Phase 2b Randomized, Double-Blind, Placebo-Controlled Trial of TransCon CNP in Pediatric Achondroplasia for Growth Efficacy and Safety Evaluation

Trial ID: 2024-515469-32-00
Protocol: ASND0036
Sponsor: Ascendis Pharma Growth Disorders A/S

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Diseases & Conditions

Osteochondrodysplasia

Objectives

The primary objective of this clinical trial is to evaluate the **efficacy** of TransCon CNP on growth in children with **achondroplasia**. Achondroplasia is a genetic disorder characterized by disproportionate short stature, and assessing the impact of TransCon CNP on growth is clinically significant as it may offer a therapeutic option to improve growth outcomes in affected children. The trial involves administering subcutaneous doses of TransCon CNP once weekly for 52 weeks, followed by an open-label extension period. The study is designed as a Phase 2b, multicenter, double-blind, randomized, placebo-controlled trial, ensuring rigorous evaluation of the treatment's efficacy and safety.

Participants

The clinical trial involves a total of **42 participants** diagnosed with **achondroplasia** in children and adolescents. The study population includes both male and female subjects, aged between 2 and 11 years. Participants were selected based on a clinical diagnosis of achondroplasia with documented genetic confirmation. The trial population is characterized by their ability to stand without assistance and the willingness of their parent(s) or legal guardian(s) to administer weekly subcutaneous injections and adhere to the study protocol. Participants have a documented history of growth and disease, either from the ACHieve trial or comparable medical records. The selection process ensured that participants were considered eligible based on medical history, physical examination, and results from vital signs, ECG, and clinical laboratory tests conducted during the screening period. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, given the age range and medical condition of the participants.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of TransCon CNP in children with **achondroplasia**. The trial will involve subcutaneous administration of the investigational medicinal product (IMP) once weekly for a duration of 52 weeks, followed by an open-label extension period. The primary objective is to assess the annualized growth velocity at Week 52, with secondary endpoints including changes from baseline in height Z-score at the same time point.

Participants will be involved in the study for a total of 52 weeks, with the possibility of continuing in an open-label extension. The trial will commence with a screening visit to confirm eligibility based on criteria such as age, clinical diagnosis, and genetic confirmation of achondroplasia. Participants must be between 2 and 11 years of age and able to stand without assistance. The screening will include a review of medical history, physical examination, and laboratory tests.

Following successful screening, participants will be randomized to receive either TransCon CNP or a placebo. Study visits will occur at regular intervals to monitor safety and efficacy, including assessments of growth velocity and height. The end-of-study visit will conclude the 52-week treatment phase, with the option for participants to enter the open-label extension.

Participant involvement may be terminated early if they experience adverse events, fail to comply with the study protocol, or withdraw consent. The trial is expected to end by August 2025, with recruitment having started in January 2022. The study is not classified as low intervention, and it is conducted under the sponsorship of Ascendis Pharma Growth Disorder A/S.

Treatment

The clinical trial involves the administration of **TransCon CNP**, an experimental medication designed for the treatment of children with **achondroplasia**. **TransCon CNP** is a **solution for injection** that contains **C-type natriuretic peptide** conjugated to a multi-arm polyethylene glycol carrier molecule through a cleavable linker. This formulation is synthetically manufactured and classified as a protein of other origin. The medication is administered via **subcutaneous injection**. The dosing regimen involves a maximum daily dose of 14.3 µg/kg, with the treatment period extending up to 104 weeks. The primary objective of the trial is to evaluate the efficacy of **TransCon CNP** on growth, with the medication being administered once weekly for 52 weeks, followed by an open-label extension period.

In addition to the experimental treatment, a **placebo** is utilized as a comparator in this double-blind, randomized, placebo-controlled trial. The **placebo** is designed to match the **TransCon CNP** in appearance but does not contain the active substance. The use of a **placebo** allows for the assessment of the efficacy and safety of **TransCon CNP** by providing a control group for comparison. The administration schedule for the **placebo** mirrors that of the experimental medication, ensuring consistency in the trial design.

Efficacy

The efficacy of TransCon CNP in the treatment of **Achondroplasia** will be assessed in a Phase 2b, multicenter, double-blind, randomized, placebo-controlled trial. The primary endpoint for evaluating efficacy is the annualized growth velocity (AGV) at Week 52. Secondary endpoints include the change from baseline in height Z-score at Week 52. These endpoints will be measured and collected at specified timepoints throughout the trial, with the primary assessment occurring at the conclusion of the 52-week treatment period.

The trial involves administering subcutaneous doses of TransCon CNP once weekly. The efficacy assessments will be conducted using standardized methods to ensure the reliability and validity of the data collected. The analysis of these efficacy parameters will be performed using appropriate statistical methods to determine the treatment's impact on growth in children with Achondroplasia. The trial is designed to provide robust data on the efficacy of TransCon CNP, contributing to the understanding of its potential benefits in this patient population.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Written, signed informed consent of the 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).
Male or female, between 2 and 11 years of age (inclusive) at the time of Screening.
Clinical diagnosis of ACH with documented genetic confirmation available.
Able to stand without assistance.
Parent(s)/legal guardian(s) willing and able to administer weekly SC injections of IMP and to follow the protocol.
At least six months of growth and disease history from ACHieve (TCC-NHS-01) trial or comparable growth and disease history available from medical records (pending confirmation by Medical Monitor).
Considered eligible based on the medical history, physical examination, and the results of vital signs, ECG and clinical laboratory tests performed during the Screening period

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Exclusion Criteria

Participation (i.e., signed informed consent) in any interventional clinical trial before within 3 months prior to screening
Closed epiphysis.
Known or suspected hypersensitivity to the IMP or related products (trehalose, tris[hydroxymethyl]aminomethane, succinate, and mPEG).
Have a growth disorder or medical condition other than ACH that results in short stature or abnormal growth such as severe ACH with developmental delay and acanthosis nigricans (SADDAN), hypochondroplasia, growth hormone deficiency, Turner syndrome, pseudoachondroplasia, inflammatory bowel disease, celiac disease, hypothyroidism, hyperthyroidism, pre-diabetes, or diabetes mellitus.
Have received any dose of prescription medications and IMP or surgical intervention intended to affect stature, growth, or body proportionality at any time.
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.
Known history of presence of injury or disease of the growth plate(s), other than ACH, that affects growth potential of long bones.
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). • Cervicomedullary decompression surgery without anticipated need for repeat decompression during the time of the trial are allowed with minimum of 6 months of bone healing. • 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).
Clinically significant findings at Screening, such as: • Expected to require surgical intervention during participation in the trial. 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. • Musculoskeletal disease, such as Salter-Harris fractures or clinical and/or radiographic evidence of severe hip pathology, or • Otherwise, are considered by the Investigator and Medical Monitor to make a participant unfit to receive trial treatment or undergo trial related procedures.
Have evidence at Screening that are consistent with severe cervicomedullary junction compression based on clinical and/or radiologic findings that indicate immediate surgical intervention is required.
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.
QTcF ≥ 450 msec at the Screening Visit.
Known history or presence of condition that impacts hemodynamic stability (such as autonomic dysfunction and orthostatic intolerance).
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 (GFR <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.
Known history or presence of malignant disease.
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.
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.
Sexually active male and female participants and female partners of male participants of childbearing potential not using a highly effective form of contraceptive (see Section 10.4 [Appendix 4]) for the entire trial period and for 90 days after last dose of trial treatment.