Efficacy and Safety Evaluation of Vosoritide in Pediatric Hypochondroplasia: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Multicenter Study
- Trial ID
- 2024-513129-22-00
- Protocol
- 111-303
- Sponsor
- Biomarin Pharmaceutical Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 3, randomized, double-blind, placebo-controlled, multicenter study is to evaluate the effect of **vosoritide** on annualized growth velocity (AGV) in children with **hypochondroplasia** compared to placebo. This is clinically relevant as hypochondroplasia is characterized by disproportionate short stature, and improving growth velocity can significantly impact the quality of life and physical development of affected children.
Secondary objectives include:
- Evaluating the effect of vosoritide on standing height versus placebo.
- Assessing the effect of vosoritide on height Z-score compared to placebo.
Participants
The clinical trial involves a total of **58 participants** diagnosed with **hypochondroplasia**, a genetic condition characterized by short stature. The study population includes both **males and females** aged between 3 and 18 years. Participants were selected based on a confirmed genetic diagnosis of hypochondroplasia, with evidence of a pathogenic FGFR3 variant. The trial includes individuals with a height Z score of ≤ -2.0 SDS, as per the CDC growth charts, ensuring that the participants have a significant deviation from the average height for their age and sex. The study population is considered vulnerable, and all participants, along with their guardians, must provide informed consent. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The trial aims to evaluate the effect of vosoritide on annualized growth velocity compared to a placebo.
Plans and Procedures
The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the efficacy and safety of **vosoritide** in children with **hypochondroplasia**. The primary objective is to assess the effect of vosoritide on annualized growth velocity (AGV) compared to placebo. The trial is expected to last for a total duration of 52 weeks, with participant involvement spanning the same period. The study will commence with a screening visit to confirm eligibility, which includes criteria such as age between 3 and 18 years, a confirmed genetic diagnosis of hypochondroplasia, and specific height measurements. Participants will be randomly assigned to receive either vosoritide or a placebo, administered via subcutaneous injection.
Throughout the trial, participants will attend regular follow-up visits to monitor safety and efficacy outcomes. These visits will include assessments of standing height and height Z-score, with changes from baseline measured at Week 52 as secondary endpoints. The end-of-study visit will conclude the trial, where final evaluations will be conducted to assess the primary and secondary endpoints. Participants may be withdrawn from the study early if they experience adverse effects, fail to comply with study procedures, or withdraw consent. The trial is not classified as low intervention, and all procedures will adhere to the highest standards of clinical research to ensure the safety and well-being of participants.
Treatment
The clinical trial involves the administration of **Voxzogo**, a pharmaceutical product containing the active substance **vosoritide**. **Voxzogo** is available in two formulations: 1.2 mg and 0.56 mg powder and solvent for solution for injection. The pharmaceutical form is a solution for injection, and the route of administration is subcutaneous use. The maximum daily dose for the 1.2 mg formulation is 0.8 mg, with a total maximum dose of 292 mg over a treatment period of 52 weeks. For the 0.56 mg formulation, the maximum daily dose is 0.4 mg, with a total maximum dose of 146 mg over the same treatment period. The product is manufactured by BioMarin International Limited and is designated as an orphan drug. The active substance, **vosoritide**, is a modified recombinant human C-type natriuretic peptide, classified under the ATC code M05BX07.
The trial also includes a placebo group, which receives a powder and solvent for solution for injection without an active substance. The placebo is used to maintain the double-blind nature of the study, ensuring that neither the participants nor the investigators know which treatment is being administered. This allows for an unbiased comparison of the efficacy and safety of **vosoritide** against the placebo. The placebo is administered in the same manner as the active treatment, via subcutaneous injection, to ensure consistency in the administration process.
Efficacy
The efficacy of **vosoritide** in the treatment of children with hypochondroplasia will be assessed in a Phase 3, randomized, double-blind, placebo-controlled, multicenter clinical trial. The primary endpoint for evaluating efficacy is the change from baseline in annualized growth velocity (AGV) at Week 52. Secondary endpoints include the change from baseline in standing height and height Z-score at Week 52 compared to placebo. These parameters will be measured and collected at specified timepoints, with the primary assessment occurring at the end of the 52-week treatment period. The trial aims to provide a comprehensive evaluation of the effect of vosoritide on growth parameters in the target population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participants must be ≥ 3 to < 18 years of age at enrollment.
- A confirmed genetic diagnosis of HCH, demonstrating evidence of a pathogenic FGFR3 variant associated with HCH, as confirmed by prior genetic testing in Study 111-902.
- At least a 6-month period of pre-treatment standing height assessments prior to randomization.
- A height Z score of ≤ − 2.0 SDS in reference to the general population of the same age and sex, as calculated using the Center for Disease Control and Prevention (CDC) growth charts (https://www.cdc.gov/growthcharts/zscore.htm).
- Males and females are eligible to participate in this clinical study.
- Females ≥ 10 years old or who have begun menses must have a negative pregnancy test at the Screening Visit and be willing to have additional pregnancy tests during the study.
- If sexually active, participants must be willing to use a highly effective method of contraception while participating in the study.
- Participants must be capable of giving signed informed consent as described in Appendix 1 in Section 10.1, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
- Parent(s) or guardian(s) must be willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to performance of any study-related procedure. Participants under the age of 18 must be willing and able to provide written assent (if required by local regulations or the IRB/IEC) after the nature of the study has been explained and prior to performance of any study-related procedure.
Exclusion Criteria
- Short stature condition other than HCH (eg, ACH, trisomy 21, pseudo-achondroplasia).
- Have any of the following documented conditions: a. Hypothyroidism or hyperthyroidism, growth hormone deficiency, hypercortisolism or hypopituitarism, or other endocrine cause of short stature b. Insulin-requiring diabetes mellitus c. Autoimmune inflammatory disease (including but not limited to systemic lupus erythematosus, juvenile dermatomyositis and scleroderma) d. Other chronic diseases that per investigator determination may be causative of a participant’s short stature, including conditions causing malnutrition (including but not limited to inflammatory bowel disease, cystic fibrosis, celiac disease and eating disorders) e. Autonomic neuropathy
- Have any of the following documented conditions: a. Renal insufficiency defined as an estimated glomerular filtration rate (eGFR) of < 60 ml/min/ 1.73 m2 using the revised Schwartz Pediatric Bedside eGFR formula (Schwartz 2009). b. Chronic anemia (hemoglobin < 10 g/dl. Note: participants with hemoglobin below the indicated threshold may receive treatment for anemia and re-screen after 8 weeks. c. Recurrent symptomatic hypotension (defined as episodes of low blood pressure generally accompanied by symptoms ie, dizziness, fainting, postural tachycardia) or recurrent symptomatic orthostatic hypotension. d. History of clinically significant cardiac or vascular disease as judged by the Investigator, including but not limited to the following: i. Cardiac dysfunction ii. Hypertrophic cardiomyopathy iii. Pulmonary hypertension iv. Congenital heart disease v. Cerebrovascular disease vi. Aortic insufficiency or other clinically significant valvular dysfunction vii. Clinically significant atrial or ventricular arrhythmias
- Have an unstable condition likely to require surgical intervention during the study.
- Evidence of decreased growth velocity (AGV < 1.5 cm/year) as assessed over a period of at least 6 months and/or growth plate closure assessed using left hand antero posterior (AP) X-rays, by the Greulich and Pyle method (Greulich 1971) as per standard of care.
- Vitamin D deficiency (concentration of blood 25-hydroxy-vitamin D < 12 ng/ml or < 30 nmol/L) at Screening. Note: participants with blood 25-hydroxy-vitamin D below the indicated threshold may receive supplementation and re-screen after 8 weeks.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 07 Oct 2024 | 6 |
 Germany | Not Recruiting | 07 Oct 2024 | 5 |
 Italy | Not Recruiting | 07 Oct 2024 | 6 |
 Spain | Not Recruiting | 07 Oct 2024 | 5 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Voxzogo 1.2 mg powder and solvent for solution for injection | Test | POWDER AND SOLVENT FOR SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 0.8 | 52 | PRD9189026 |
powder and solvent for solution for injection | Placebo | N/A | — | — | — | N/A |
Voxzogo 0.56 mg powder and solvent for solution for injection | Test | POWDER AND SOLVENT FOR SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 0.4 | 52 | PRD9189025 |