Trial Investigating the Efficacy and Safety of Weekly Lonapegsomatropin Compared to Daily Somatropin in Children and Adolescents With Short Stature or Growth Failure Due to Growth Hormone Sufficient Disorders

A Pivotal, Parallel-Arm, Phase 3, Open-Label, Active-controlled, Global, Multicenter, Randomized Basket Trial Investigating the Efficacy and Safety of Once-weekly Lonapegsomatropin Compared to Daily Somatropin in Prepubertal Children and Adolescents With Growth Failure or Short Stature Due to Growth Hormone Sufficient Disorders - Turner Syndrome, SHOX Deficiency, Small for Gestational Age, and Idiopathic Short Stature

This basket trial will enroll prepubertal children and adolescents with clinically diagnosed and genetically confirmed (if applicable) TS, SHOX-D, SGA, or ISS between ages of ≥2 and <18 years with open growth plates. The purpose of the study is to see how well treatment with once-weekly lonapegsomatropin works compared to treatment with daily somatropin. Approximately 186 participants will be distributed equally (1:1), to receive either lonapegsomatropin for 2 years or somatropin for 1 year followed by lonapegsomatropin for 1 year. This trial will be conducted in the United States, France, Germany, Italy, Romania, Spain and South Korea.

Study Overview

• Status: Recruiting
• Conditions: Turner Syndrome; Small for Gestational Age at Delivery; Idiopathic Short Stature; Short Stature Homeobox Gene Mutation
• Intervention / Treatment: Combination product: Lonapegsomatropin [SKYTROFA®]; Combination product: Somatropin Pen Injector

• Study Type: Interventional
• Enrollment (Estimated): 186
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Ascendis Registry Inquiries; Phone Number: +4561161658; Email: asnd_registryinquiries@ascendispharma.com

Study Locations

• France
  • Le Kremlin-Bicêtre, France, 94270
    • Recruiting
    • Ascendis PharmaInvestigational Site
• Germany
  • Hanover, Germany, 30173
    • Recruiting
    • Ascendis Pharma Investigational Site
• South Korea
  • Sejong, South Korea, 30099
    • Recruiting
    • Ascendis Pharma Investigational Site
  • Seoul, South Korea, 06273
    • Recruiting
    • Ascendis Pharma Investigational Site
• Spain
  • Madrid, Spain, 28046
    • Recruiting
    • Ascendis Pharma Investigational Site
  • Málaga, Spain, 29011
    • Recruiting
    • Ascendis Pharma Investigational Site
• United States
  • California
    • Sacramento, California, United States, 95821
      • Recruiting
      • Ascendis Pharma Investigational Site
  • Colorado
    • Centennial, Colorado, United States, 80112
      • Recruiting
      • Ascendis Pharma Investigational Site
  • Florida
    • Orlando, Florida, United States, 32806
      • Recruiting
      • Ascendis Pharma Investigational Site
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Recruiting
      • Ascendis Pharma Investigational Site
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
      • Recruiting
      • Ascendis Pharma Investigational Site
  • Louisiana
    • New Orleans, Louisiana, United States, 70118
      • Recruiting
      • Ascendis Pharma Investigational Site
  • Minnesota
    • Saint Paul, Minnesota, United States, 55102
      • Recruiting
      • Ascendis Pharma Investigational Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Recruiting
      • Ascendis Pharma Investigational Site
  • Texas
    • San Antonio, Texas, United States, 78229
      • Recruiting
      • Ascendis Pharma Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Chronological age between ≥2 and <18 years, at start of screening.
2. Naïve to growth hormone and growth hormone promoting therapies.
3. Prepubertal.
4. Able to stand without assistance.

5. Diagnosis of TS, SHOX-D, SGA, or ISS with impaired growth or short stature, according to the following disease-specific criteria:

   TS or SHOX-D (Léri-Weill dyschondrosteosis):

   1. Diagnosis confirmed by a genetic test. NOTE: Historical test results are acceptable for proof of diagnosis. For karyotypes, a minimum of 20 cells must be counted.
   2. Impaired growth or short stature defined as:

   (i.) AHV <25th percentile over a time span of 6-16 months prior to screening utilizing a historical height properly documented in a health care setting (self-measurement record is not accepted) OR (ii.) Height <5th percentile for sex and age according to the Centers for Disease Control Growth Charts for the United States

   SGA without catch-up growth:

   c. Birth weight and/or birth length < -2.0 SDS for gestational age according to the 2006 World Health Organization Child Growth Standards. For infants born premature, the Fenton Preterm Infant Growth Chart (Fenton 2013) should be used.

   d. Impaired growth or short stature defined as: (i.) AHV <25th percentile over a time span of 6-16 months prior to screening properly documented in a health care setting (self-measurement record is not accepted) OR (ii.) Height < -2.0 SDS for age and sex according to the 2000 Centers for Disease Control Growth Charts for the United States for children ≥ 3 years or height < -2.5 SDS for age and sex according to the for children ≥ 2 years and < 3 years

   ISS:

   e. Height < -2.25 SDS for sex and age according to the Centers for Disease Control Growth Charts for the United States with no identifiable cause for short stature.

   f. Documented normal GH-IGF-1 axis, defined as either: (i.)IGF-1 SDS >0 at screening based on central laboratory OR (ii.)Historical documentation of normal peak GH upon stimulation test (as defined by local institution) g. 46,XX chromosome as determined by karyotype or microarray if female. For karyotypes, a minimum of 30 cells must be counted.

6. If on hormone replacement therapies for any hormone deficiencies other than growth hormone (e.g., adrenal, thyroid), must be on adequate and stable doses for ≥4 weeks prior to and throughout screening.
7. Written, signed informed consent provided by parent(s) or legal guardian(s) of the participant. Assent should be signed by participant as required by IRB/HREC/IEC.

Exclusion Criteria:

1. Advanced bone age X-ray by central reading defined as >20% above chronological age in months (Greulich 1959).
2. Closed epiphyses as defined as bone age of ≥14.0 years in females or ≥16.0 years in males.
3. Current clinical diagnosis of diabetic retinopathy

4. Any diagnosis or presence at screening of the following:

   1. Untreated moderate or severe sleep apnea as determined by formal (local) read of an inpatient or at-home sleep study.
   2. Prader Willi syndrome with severe obesity, history of severe upper airway obstruction, or severe respiratory impairment.
5. Signs/symptoms of intracranial hypertension, active proliferative retinopathy.
6. Uncontrolled hypo- or hyperthyroidism.
7. Uncontrolled diabetes mellitus (defined as: HbA1c >7.5% from central laboratory at screening).
8. Known history or diagnosis of any gastrointestinal inflammatory condition, HIV, radiation exposure, other skeletal dysplasias, growth hormone deficiency, and/or cardio-thoracic surgery due to their independent effects on growth.
9. Any significant hepatic or renal abnormality, such as abnormal renal function (defined as eGFR <60 mL/min/1.73m2).
10. Undiagnosed or uncontrolled hypertension.
11. Receiving treatment with any agent that might influence growth or interfere with GH secretion or action including any sex steroids and stimulants for attention-deficit/hyperactivity disorder (ADHD).
12. High dose inhaled glucocorticoid for more than 28 consecutive days total over the course of 12 months.
13. Female who is pregnant, plans to be pregnant, or breastfeeding.
14. Participation in another interventional clinical trial involving an investigational compound within 90 days prior to screening or in parallel to this trial.
15. Any disease or condition that, in the judgement of the investigator, may make the participant unlikely to comply with the requirements of the protocol or any condition that presents undue risk from the investigational product or trial procedures.

16. Exclusion Criteria only applicable to TS:

    1. Presence of Y chromosome material on genetic testing without history of gonadectomy.
    2. Less than 10% of 45,X mosaicism.
    3. Any known, clinically significant, congenital or acquired cardiovascular dysfunction that might interfere with growth.

17. Exclusion Criteria only applicable to SGA:

    a. Any known clinically significant abnormality likely to affect growth or the ability to evaluate growth with standing height measurements: (i.)Chromosomal aneuploidy, significant gene mutations, or medical syndromes with short stature, including but not limited to Turner syndrome, Laron syndrome, Noonan syndrome, Prader-Willi syndrome, abnormal SHOX-1 gene analysis or absence of GH receptors.

    (ii.)Congenital abnormalities (causing skeletal abnormalities), including but not limited to skeletal dysplasias.

18. Exclusion Criteria only applicable to ISS:

    1. Known history of any condition that causes disproportionate short stature (i.e. skeletal dysplasias), chromosomal aneuploidy, significant gene mutations, or medical syndromes with short stature, including but not limited to Turner syndrome, Laron syndrome, Noonan syndrome, Prader-Willi syndrome, abnormal SHOX-1 gene analysis or absence of gH receptors.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lonapegsomatropin, once daily; Participants will receive Lonapegsomatropin by subcutaneous injection for 2 years (104 weeks)	Combination product: Lonapegsomatropin [SKYTROFA®]; Subcutaneous injection once weekly
Active Comparator: somatropin, once daily; Participants will receive somatropin by subcutaneous injection for 1 year (52 weeks) followed by lonapegsomatropin for 1 year (52 weeks)	Combination product: Somatropin Pen Injector; Subcutaneous injection once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Annualized Height Velocity (AHV) (cm/year)	To evaluate the efficacy of lonapegsomatropin as compared to somatropin in children and adolescents with TS, SHOX-D, SGA, or ISS	52 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Annualized Height Velocity (AHV) (cm/year)	To evaluate lonapegsomatropin as compared to somatropin on additional measures of efficacy in children and adolescents with TS, SHOX-D, SGA, or ISS	104 Weeks
Change from baseline in height standard deviation score (SDS)	To evaluate lonapegsomatropin as compared to somatropin on additional measures of efficacy in children and adolescents with TS, SHOX-D, SGA, or ISS	52 Weeks and 104 Weeks
Change from baseline in Bone Age (years)	To evaluate the safety and tolerability of lonapegsomatropin in children and adolescents with TS, SHOX-D, SGA, or ISS via Central Reader	52 Weeks and 104 Weeks
Change from baseline in ratio of Bone Age/chronological age	To evaluate the safety and tolerability of lonapegsomatropin in children and adolescents with TS, SHOX-D, SGA, or ISS via Central Reader	52 Weeks and 104 Weeks
Number of participants with treatment-related adverse events (AEs)	To evaluate the safety and tolerability of lonapegsomatropin in children and adolescents with TS, SHOX-D, SGA, or ISS	52 Weeks and 104 Weeks

Collaborators and Investigators

• Sponsor: Ascendis Pharma A/S
• Investigators: Study Director: Medical Director, MD, Ascendis Pharma A/S

Study record dates

Study Major Dates

• Study Start (Actual): December 12, 2025
• Primary Completion (Estimated): February 1, 2028
• Study Completion (Estimated): March 1, 2029

Study Registration Dates

• First Submitted: October 14, 2025
• First Submitted That Met QC Criteria: October 24, 2025
• First Posted (Actual): October 28, 2025

Study Record Updates

• Last Update Posted (Actual): May 29, 2026
• Last Update Submitted That Met QC Criteria: May 28, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: somatropin; Growth Hormone; Turner Syndrome; Endocrine System Diseases; Hormones; Human Growth Hormone; Growth Failure; Short Stature; Chromosome Disorders; Noonan Syndrome; Hormone Substitutes; Lonapegsomatropin; Sex Chromosome Disorders; Pituitary Hormones, Anterior; Pituitary Hormones; Sex Chromosome Disorders of Sex Development; Impaired Growth; Growth Hormone Sufficiency; Short Stature Homeobox Gene Mutation; Short Stature Children Born Small for Gestational Age; Idiopathic Short Stature
• Additional Relevant MeSH Terms: Urogenital Diseases; Bone Diseases; Musculoskeletal Diseases; Cardiovascular Diseases; Male Urogenital Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Heart Diseases; Genetic Diseases, Inborn; Connective Tissue Diseases; Gonadal Disorders; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Defects, Congenital; Disorders of Sex Development; Urogenital Abnormalities; Bone Diseases, Developmental; Gonadal Dysgenesis; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Skin and Connective Tissue Diseases; Signs and Symptoms; Endocrine System Diseases; Dwarfism; Noonan Syndrome; Chromosome Disorders; Turner Syndrome; Failure to Thrive; Sex Chromosome Disorders of Sex Development; Sex Chromosome Disorders; lonapegsomatropin
• Other Study ID Numbers: ASND0047

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes