Efficacy and Safety of Navepegritide in Adolescents with Achondroplasia

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ascendis Pharma Growth Disorders A/S

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

10 Dec 2024 → ongoing

Decision date (initial)

2024-09-19

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To evaluate efficacy of navepegritide on growth

Secondary objectives 1

1. To evaluate efficacy of navepegritide on growth

Conditions and MedDRA coding

Achondroplasia in Children and Adolescents

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Austrian Agency For Health And Food Safety, Federal Institute For Drugs And Medical Devices, Food And Drug Administration

EMA paediatric investigation plan (PIP)

EMEA-002689-PIP02-23

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Written, signed informed consent and/or assent of the participant, participant parent(s) or legal guardian(s) of the participant, and as required by the institutional review board/human research ethics committee/independent ethics committee (IRB/HREC/IEC). For participants who are below the age of consent, a written assent will be obtained in accordance with applicable requirements as required by IRB/HREC/IEC. Upon reaching the legal age of consent, depending on applicable requirements, these participants will be asked to give their own written consent.
2. Male or female, between 12 (inclusive) and <18 years of age at the time of randomization
3. Clinical diagnosis of ACH with documented genetic confirmation available. Documentation of historic test results are acceptable for proof of diagnosis.
4. Parent(s)/legal guardian(s) willing and able to administer weekly SC injections of IMP and to follow the protocol.
5. At least one historical standing height measurement available from medical records. The measurement must have been collected between 6 months to 15 months prior to the time of screening.

Exclusion criteria 19

1. Participation (signed informed consent) in any interventional clinical trial within 3 months prior to Screening unless no doses of IMP was given.
2. Decreased growth velocity (AGV < 1.5 cm/year based on measurement over a period of at least 6 months) or radiological evidence of growth plate closure.
3. Known or suspected hypersensitivity to the IMP or related products (trehalose, tris[hydroxymethyl]aminomethane, succinate, and mPEG).
4. Have a growth disorder or medical condition other than ACH that results in short stature, or abnormal growth such as SADDAN, hypochondroplasia, growth hormone deficiency, Turner syndrome, pseudo-ACH, inflammatory bowel disease, celiac disease, hypothyroidism, hyperthyroidism, or diabetes mellitus.
5. Severe mutation in the FGFR3 gene, e.g. two variants on the same allele or severe ACH with developmental delay and acanthosis nigricans , are not eligible for trial participation.
6. Have received any dose of prescription medications and/or IMP (placebo treatment only is allowed, if documented) or surgical intervention intended to affect stature, growth, or body proportionality at any time.
7. Requires, or anticipated to require, chronic (> 4 weeks) or repeated treatment (more than twice/year and >3 weeks/year) with systemic corticosteroids during participation in the trial. Chronic use of high dose inhaled corticosteroids is not allowed.
8. Known history of presence of injury or disease of the growth plate(s), other than ACH, that affects growth potential of long bones.
9. Known history of any bone-related surgery affecting growth potential of long bones, such as: • Orthopedic reconstructive surgery for bone lengthening (e.g., procedures for leg bowing such as 8-plate are not exclusionary). • Ventriculoperitoneal (VP) shunt and laminectomy with full recovery are allowed with minimum of 6 months of bone healing. • Bone fracture within 6 months prior to screening (within 2 months for fracture of digits and buckle fractures).
10. Clinically significant findings at Screening, such as: • Expected to require surgical intervention during participation in the trial that may significantly affect trial parameters (confounding of safety events) or would prevent the participant from performing trial procedures. Common surgeries, such as insertion of grommets, adenoidectomy, tonsillectomy, or myringotomy tube placement, are permitted. • Severe untreated sleep apnea or newly initiated sleep apnea treatment (e.g., Continuous Positive Airway Pressure [CPAP] in the previous 2 months prior to Screening. MS disease, such as Salter-Harris fractures or clinical and/or radiographic evidence of severe hip pathology • Otherwise, are considered by the Investigator to be unfit to receive trial treatment or undergo trial related procedures.
11. Have a clinically significant finding or arrhythmia as determined by the investigator in consultation with the medical monitor that indicates abnormal cardiac function or conduction that includes, but is not exclusive to: • Repaired or unrepaired coarctation. • Moderate or greater complexity congenital heart disease including tetralogy of Fallot, Atrioventricular septal defects, truncus arteriosus, total anomalous pulmonary venous return, double outlet right ventricle, or single ventricle heart disease.
12. QT corrected using Fridericia’s correction (QTcF) ≥ 450 msec at Screening
13. Known history or presence of condition that impacts hemodynamic stability (such as autonomic dysfunction and orthostatic intolerance).
14. Known history or presence of the following: • Chronic anemia (iron deficiency anemia that is resolved or adequately treated in the Investigator’s opinion is allowed). • Chronic renal insufficiency defined as estimated glomerular filtration rate (eGFR) according to the revised bedside Schwartz equation < 60 mL/min/1.73 m2 for >3 months. • Chronic or recurrent illness that can affect hydration or volume status, including conditions associated with decreased nutritional intake or increased volume loss.
15. Known history or presence of malignant disease
16. Participant with serum 25-hydroxy-vitamin D (25OHD) levels of <30 nmol/L (<12 ng/mL) at Screening Visit will be excluded. Participants with 25OHD levels between 30-50 nmol/L (12-20 ng/mL) can be randomized provided treatment with Vitamin D supplementation is initiated according to local standards
17. Any disease or condition that, in the opinion of the Investigator, may make the participant unlikely to fully complete the trial, may confound interpretation of trial results, or may present undue risk from receiving trial treatment. This could include family situations, complications or manifestations, or medications that might impact safety or be considered confounding.
18. Sexually active male and female participants and female partners of male participants of childbearing potential not using a highly effective form of contraceptive for the entire trial period and for 90 days after last dose of trial treatment.
19. Female participants who are pregnant, lactating or breastfeeding.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. AGV at Week 52

Secondary endpoints 1

1. Change from baseline in height Z-score at Week 52

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ascendis Pharma Growth Disorders A/S

Sponsor organisation

Ascendis Pharma Growth Disorders A/S

Address

Tuborg Boulevard 12

City

Hellerup

Postcode

2900

Country

Denmark

Scientific contact point

Organisation

Ascendis Pharma Growth Disorders A/S

Contact name

Clinical Trial Information Desk

Public contact point

Organisation

Ascendis Pharma Growth Disorders A/S

Contact name

Clinical Trial Information Desk

Third parties 17

Locations

3 EU/EEA countries · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 46 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

11 submissions — initial application plus substantial / non-substantial modifications