A Phase 2 Clinical Trial to Investigate Safety, Tolerability and Efficacy of TransCon CNP, Weekly Subcutaneous Injections, Compared with Placebo, in Infants 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

19 Sep 2024 → ongoing

Decision date (initial)

2024-04-22

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Ascendis Pharma Growth Disorders A/S, Denmark

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To evaluate the safety and tolerability of TransCon CNP
To evaluate the effect of TransCon CNP on growth

Secondary objectives 6

1. To evaluate the effect of TransCon CNP on annualized growth velocity (AGV)
2. To evaluate the effect of TransCon CNP on long-term growth
3. To evaluate the effect of TransCon CNP on developmental milestones
4. To evaluate the effect of TransCon CNP on morphology and growth of bones and spine
5. To evaluate the effect of TransCon CNP on foramen magnum morphology and growth
6. To evaluate the treatment impact of TransCon CNP on non-linear growth manifestations and complications in children with achondroplasia

Conditions and MedDRA coding

Achondroplasia in Children and Adolescents

Regulatory references

Scientific advice from competent authorities

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

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 7

1. Written, signed informed consent by the parent(s)/caregiver(s) of the participant, and as required by the institutional review board/human research ethics committee/independent ethics committee (IRB/HREC/IEC).
2. Male or female younger than 2 years of age at the time of randomization; or for open label sentinel participants, at the time of first administration of IMP.
3. Clinical diagnosis of achondroplasia (ACH) with genetic confirmation of heterozygous genotype present during screening.
4. Parent(s)/caregiver(s) willing to follow the protocol and instructions provided, including being able to administer weekly subcutaneous injections of trial treatment.
5. Compliance to daily Vitamin D supplementation for infants aged 14 days to 1 year. All participants older than 1 year of age with serum 25-hydroxyvitamin D (25OHD) measured below lower limit of reference range at screening should start daily Vitamin D supplementation prior to randomization.
6. Considered eligible based on the medical history, physical examination, and the results of vital signs, ECG, imaging, and clinical laboratory tests performed during the screening period
7. Not eligible for treatment with vosoritide for any of the following reasons: − vosoritide is not available (licensed) in the country where the participant resides or not available (licensed) for the age of the participant, − the participant’s parents(s)/caregiver(s) are not willing to initiate treatment with vosoritide despite being thoroughly informed by the investigator of the benefits and risks of vosoritide treatment, − the participant’s parent(s)/caregiver(s) does not have the possibility to cover any expenses related to vosoritide treatment if not fully reimbursed in the country where the participant resides.

Exclusion criteria 14

1. Known or suspected hypersensitivity to the investigational product or related products (trehalose, tris[hydroxymethyl]aminomethane, succinate, and polyethylene glycol [PEG])
2. Genetic confirmation of ACH homozygous genotype
3. Premature birth with gestational age < 32 weeks.
4. Premature birth with gestational age 32 to 37 weeks, unless time from birth is > 6 months at the time of screening and the child is in good nutritional status, defined as gain in body weight expected for age and diagnosis of ACH, as determined by the Investigator and confirmed with the Medical Monitor.
5. Anticipated, as assessed by Investigator and confirmed with Medical Monitor, to undergo surgical intervention during trial participation, including cervicomedullary decompression. Evaluation of immediate risk of requiring cervicomedullary decompression surgery will rely on the following assessments: • Physical examination (e.g., neurologic findings of clonus, opisthotonus, exaggerated reflexes, dilated facial veins) • Evidence of uncontrolled sleep apnea as confirmed by local standard of care assessment (e.g. polysomnography or simple sleep test) performed within 6 months prior to screening.• MRI performed at screening indicating presence of severe cervicomedullary compression (CMC) or spinal cord damage. Presence of abnormal MRI T2 signal intensity at and immediately above and below the cervicomedullary junction should be considered high risk for requiring surgery and the participant is not eligible for trial participation. Common surgeries, such as insertion of grommets, adenoidectomy, tonsillectomy, or myringotomy tube placement are permitted during trial participation.
6. Have a growth disorder or medical condition, other than ACH, resulting in short stature or abnormal growth as determined by the Investigator and confirmed with the Medical Monitor
7. Have received any dose of prescription medications and/or investigational medicinal product or device intended to affect stature, growth, or body proportionality (including human growth hormone or vosoritide) at any time.
8. Requires or anticipated to require chronic (> 4 weeks) or repeated treatment (more than twice/year) with oral corticosteroids, or high-dose inhaled corticosteroids during trial participation.
9. History or presence of injury or disease of the growth plate(s), other than ACH, affecting growth potential of long bones, including Salter-Harris fracture and recent bone-related surgery, as determined by Investigator and confirmed with the Medical Monitor.
10. Have a clinically significant finding indicating abnormal cardiac function, including but not limited 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. • QTcF ≥ 450 msec on screening 12-lead ECG.
11. History or presence of a condition impacting hemodynamic stability (such as autonomic dysfunction and orthostatic intolerance).
12. History or presence of the following: • Chronic anemia. • Chronic renal insufficiency. • Chronic or recurrent illness that can affect hydration or volume status, including conditions associated with decreased nutritional intake or increased volume loss.
13. History or presence of malignant disease.
14. Any disease or condition that, in the opinion of the Investigator, may make the participant unlikely to fully complete the trial, not adhering to trial procedures, may confound interpretation of trial results, or may present undue risk from receiving trial treatment. This could include family situations, comorbid conditions, or medications that might impact safety or be considered confounding.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Incidence of treatment emergent adverse events (TEAEs) over 52 weeks, including Grade ≥ 3 TEAEs; serious adverse events (SAEs); TEAEs leading to discontinuation; deaths due to TEAEs, and all deaths
2. Change from baseline to 52 weeks in length/height Z-score

Secondary endpoints 7

1. Annualized growth velocity (AGV) (cm/year) at 52 weeks and 104 weeks
2. Change from baseline to 104 weeks in length/height Z-score
3. Change from baseline to 52 weeks and 104 weeks in Bayley Scales, motor and language scales (4th edition)
4. Change from baseline to 52 weeks and 104 weeks in evaluation (X-ray) of long bones and angles in lower limbs (e.g., femur, tibia, fibula, and tibia/fibula and femur/tibia ratio, mechanical axis deviations)
5. Change from baseline to 52 weeks and 104 weeks in evaluation of MRI of spine (e.g., spine interpedicular distance (IPD), spine pedicle width (PW), spinal cord volume, and ratio of area of spinal cord to spinal canal)
6. Change from baseline to 52 weeks and 104 weeks in evaluation of MRI of foramen magnum (e.g., sagittal and transverse diameters, surface area (cm2 ) of foramen magnum, ratio of spinal cord to foramen magnum area, and Achondroplasia Foramen Magnum Score (AFMS))
7. Incidence of complications and manifestations of ACH, for example, breathing related sleep disorder, otitis media, hearing loss, musculoskeletal (MS) pain and MS deformities, ACH-related TEAEs reported by investigators

Investigational products

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

Test 3

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 12

Locations

11 EU/EEA countries · 12 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 117 files

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

Application history

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