A Clinical Trial to Evaluate the Safety and Efficacy of BMN 111 in Infants and Young Children With Achondroplasia

Study Overview
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Brief Summary
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Study 111-206 is a Phase 2 randomized, double-blind, placebo-controlled clinical trial of BMN 111 in infants and young children with a diagnosis of Achondroplasia.

Official Title
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A Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Evaluate the Safety and Efficacy of BMN 111 in Infants and Young Children With Achondroplasia, Age 0 to < 60 Months

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: Diagnosis of ACH, confirmed by genetic testing Age 0 to < 60 months at study entry (Day 1) At least 6-month period of pretreatment growth assessment in Study 111-901 immediately before study entry (cohort 1 & 2) or at least 3 months of observation prior to treatment (cohort 3) Exclusion Criteria: Have hypochondroplasia or short-stature condition other than achondroplasia (e.g., trisomy 21, pseudoachondroplasia, etc.) Have any of the following: Hypothyroidism or hyperthyroidism Insulin-requiring diabetes mellitus Autoimmune inflammatory disease (including celiac disease, systemic lupus erythematosus, juvenile dermatomyositis, scleroderma, etc.) Inflammatory bowel disease Autonomic neuropathy Have a clinically significant finding or arrhythmia that indicates abnormal cardiac function or conduction or QTc-F > 450 msec on screening ECG Have evidence of cervicomedullary compression (CMC) likely to require surgical intervention within 60 days of Screening as determined by the Investigator and informed by the following assessments: Physical exam (eg, neurologic findings of clonus, opisthotonus, exaggerated reflexes, dilated facial veins) Polysomnography (eg, severe central sleep apnea) MRI indicating presence of severe CMC or spinal cord damage Subject weight < 5.0 kg (cohort 1 & 2) or < 4.0 kg (cohort 3) Treatment with growth hormone within 6-months prior to screening or prolonged treatment (> 3 months) at any time Any history of spine or long-bone surgery or any bone-related surgery with chronic complications Any history of limb-lengthening surgery or planned limb-lengthening during the study Fracture of the long bones within 6 months prior to screening

Ages Eligible for Study
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Maximum Age: 59 Months

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active BMN111<br>Daily subcutaneous injection of 15 micrograms per kilogram BMN111 daily | Drug: BMN 111<br>* Subcutaneous injection of 15 μg/kg of BMN 111 daily, Subject to adjustment per protocol<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, Subject to adjustment per protocol<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the effect of BMN 111 on change from baseline in length/height Z-scores | Evaluate change from baseline in length/height Z-score in subjects treated with BMN 111 compared with control subjects in the placebo group at 52 weeks | One year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] |  | One year | 
| Evaluate the effect of BMN 111 on change from baseline in AGV |  | One year | 
| Evaluate the effect of BMN 111 on bone morphology/quality by X-ray and dual X-ray absorptiometry (DXA) |  | One year | 
| Characterize maximum concentration (Cmax) of BMN 111 in plasma |  | One year | 
| Characterize the area under the plasma concentration time-curve from time 0 to infinity (AUC0-∞) |  | One year | 
| Characterize the area under the plasma concentration time-curve from time 0 to the last measurable concentration (AUC0-t) |  | 52 Weeks | 
| Characterize the elimination half-life of BMN 111 (t½) |  | 52 weeks | 
| Characterize the apparent clearance of drug |  | 52 weeks | 
| Characterize the apparent volume of distribution based upon the terminal phase (Vz/F) |  | 52 weeks | 
| Characterize the amount of time BMN 111 is present at maximum concentration (Tmax) |  | 52 weeks | 
| Potential Changes in health-related quality of life as measured by the quality of life in Short- statured youth |  | One year | 
| BMN 111 activity will be assessed by measuring bone and collagen metabolism |  | One year | 
| Evaluate the effect of BMN 111 on growth parameters and body proportions, including change from baseline in upper:lower segment body ratio |  | One year | 
| Evaluate the effect of BMN 111 on Sleep study scores by polysomnography |  | One year | 

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