Clinical trial NCT03583697: A Clinical Trial to Evaluate the Safety and Efficacy of BMN 111 in Infants and Young Children With Achondroplasia
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Achondroplasia
Keywords: 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
Lead sponsor: BioMarin Pharmaceutical
Sponsor class: INDUSTRY
First posted: 2018-07-11
Enrollment: 75
Sex: ALL
Maximum age (years): 59
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

1. 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.
2. Age 0 to \< 60 months, at study entry (Day 1)
3. 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 111-206. 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.
4. 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
5. Willing and able to perform all study procedures as physically possible
6. Parent(s) or caregiver(s) are willing to administer daily injections to the subjects and complete the required training

Exclusion Criteria:

1. Have hypochondroplasia or short-stature condition other than achondroplasia (e.g., trisomy 21, pseudoachondroplasia, etc.)
2. Subject weighs \< 5.0 kg (Cohort 1 and 2) or \< 4.0 kg (Cohort 3)
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
4. 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
5. 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
6. 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
7. 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
8. Have documented uncorrected Vitamin D deficiency: 25(OH)D \<=15 ng/mL (37.5 nmol/L)
9. Require any other investigational product prior to completion of the study period
10. Have received another investigational product or investigational medical device within 30 days prior to the Screening visit
11. Have used any other investigational product or investigational medical device for the treatment of achondroplasia or short stature at any time
12. 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)
13. 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
14. 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
15. 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.
16. Have ever had limb-lengthening surgery or plan to have limb-lengthening surgery during the study period
17. Have had a fracture of the long bones or spine within 6 months prior to screening
18. 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)
19. 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
20. Have current malignancy, history of malignancy, or currently under work-up for suspected malignancy
21. Have known hypersensitivity to BMN 111 or its excipients
22. Have a history of hip surgery or severe hip dysplasia
23. Have a history of clinically significant hip injury in the 30 days prior to screening
24. Have a history of slipped capital femoral epiphysis or avascular necrosis of the femoral head
25. Have abnormal findings on baseline clinical hip exam or imaging assessments that are determined to be clinically significant as determined by the Investigator
26. 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
27. 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

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. 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.
2. Birth to \<= 3 months of age at study entry.
3. Have ACH, documented by genetic testing
4. Are willing and able to perform all study procedures as physically possible

Exclusion Criteria for Cohort 3 Observation Period

1. Have hypochondroplasia or short stature condition other than ACH (e.g., trisomy 21, pseudoachondroplasia)
2. Have any of the following disorders:

   * Hypothyroidism
   * Insulin-requiring diabetes mellitus
   * Autoimmune inflammatory disease (including celiac disease, lupus (SLE), juvenile dermatomyositis, scleroderma, and others)
   * Inflammatory bowel disease
   * Autonomic neuropathy
3. Have an unstable clinical condition likely to lead to intervention during the course of the study, including progressive cervical medullary compression
4. Have a history of any of the following:

   * Renal insufficiency
   * Anemia
5. Have a history of cardiac or vascular disease, including the following:

   * Cardiac dysfunction
   * Hypertrophic cardiomyopathy
   * Congenital heart disease
   * Cerebrovascular disease, aortic insufficiency
   * Clinically significant atrial or ventricular arrhythmias
6. Current treatment with antihypertensive medications, angiotensin-converting enzyme (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. Have had regular long-term treatment (\> 1 month) with oral corticosteroids (low-dose ongoing inhaled steroid for asthma is acceptable) in the previous 3 month
8. Concomitant medication that prolongs the QT/QTc interval within 14 days or 5 half-lives, whichever is longer, before the Screening visit
9. Have used any other investigational product or investigational medical device for the treatment of ACH or short stature
10. Planned or expected bone-related surgery (ie. surgery involving disruption of bone cortex), during the study period.
11. Planned or expected to have limb-lengthening surgery during the study period.
12. Have any condition that, in the view of the Investigator, places the subject at high risk of poor compliance with the visit schedule or of not completing the study.
13. Concurrent disease or condition that, in the view of the Investigator, would interfere with study participation

Primary outcomes:
measure: Number of Participants With Adverse Events (AEs) by Severity Grade and Study Drug Treatment-emergent Adverse Events (TEAEs)
timeFrame: Up to Week 56 (Safety Follow-Up +/-7d)
measure: Change From Baseline in Height Z-score at Week 52.
timeFrame: Baseline to Week 52
Secondary outcomes:
measure: Change From Baseline in Height at Week 52
timeFrame: Baseline to Week 52
measure: Change From Baseline in Annualized Growth Velocity (AGV) at Week 52
timeFrame: Baseline to Week 52
measure: Change From Baseline in Upper to Lower Body Segment Ratio at Week 52
timeFrame: Baseline to Week 52
measure: 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
timeFrame: Baseline to Week 52
measure: 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
timeFrame: Baseline to Week 52
measure: Change From Baseline in Body Mass Index (BMI) at Week 52
timeFrame: Baseline to Week 52
measure: Change From Baseline in BMI Z-score at Week 52
timeFrame: Baseline to Week 52
measure: Change From Baseline in Weight Z-score at Week 52
timeFrame: Baseline to Week 52
measure: Change From Baseline in Infant Toddler Quality of Life (ITQoL) Scores at Week 52
timeFrame: Baseline to Week 52
measure: Change From Baseline in ITQoL-Behavior Scores at Week 52
timeFrame: Baseline to Week 52
measure: Change From Baseline in ITQoL-Global Behavior Scores at Week 52
timeFrame: Baseline to Week 52
measure: Change From Baseline in ITQoL-Getting On With Other Score at Week 52
timeFrame: Baseline to Week 52
measure: Change From Baseline in ITQoL-Health Score at Week 52
timeFrame: Baseline to Week 52
measure: Change From Baseline in Functional Independence Measure for Children (WeeFIM-II) Score at Week 52
timeFrame: Baseline to Week 52
measure: Change From Baseline in Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) Scores at Week 52
timeFrame: Baseline to Week 52
measure: Change From Baseline in Child Behaviour Checklist (CBCL) at Week 52
timeFrame: Baseline to Week 52
measure: Change From Baseline in Bilateral X-rays of Lower Extremities at Week 52
timeFrame: Baseline to Week 52
measure: Change From Baseline in Bilateral X-rays of Left/Right Tibia Bowing Angle at Week 52
timeFrame: Baseline to Week 52
measure: 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
timeFrame: Baseline to Week 52 End point timeframe:
measure: 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
timeFrame: Baseline to Week 52
measure: Change From Baseline in X-ray of Lumbar Spine Vertebral Ratios at Week 52
timeFrame: Baseline to Week 52
measure: Change From Baseline in X-ray of Lumbar Spine Transverse Diameter at Week 52
timeFrame: Baseline to Week 52
measure: Change From Baseline in X-ray of Lumbar Spine Sagittal Width and Week 52
timeFrame: Baseline to Week 52
measure: Change From Baseline in X-ray of Lumbar Spine Angles at Week 52
timeFrame: Baseline to Week 52
measure: Changes From Baseline in X-ray of Lumbar Spine Angle Changes: Number of Participants With an Increase in Lumbar Spine Angle at Week 52
timeFrame: Baseline to Week 52
measure: MRI Parameter: Change From Baseline to Week 52 for Volume of Face, Sinus, Calvarium, Whole Brain Total Volume, Ventricles Total Volume.
timeFrame: Baseline to Week 52
measure: MRI Parameter: Percentage Change From Baseline to Week 52 for Volume of Face, Sinus, Calvarium, Whole Brain Total Volume, Ventricles Total Volume.
timeFrame: Baseline to Week 52
measure: MRI Parameter: Change From Baseline to Week 52 for Area of Foramen Magnum & Area of Spinal Cord at the Foramen Magnum Level
timeFrame: Baseline to Week 52
measure: MRI Parameter: Percentage Change From Baseline to Week 52 for Area of Foramen Magnum & Area of Spinal Cord at the Foramen Magnum Level
timeFrame: Baseline to Week 52
measure: 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
timeFrame: Baseline to Week 52
measure: 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
timeFrame: Baseline to Week 52
measure: Dual X Ray Absorptiometry (DEXA) Parameter: Change From Baseline to Week 52 for Whole Body Less Head Bone Mineral Content (BMC)
timeFrame: Baseline to Week 52
measure: DEXA Parameter: Change From Baseline to Week 52 of Whole Body Less Head Bone Mineral Density (BMD)
timeFrame: Baseline to Week 52
measure: DEXA Parameter: Change From Baseline to Week 52 of Whole Body BMC
timeFrame: Baseline to Week 52
measure: DEXA Parameter: Change From Baseline to Week 52 of Lumbar Spine BMC
timeFrame: Baseline to Week 52
measure: DEXA Parameter: Change From Baseline to Week 52 of Whole Body BMD
timeFrame: Baseline to Week 52
measure: DEXA Parameter: Change From Baseline to Week 52 of Lumbar Spine BMD
timeFrame: Baseline to Week 52
measure: Change From Baseline to Week 52 in Whole Body BMD Z-score
timeFrame: Baseline to Week 52
measure: Change From Baseline to Week 52 in Lumbar Spine BMD Z-Score
timeFrame: Baseline to Week 52
measure: Immunogenicity: Number of Participants With Incidence of Antibody Positivity at Scheduled Visits
timeFrame: At Day 1, Week 3, Week 13, Week 26, Week 52, & Ever Positive.
measure: Biomarker: Bone Specific Alkaline Phosphatase (BSAP) Overtime
timeFrame: At Baseline, Day 8, Week 6, Week 20, & Week 39.
measure: Biomarker: Type II Collagen C-Telopeptides Normalized for Creatinine (CTX-II)
timeFrame: Baseline to Week 52.
measure: Biomarker: Plasma Cyclic Guanosine Monophosphate (cGMP) Change From Pre-Dose to Maximum Post-Dose at Week 52
timeFrame: Week 52 Pre-Dose to Week 52 Maximum Post-Dose.
measure: Biomarker: Bone and Collagen Metabolism Biomarker Over Time-CNP Col X BM
timeFrame: At Baseline, Day 8, Week 6, Week 20, & Week 39.
measure: Change in Sleep Study Indices at Week 52
timeFrame: Baseline to Week 52
measure: 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
timeFrame: At Day1, Week 13, Week 26, Week 39, & Week 52.
measure: 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
timeFrame: At Day 01, Week 13, Week 26, Week 39, & Week 52
measure: 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
timeFrame: At Day 01, Week 13, Week 26, Week 39, & Week 52
measure: PK Parameter: Maximum Observed Plasma Concentration (Cmax) at Day 01, Week 13, Week 26, Week 39, & Week 52
timeFrame: At Day 01, Week 13, Week 26, Week 39, & Week 52
measure: PK Parameter: Time to Reach Maximum Concentration (Tmax) at Day 01, Week 13, Week 26, Week 39, & Week 52
timeFrame: At Day 01, Week 13, Week 26, Week 39, & Week 52.
measure: PK Parameter: Apparent Clearance (CL/F) at Day 01, Week 13, Week 26, Week 39, & Week 52
timeFrame: At Day 01, Week 13, Week 26, Week 39, & Week 52.
measure: PK Parameter: Apparent Volume of Distribution (Vz/F) at Day 01, Week 13, Week 26, Week 39, & Week 52
timeFrame: At Day 01, Week 13, Week 26, Week 39, & Week 52.
measure: PK Parameter: Elimination Half-life (t1/2) at Day 01, Week 13, Week 26, Week 39, & Week 52
timeFrame: At Day 01, Week 13, Week 26, Week 39, & Week 52.
Other outcomes:
Locations:
city: Oakland
country: United States
facility: Children's Hospital & Research Center Oakland
state: California
city: Torrance
country: United States
facility: Harbor - UCLA Medical Center
state: California
city: Wilmington
country: United States
facility: Alfred I. duPont Hospital for Children
state: Delaware
city: Decatur
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Ann and Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Milwaukee
country: United States
facility: Medical College of Wisconsin, Children's Hospital
state: Wisconsin
city: Westmead
country: Australia
facility: The Children's Hospital at Westmead
state: New South Wales
city: Parkville
country: Australia
facility: Murdoch Children's Research Institute
state: Victoria
city: Osaka
country: Japan
facility: Osaka University Hospital
city: Saitama
country: Japan
facility: Saitama Children's Medical Center
city: Tokushima
country: Japan
facility: Tokushima University Hospital
city: London
country: United Kingdom
facility: Guy's and St. Thomas NHS Foundation Trust Evelina Children's Hospital
city: Sheffield
country: United Kingdom
facility: Sheffield Children's NHS Foundation Trust
Study officials:
affiliation: BioMarin Pharmaceutical
name: Medical Director, MD
role: STUDY_DIRECTOR
References: