not limited to scoliosis,
kyphosis and spina bifida variants.
c. Any other disorder/condition that can cause short stature such as, but not
limited to, psychosocial deprivation, nutritional disorders, chronic systemic
illness and chronic renal disease.
d. TS (including mosaicism). India: Please see local requirements in Appendix 11
e. Noonan-related disorders: Noonan syndrome with multiple lentigines (formerly
called *LEOPARD* syndrome), Noonan syndrome with loose anagen hair,
cardiofaciocutaneous syndrome (CFC), Costello syndrome, neurofibromatosis type
1 (NF1) and Legius syndrome. Genetic testing results must be available prior to
randomisation to exclude these.
f. Coeliac disease where participant is not stable on gluten free diet for the
previous 12 months prior to screening.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-506927-27-00 |
| EudraCT | EUCTR2021-005607-13-NL |
| ClinicalTrials.gov | NCT05330325 |
| CCMO | NL81002.078.22 |