achondroplasia MedDRA version: 20.0 Level: LLT Classification code 10000452 Term: Achondroplasia System Organ Class: 100000004850
Conditions
Interventions
Product Name: modified recombinant human C-type natriuretic peptide
Product Code: BMN 111
Pharmaceutical Form: Lyophilisate for solution for injection
INN or Proposed INN: vosoritide
CAS Number: 14807
Sponsors
BioMarin Pharmaceutical Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Individuals eligible to participate in this study must meet all of the following criteria: 1. Parent(s) or guardian(s) willing and able to provide signed informed consent after the nature of the study has been explained and prior to performance of any research related procedure. 2. Have ACH, documented by genetic testing. 3. Are willing and able to perform all study procedures as physically possible. 4. Age from 0 months to =12 months, at study entry (Day 1). 5. Parent(s) or caregiver(s) are willing to administer daily injections to the subject and complete the required training. 6. Have evidence of cervicomedullary compression (CMC) that “may” require surgical intervention defined as: o Baseline MRI assessment from central blinded evaluation showing at least one of the following findings: -Narrowing of the foramen magnum with loss of cerebrospinal fluid space surrounding the cord. -Narrowing of the foramen magnum with flattening of the cervical cord without T2 signal change. o Supported by (but not required for eligibility) the following clinical findings: Baseline physical examination -Gross or fine motor developmental milestone delay compared to expected for ACH (eg, lifting head when lying on stomach). • Abnormal reflex (eg, brisk reflex / abnormal clonus for age). • Weakness (eg, opisthotonus). -Baseline sleep study • Sleep apnea with a primary central component (eg, not secondary to obstructive sleep apnea). Are the trial subjects under 18? yes Number of subjects for this age range: 20 F.1.2 Adults (18-64 years) no F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study: 1. Have hypochondroplasia or short-stature condition other than achondroplasia (eg, trisomy 21, pseudoachondroplasia, etc). 2. Have CMC that either does not require surgical intervention (for example foramen magnum narrowing with preservation of the cerebrospinal fluid space) or does require immediate surgical intervention (for example narrowing of the foramen magnum with cervical cord signal change). 3. Have any of the following: o Untreated congenital hypothyroidism or maternal history of hyperthyroidism. o Insulin-requiring neonatal diabetes mellitus. o Autoimmune inflammatory disease. o Inflammatory bowel disease. o Autonomic neuropathy. 4. Have a history of any of the following: o Renal insufficiency. o Chronic anemia. o Baseline systolic blood pressure below age and gender specified normal range or recurrent symptomatic hypotension (defined as episodes of low blood pressure generally accompanied by symptoms eg, pallor, cyanosis, irritability, poor feeding). o Cardiac or vascular disease, including the following: ? Cardiac dysfunction (abnormal echocardiogram determined to be clinically significant by Investigator and Medical Monitor) at Screening. ? Hypertrophic cardiomyopathy. ? Pulmonary hypertension. ? Clinically significant structural heart disease or valvular insufficiency (associated with symptoms or requiring intervention). ? Clinically significant cerebrovascular disease. ? Clinically significant atrial or ventricular arrhythmias. 5. Have a clinically significant finding or arrhythmia that indicates abnormal cardiac function or conduction or QTc-F = 450 msec on screening ECG. 6. Current treatment with antihypertensive medications, ACE inhibitors, angiotensin II receptor blockers, diuretics, beta-blockers, calcium-channel blockers, cardiac glycosides, systemic anticholinergic agents, any medication that may impair or enhance compensatory tachycardia, drugs known to alter renal function that is expected to continue for the duration of the study. 7. Require any other investigational product prior to completion of the study period. 8. Have received another investigational product or investigational medical device within 30 days prior to Screening. 9. Have used any other investigational product or investigational medical device for the treatment of achondroplasia or short stature at any time. 10. Require current chronic therapy with antihypertensive medication or any medication that, in the Investigator’s judgment, may compromise the safety or ability of the subject to participate in this clinical study. 11. Have been treated with growth hormone, insulin-like growth factor 1, or anabolic steroids in the 6 months prior to Screening, or long-term treatment (> 3 months) at any time. 12. Have had regular long-term treatment ( > 1 month) with oral corticosteroids (low-dose ongoing inhaled steroid for asthma, or intranasal steroids, are acceptable) prior to Screening 13. Have ever had prior cervicomedullary decompression surgery. 14. Have had a fracture of the long bones or spine within 6 months prior to Screening. 15. Have aspartate aminotransferase, alanine aminotransferase, or total bilirubin > 2 × the upper limit of normal at Screening (except for subjects with a known history of Gilbert’s syndrome or transient indirect hyperbilirubinemia). 16. Have current malignancy, history of malig
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of the study is to evaluate the safety of BMN 111 in children who are at risk of requiring cervicomedullary decompression surgery.;Secondary Objective: The secondary objective of the study is to evaluate the efficacy of BMN 111 in children who are at risk of requiring cervicomedullary decompression surgery.;Primary end point(s): Safety will be evaluated by the incidence of AEs, SAEs, laboratory test results (chemistry and hematology), vital signs (heart rate, blood pressure, respiratory rate, and temperature), physical examination, electrocardiogram, echocardiography, and concomitant medications. Clinical laboratory tests will be limited to the minimum necessary for evaluation of safety in order to minimize the required blood draw volume in this young pediatric population.;Timepoint(s) of evaluation of this end point: AE, SAE recording: All visits Concomitant meds: All visits Clin lab assessments: Screen, Day 1, Weeks 6, 13, 26, 39, 52, 65, 78, 91, 104, every 26 weeks up to Week 260, Safety Follow up Vital Signs: Screening, Day 1, Day 2 and 3 for subjects randomized to BMN 111+ SoC only, Weeks 6, 13, 26, 39, 52, 65, 78, 91, 104, week 104 Day 2 and 3 for subjects crossing-over to BMN 111 + SoC only, every 26 weeks up to Week 260, Safety FU Phys exam: Screen, Day 1, Weeks 6, 13, 26, 39, 52, 65, 78, 91, 104, every 26 weeks up to Week 260 Safety Follow up ECG: Screen, Day 1, Day 2 and 3 for subjects randomized to BMN 111 + SoC only, Weeks 6, 13, 26, 39, 52, 65, 78, 91, 104, week 104 Day 2 and 3 for subjects crossing-over to BMN 111 + SoC only, every 26 weeks up to Week 260, Safety Follow up | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Efficacy will be assessed by careful neurological clinical examination, MRI including the brain stem, foramen magnum, and spine, and age-specific developmental milestone acquisition (Bayley-III score). A board-certified, fellowship-trained (or equivalent) pediatric anesthesiologist will administer anesthesia during MRI measurements. Independent expert review of all MRI assessments will be performed to standardize eligibility assessment and interpretation of changes during study). Specific criteria for evaluation of signs and symptoms of foramen magnum stenosis leading to CMC include: • Incidence of surgical interventions for CMC including cervicomedullary decompression. • The effect of BMN 111 on the foramen magnum and neuroanatomy at the cervicomedullary junction. • The effect of BMN 111 on the anatomy of the spine including the thoracolumbar spine. • The effect of BMN 111 on neurological signs and symptoms of CMC. • The effect of BMN 111 on age-specific developmental milestones using the Bayley-III score. In addition, the effect of BMN 111 on sleep apnea will be evaluated and anthropometric measurements will be performed ;Timepoint(s) of evaluation of this end point: Anthropometric measurements: Day 1, Weeks 13, 26, 39, 52, 65, 78, 91, 104, every 26 weeks up to Week 260 MRI measurements: Screening, Weeks 26, 52, 78, 104, every 52 weeks up to Week 260 Bayley-III: Screening, Weeks 26, 52, 78, 104, every 52 weeks up to Week 260 Neurological examination: Screening, Day 1, Weeks 6, 13, 26, 39, 52, 65, 78, 91, 104, every 52 weeks up to Week 260, Safety Follow up | — |
Countries
Australia, United Kingdom
Contacts
Public ContactClinical Trials Information
BioMarin Pharmaceutical Inc.
Outcome results
None listed