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Clinical Trials/NCT03583697
NCT03583697CompletedPhase 2

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

BioMarin Pharmaceutical16 sites in 4 countries75 target enrollmentStarted: June 13, 2018Last updated:
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Conditions
Interventions

Trial Snapshot

Phase
Phase 2
Status
Completed
Enrollment
75
Locations
16
Primary Endpoint
Number of Participants With Adverse Events (AEs) by Severity Grade and Study Drug Treatment-emergent Adverse Events (TEAEs)
Study OverviewStudy DesignEligibility CriteriaArms & InterventionsOutcomesInvestigatorsSitesRecords & IdentifiersSimilar Trials

Study Overview

Brief Summary

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.

Study Design

Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel
Primary Purpose
Treatment
Masking
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Eligibility Criteria

Ages
— to 59 Months (Child)
Sex
All
Accepts Healthy Volunteers
No

Inclusion Criteria

  • •Diagnosis of achondroplasia (ACH), confirmed by genetic testing. If subjects had previous genetic testing, subjects must have a lab report from a certified laboratory with the study specific mutation documented.
  • •Age 0 to < 60 months, at study entry (Day 1)
  • •Cohort 1 and 2 subjects must have at least a 6-month period of pretreatment growth assessment in Study 111 901 immediately before screening, and have one documented measurement of height/body length a minimum of 6 months prior to the screening visit for 111-
  • •Cohort 3 subjects must have a minimum of 3 months of observation prior to treatment. This observational period can be obtained either (1) via prior enrollment in Study 111-901 or (2) via enrollment in this Study 111 206 for a minimum of 3 months of non-treatment observation prior to commencement of treatment.
  • •Parent(s) or guardian(s) (and the subjects themselves, if required by local regulations or ethics committee) are willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to performance of any research-related procedure
  • •Willing and able to perform all study procedures as physically possible
  • •Parent(s) or caregiver(s) are willing to administer daily injections to the subjects and complete the required training

Exclusion Criteria

  • •Have hypochondroplasia or short-stature condition other than achondroplasia (e.g., trisomy 21, pseudoachondroplasia, etc.)
  • •Subject weighs < 5.0 kg (Cohort 1 and 2) or < 4.0 kg (Cohort 3)
  • •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 history of any of the following:
  • •Renal insufficiency defined as serum creatinine > 2 mg/dL
  • •Chronic anemia or Hgb <10.0 g/dL (based on screening clinical laboratory testing)
  • •Baseline systolic blood pressure (BP) below age and gender specified normal range or recurrent symptomatic hypotension (defined as episodes of low BP generally accompanied by symptoms e.g., dizziness, fainting) or recurrent symptomatic orthostatic hypotension
  • •Cardiac or vascular disease, including the following
  • •Cardiac dysfunction (abnormal echocardiogram determined to be clinically significant by principal investigator PI and medical monitor) at Screening Visit
  • •Hypertrophic cardiomyopathy
  • •Pulmonary hypertension
  • •Congenital heart disease with ongoing cardiac dysfunction
  • •Cerebrovascular disease
  • •Aortic insufficiency or other clinically significant valvular dysfunction
  • •Clinically significant atrial or ventricular arrhythmias
  • •Have a clinically significant finding or arrhythmia that indicates abnormal cardiac function or conduction or Fridericia's corrected QT interval (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 based on the following assessments
  • •Physical exam (e.g., neurologic findings of clonus, opisthotonus, exaggerated reflexes, dilated facial veins)
  • •Polysomnography (e.g., severe central sleep apnea)
  • •MRI indicating presence of severe CMC or spinal cord damage
  • •Have an unstable medical condition likely to require surgical intervention in the next 6 months, or planned spine or long-bone surgery (i.e., surgery involving significant disruption of bone cortex) during the study period
  • •Have documented uncorrected Vitamin D deficiency: 25(OH)D <=15 ng/mL (37.5 nmol/L)
  • •Require any other investigational product prior to completion of the study period
  • •Have received another investigational product or investigational medical device within 30 days prior to the Screening visit
  • •Have used any other investigational product or investigational medical device for the treatment of achondroplasia or short stature at any time
  • •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 (Table 9.3.5.1)
  • •Have been treated with growth hormone, insulin-like growth factor 1 (IGF-1), or anabolic steroids in the 6 months prior to screening, or long-term treatment (>3 months) at any time
  • •Have had regular long-term treatment (> 1 month) with oral corticosteroids (low-dose ongoing inhaled steroid for asthma, or intranasal steroids, are acceptable) in the 12 months prior to screening
  • •Have ever had cervicomedullary decompression surgery (Cohorts 2 and 3 only), spine or long-bone surgery (i.e., surgery involving disruption of bone cortex) or have ever had bone-related surgery with chronic complications
  • •NOTE: Subjects with prior cervicomedullary decompression may be allowed into Cohort 1 only after discussion and agreement with Medical Monitor.
  • •Have ever had limb-lengthening surgery or plan to have limb-lengthening surgery during the study period
  • •Have had a fracture of the long bones or spine within 6 months prior to screening
  • •Have aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or total bilirubin greater than upper limit of normal (ULN) at screening (except for subjects with a known history of Gilberts or newborns entering screening in Cohort 3)
  • •Have evidence of severe untreated sleep apnea; or have newly initiated sleep apnea treatment (eg, Continuous positive airway pressure (CPAP) or sleep apnea-mitigating surgery) in the 2 months prior to screening
  • •Have current malignancy, history of malignancy, or currently under work-up for suspected malignancy
  • •Have known hypersensitivity to BMN 111 or its excipients
  • •Have a history of hip surgery or severe hip dysplasia
  • •Have a history of clinically significant hip injury in the 30 days prior to screening
  • •Have a history of slipped capital femoral epiphysis or avascular necrosis of the femoral head
  • •Have abnormal findings on baseline clinical hip exam or imaging assessments that are determined to be clinically significant as determined by the Investigator
  • •Have a condition or circumstance that, in the view of the Investigator, places the subject at high risk for poor treatment compliance or for not completing the study
  • •Have any concurrent disease or condition that, in the view of the Investigator, would interfere with study participation or safety evaluations, for any reason
  • •Inclusion Criteria for Cohort 3 Observation Period
  • •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. Also, willing and able to provide written assent (if applicable) after the nature of the study has been explained and prior to performance of any research-related procedure.
  • •Birth to <= 3 months of age at study entry.
  • +27 more not shown

Arms & Interventions

Active BMN111

Experimental

Subcutaneous injection of 15 μg/kg/day and/or 30 μg/kg/day of BMN111 daily.

Intervention: BMN 111 (Drug)

Placebo

Placebo Comparator

Daily subcutaneous injection of placebo

Intervention: Placebo (Drug)

Outcomes

Primary Outcomes

Number of Participants With Adverse Events (AEs) by Severity Grade and Study Drug Treatment-emergent Adverse Events (TEAEs)

Time Frame: Up to Week 56 (Safety Follow-Up +/-7d)

A treatment-emergent Adverse Events (TEAE) is any Adverse Events that newly appeared, increased in frequency or worsened in severity following initiation of study drug administration. A severity grade was defined by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. As per CTCAE, Grade 1 scales as Mild; Grade 2 scales as Moderate; Grade 3 scales as severe or medically significant but not immediately life threatening; Grade 4 scales as life-threatening consequences; and Grade 5 scales as death related to AE. Safety Population includes all sentinel and randomized participants in the FAS who received at least one dose of vosoritide or placebo in this study. Serious adverse event (SAE)

Change From Baseline in Height Z-score at Week 52.

Time Frame: Baseline to 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. standard deviation score (SDS). The primary efficacy analysis population was the subset of randomized participants in the FAS.

Secondary Outcomes

  • Change From Baseline in Height at Week 52(Baseline to Week 52)
  • Change From Baseline in Annualized Growth Velocity (AGV) at Week 52(Baseline to Week 52)
  • Change From Baseline in Upper to Lower Body Segment Ratio at Week 52(Baseline to Week 52)
  • Change From Baseline in Other Growth Measures (Upper Body Length, Head Circumference, Arm Span, Upper Arm Length, Lower Arm Length, Lower Body Length, Upper Leg Length, Knee to Heel Length, and Tibial Length) at Week 52(Baseline to Week 52)
  • Change From Baseline in Other Body Proportion Ratios (Arm Span to Height Ratio, Upper Arm Length to Lower Arm [Forearm] Length Ratio, Upper Leg Length [Thigh] to Knee to Heel Length Ratio, and Upper Leg Length (Thigh) to Tibial Length Ratio) at Week 52(Baseline to Week 52)
  • Change From Baseline in Body Mass Index (BMI) at Week 52(Baseline to Week 52)
  • Change From Baseline in BMI Z-score at Week 52(Baseline to Week 52)
  • Change From Baseline in Weight Z-score at Week 52(Baseline to Week 52)
  • Change From Baseline in Infant Toddler Quality of Life (ITQoL) Scores at Week 52(Baseline to Week 52)
  • Change From Baseline in ITQoL-Behavior Scores at Week 52(Baseline to Week 52)
  • Change From Baseline in ITQoL-Global Behavior Scores at Week 52(Baseline to Week 52)
  • Change From Baseline in ITQoL-Getting On With Other Score at Week 52(Baseline to Week 52)
  • Change From Baseline in ITQoL-Health Score at Week 52(Baseline to Week 52)
  • Change From Baseline in Child Behaviour Checklist (CBCL) at Week 52(Baseline to Week 52)
  • Change From Baseline in Bilateral X-rays of Lower Extremities at Week 52(Baseline to Week 52)
  • Change From Baseline in Functional Independence Measure for Children (WeeFIM-II) Score at Week 52(Baseline to Week 52)
  • Change From Baseline in Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) Scores at Week 52(Baseline to Week 52)
  • Change From Baseline in Bilateral X-rays of Left/Right Tibia Bowing Angle at Week 52(Baseline to Week 52)
  • MRI Parameter: Percentage Change From Baseline to Week 52 for Volume of Face, Sinus, Calvarium, Whole Brain Total Volume, Ventricles Total Volume.(Baseline to Week 52)
  • MRI Parameter: Change From Baseline to Week 52 for Area of Foramen Magnum & Area of Spinal Cord at the Foramen Magnum Level(Baseline to Week 52)
  • MRI Parameter: Percentage Change From Baseline to Week 52 for Ratio of Face Volume to Calvarium, Ratio of Area of Spinal Cord to Foramen Magnum, Ratio of Face Volume to Sinus(Baseline to Week 52)
  • DEXA Parameter: Change From Baseline to Week 52 of Lumbar Spine BMD(Baseline to Week 52)
  • Change From Baseline to Week 52 in Whole Body BMD Z-score(Baseline to Week 52)
  • Change From Baseline in Bilateral X-rays of Left Femur Length (cm) to Tibia Length (cm) Ratio and Right Femur Length (cm) to Tibia Length (cm) Ratio at Week 52(Baseline to Week 52 End point timeframe:)
  • Change From Baseline in Bilateral X-rays of Left Tibia Length (cm) to Fibula Length (cm) Ratio & Right Tibia Length (cm) to Fibula Length (cm) Ratio at Week 52(Baseline to Week 52)
  • Change From Baseline in X-ray of Lumbar Spine Sagittal Width and Week 52(Baseline to Week 52)
  • MRI Parameter: Percentage Change From Baseline to Week 52 for Area of Foramen Magnum & Area of Spinal Cord at the Foramen Magnum Level(Baseline to Week 52)
  • Dual X Ray Absorptiometry (DEXA) Parameter: Change From Baseline to Week 52 for Whole Body Less Head Bone Mineral Content (BMC)(Baseline to Week 52)
  • DEXA Parameter: Change From Baseline to Week 52 of Whole Body BMC(Baseline to Week 52)
  • Change From Baseline in X-ray of Lumbar Spine Vertebral Ratios at Week 52(Baseline to Week 52)
  • Change From Baseline in X-ray of Lumbar Spine Transverse Diameter at Week 52(Baseline to Week 52)
  • Change From Baseline in X-ray of Lumbar Spine Angles at Week 52(Baseline to Week 52)
  • MRI Parameter: Change From Baseline to Week 52 for Ratio of Face Volume to Calvarium, Ratio of Area of Spinal Cord to Foramen Magnum, Ratio of Face Volume to Sinus(Baseline to Week 52)
  • DEXA Parameter: Change From Baseline to Week 52 of Whole Body Less Head Bone Mineral Density (BMD)(Baseline to Week 52)
  • DEXA Parameter: Change From Baseline to Week 52 of Lumbar Spine BMC(Baseline to Week 52)
  • DEXA Parameter: Change From Baseline to Week 52 of Whole Body BMD(Baseline to Week 52)
  • Changes From Baseline in X-ray of Lumbar Spine Angle Changes: Number of Participants With an Increase in Lumbar Spine Angle at Week 52(Baseline to Week 52)
  • MRI Parameter: Change From Baseline to Week 52 for Volume of Face, Sinus, Calvarium, Whole Brain Total Volume, Ventricles Total Volume.(Baseline to Week 52)
  • Change From Baseline to Week 52 in Lumbar Spine BMD Z-Score(Baseline to Week 52)
  • Immunogenicity: Number of Participants With Incidence of Antibody Positivity at Scheduled Visits(At Day 1, Week 3, Week 13, Week 26, Week 52, & Ever Positive.)
  • Biomarker: Bone Specific Alkaline Phosphatase (BSAP) Overtime(At Baseline, Day 8, Week 6, Week 20, & Week 39.)
  • Biomarker: Type II Collagen C-Telopeptides Normalized for Creatinine (CTX-II)(Baseline to Week 52.)
  • Biomarker: Plasma Cyclic Guanosine Monophosphate (cGMP) Change From Pre-Dose to Maximum Post-Dose at Week 52(Week 52 Pre-Dose to Week 52 Maximum Post-Dose.)
  • Biomarker: Bone and Collagen Metabolism Biomarker Over Time-CNP Col X BM(At Baseline, Day 8, Week 6, Week 20, & Week 39.)
  • Change in Sleep Study Indices at Week 52(Baseline to Week 52)
  • PK Parameter: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-∞) at Day1, Week 13, Week 26, Week 39, & Week 52(At Day1, Week 13, Week 26, Week 39, & Week 52.)
  • PK Parameter: Area Under the Plasma Concentration-time Curve From Time 0 to Nominal 120 Minutes Postdose (AUC 0- 120 Min) at Day 01, Week 13, Week 26, Week 39, & Week 52(At Day 01, Week 13, Week 26, Week 39, & Week 52)
  • PK Parameter: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of Last Measurable Concentration (AUC0-t) at Day 01, Week 13, Week 26, Week 39, & Week 52(At Day 01, Week 13, Week 26, Week 39, & Week 52)
  • PK Parameter: Maximum Observed Plasma Concentration (Cmax) at Day 01, Week 13, Week 26, Week 39, & Week 52(At Day 01, Week 13, Week 26, Week 39, & Week 52)
  • PK Parameter: Time to Reach Maximum Concentration (Tmax) at Day 01, Week 13, Week 26, Week 39, & Week 52(At Day 01, Week 13, Week 26, Week 39, & Week 52.)
  • PK Parameter: Apparent Clearance (CL/F) at Day 01, Week 13, Week 26, Week 39, & Week 52(At Day 01, Week 13, Week 26, Week 39, & Week 52.)
  • PK Parameter: Apparent Volume of Distribution (Vz/F) at Day 01, Week 13, Week 26, Week 39, & Week 52(At Day 01, Week 13, Week 26, Week 39, & Week 52.)
  • PK Parameter: Elimination Half-life (t1/2) at Day 01, Week 13, Week 26, Week 39, & Week 52(At Day 01, Week 13, Week 26, Week 39, & Week 52.)

Investigators

Sponsor Class
Industry
Responsible Party
Sponsor

Study Sites (16)

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