A Study to Evaluate the Efficacy and Safety of BMN 111 in Children With Achondroplasia

Study Overview
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Brief Summary
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The intent and design of this Phase 3 study is to assess BMN 111 as a therapeutic option for the treatment of children with Achondroplasia.

Detailed Description
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This is a Phase 3 randomized, placebo-controlled, double-blind multicenter study with approximately 110 subjects, aged 5 to < 18 years old. Subjects with documented Achondroplasia confirmed by genetic testing will have been enrolled in Study 111-901 for at least a 6-month period immediately before entering into the 111-301 study. Eligible subjects will be randomly assigned to one of two treatment groups: placebo or BMN 111 at 15 μg/kg. The route of administration is subcutaneous injection and the frequency is daily.

Official Title
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A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of BMN 111 in Children With Achondroplasia

Conditions
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Achondroplasia

Intervention / Treatment
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* Drug: BMN 111
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Parent(s) or guardian(s) consent 5 to < 18 years old ACH, documented and confirmed by genetic testing At least a 6-month period of pretreatment growth assessment in Study 111-901 before study entry If sexually active, willing to use a highly effective method of contraception Ambulatory and able to stand without assistance Exclusion criteria: Hypochondroplasia or short stature condition other than ACH Have any of the following: Hypothyroidism or hyperthyroidism Insulin-requiring diabetes mellitus Autoimmune inflammatory disease Inflammatory bowel disease Autonomic neuropathy History of any of the following: Renal insufficiency defined as serum creatinine > 2 mg/dL Chronic anemia Baseline systolic blood pressure (BP) < 70 millimeters of mercury (mm Hg) or recurrent symptomatic hypotension (defined as episodes of low BP generally accompanied by symptoms ie, dizziness, fainting) or recurrent symptomatic orthostatic hypotension Cardiac or vascular disease Have a clinically significant finding or arrhythmia on screening electrocardiogram (ECG) that indicates abnormal cardiac function or conduction or Fridericias corrected QTc-F > 450 msec Have an unstable condition likely to require surgical intervention during the study (including progressive cervical medullary compression or severe untreated sleep apnea) Decreased growth velocity (< 1.5 cm/yr) over a period of 6 months or evidence of growth plate closure (proximal tibia, distal femur) Treated with growth hormone, insulin-like growth factor 1 (IGF-1), or anabolic steroids in the previous 6 months or treatment greater than 6 months at any time Greater than 1 month treatment with oral corticosteroids (low-dose ongoing inhaled steroid for asthma, or intranasal steroids, are acceptable) in the previous 12 months Planned or expected to have limb-lengthening surgery during the study period. Subjects with previous limb- lengthening surgery may enroll if surgery occurred at least 18 months prior to the study and healing is complete without sequelae. Planned or expected bone-related surgery (ie. surgery involving disruption of bone cortex, excluding tooth extraction), during the study period. Subjects with previous bone-related surgery may enroll if surgery occurred at least 6 months prior to the study and healing is complete without sequelae. Had a fracture of the long bones or spine within 6 months prior to screening History of severe untreated sleep apnea New initiation of sleep apnea treatment (e.g. CPAP or sleep apnea-mitigating surgery) in the previous 2 months prior to screening History of hip surgery or hip dysplasia atypical for achondroplastic subjects History of clinically significant hip injury in the 30 days prior to screening History of slipped capital femoral epiphysis or avascular necrosis of the femoral head Abnormal findings on baseline clinical hip exam or imaging assessments that are determined to be clinically significant Concurrent disease or condition that would interfere with study participation or safety evaluations, for any reason Condition or circumstance that places the subject at high risk for poor treatment compliance or for not completing the study

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active BMN 111<br>Daily subcutaneous injection of 15 micrograms per kilogram BMN111 | Drug: BMN 111<br>* Subcutaneous injection of 15 μg/kg of BMN 111 daily<br>* Other names: Modified recombinant human C-type natriuretic peptide;|
| Placebo Comparator: Placebo<br>Daily subcutaneous injection of placebo | Drug: Placebo<br>* Subcutaneous injection of 15 μg/kg of placebo daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Annualized Growth Velocity (AGV) at Week 52 | AGV at a Post-baseline Visit is defined as [(Height at Post-baseline Visit - Height at Baseline)/(Date of Post-baseline Visit - Date of Baseline Assessment)] x 365.25 AGV at Baseline is defined as [(Height at Baseline - last height measurement in Study 111-901 at least 6 months prior to Baseline)/(Date of Baseline Assessment - Date of last height measurement in Study 111-901 at least 6 months prior to Baseline)] x 365.25 | At Baseline and Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Height Z-score at Week 52 | Z-Scores were derived using age-sex specific reference data (means and SDS) for average stature children per the Centers for Disease Control and Prevention. A height Z score of 0 would indicate that the subject's height is equal to the mean height for the average stature population of the same sex and age. A positive height Z score indicates that the subjects height is above the mean height for the average stature population of the same sex and age, whilst a negative height Z score indicates that the subjects height is below the mean height for the average stature population of the same sex and age. To conclude if the height Z score increases then this means the height deficit has decreased. | At baseline and Week 52 | 
| Change From Baseline in Upper to Lower Segment Body Ratio at Week 52 | Evaluate change from baseline in mean upper:lower segment body ratio in subjects treated with BMN 111 compared with control subjects in the placebo group at 52 weeks | At baseline and Week 52 | 
| Summary of Subjects Experiencing Adverse Events (AEs) During Treatment | AEs with onset or worsening after the initiation of study drug and up to 30 days after study drug discontinuation were included. serious adverse event (SAE) | Up to Week 56 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Achondroplasia, Dwarfism, Bone Diseases, Bone Diseases, Developmental, ACH, Natriuretic Peptide, C-Type, Musculoskeletal Diseases, Natriuretic Agents, Physiological Effects of Drugs, Skeletal Dysplasias, Genetic Diseases, Inborn, Osteochondrodysplasias