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A Phase 2 Study of BMN 111 to Evaluate Safety, Tolerability, and Efficacy in Children With Achondroplasia (ACH)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02055157
Recruitment Status : Completed
First Posted : February 5, 2014
Last Update Posted : December 7, 2018
Sponsor:
Information provided by (Responsible Party):
BioMarin Pharmaceutical

Tracking Information
First Submitted Date  ICMJE April 18, 2013
First Posted Date  ICMJE February 5, 2014
Last Update Posted Date December 7, 2018
Actual Study Start Date  ICMJE January 13, 2014
Actual Primary Completion Date October 2, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 2, 2015)
Safety Measures [ Time Frame: 6 months and approximately 24 months ]
Safety evaluations by incidence of adverse events, serious adverse events, laboratory test results (urinalysis, chemistry, hematology), clinically significant changes in vital signs, physical examination, ECG and ECHO results, imaging, hip monitoring and anti-BMN 111 immunogenicity assessments.
Original Primary Outcome Measures  ICMJE
 (submitted: February 3, 2014)
Safety Measures [ Time Frame: Approximately 6 months. Following completion of study (Month 6), a safety follow up visit will be conducted (Month 7). ]
Safety evaluations by indicence of adverse events, serious adverse events, laboratory test results (urinaysis, chemistry, hematology), clinically significant changes in vital signs, physical examination, ECG and ECHO results, imaging, and anti-BMN 111 immunogenicity assessments.
Change History Complete list of historical versions of study NCT02055157 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 28, 2015)
Efficacy measure [ Time Frame: 6 months and approximately 24 months ]
Efficacy will be assessed by change from baseline in height growth velocity (annualized to cm/yr), absolute growth, subject growth compared with ACH and non-ACH standardized pediatric growth curves, and change in body proportions. These will be assessed by anthropometric measurements and measurement ratios.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 3, 2014)
Efficacy measure [ Time Frame: Approximately 6 months ]
Efficacy will be assessed by change from baseline in height growth velocity (annualized to cm/yr), absolute growth, subject growth compared with ACH and non-ACH standardized pediatric growth curves, and change in body proportions. These will be assessed by anthropometric measurements and measurement ratios.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Phase 2 Study of BMN 111 to Evaluate Safety, Tolerability, and Efficacy in Children With Achondroplasia
Official Title  ICMJE A Phase 2, Open-label, Sequential Cohort Dose-escalation Study of BMN 111 in Children With Achondroplasia
Brief Summary This is a Phase 2, open-label, sequential cohort dose-escalation study of BMN 111 in children with achondroplasia. The primary objective is to assess the safety and tolerability of daily BMN 111 administered to children with achondroplasia.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Achondroplasia
Intervention  ICMJE Drug: BMN 111
BMN 111 will be administered daily for 24 months in an open-label sequential dose adjustment fashion.
Other Names:
  • Modified recombinant human C-type natriuretic peptide
  • Vosoritide
Study Arms  ICMJE
  • Experimental: Cohort 1
    Cohort 1: 2.5 ug/kg
    Intervention: Drug: BMN 111
  • Experimental: Cohort 2
    Cohort 2: 7.5 ug/kg,
    Intervention: Drug: BMN 111
  • Experimental: Cohort 3
    Cohort 3: 15 ug/Kg
    Intervention: Drug: BMN 111
  • Experimental: Cohort 4
    Cohort 4: 30 ug/kg
    Intervention: Drug: BMN 111
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 22, 2018)
35
Original Estimated Enrollment  ICMJE
 (submitted: February 3, 2014)
24
Actual Study Completion Date  ICMJE October 2, 2017
Actual Primary Completion Date October 2, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Parent(s) or guardian(s) are willing and able to provide written, signed informed consent
  • 5 to 14 years old at end of study
  • ACH, documented by clinical grounds, confirmed by genetic testing
  • At least 6-month of pretreatment growth assessment in Study 111-901 before study entry, and one standing height at least 6 months prior to screening for 111-202
  • Negative pregnancy test at the Screening Visit for females ≥ 10 years old or who have begun menses
  • If sexually active, willing to use a highly effective method of contraception while participating in the study
  • Ambulatory, able to stand without assistance
  • Willing and able to perform all study procedures as physically possible
  • Parents/caregivers willing to administer daily injections to the subjects

Additional inclusion Criteria Optional, Open-label Extension Phase:

  • Appropriate written informed consent

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
    • Recent acute illness associated with volume dehydration not completely resolved prior to the first dose of study drug
  • Unstable condition requiring surgical intervention during the study
  • Growth plates have fused
  • Have a history of any of the following:

    • Renal insufficiency, defined as creatinine > 2 mg/dl
    • Anemia
    • Baseline systolic BP < 75 mm Hg or recurrent symptomatic hypotension or recurrent symptomatic hypotension, recurrent symptomatic orthostatic hypotension
    • Cardiac or vascular disease, including the following:

      • Cardiac dysfunction (abnormal echocardiogram [ECHO] including left ventricle [LV] mass) at Screening Visit
      • Hypertrophic cardiomyopathy
      • Pulmonary Hypertension
      • Congenital heart disease with ongoing cardiac dysfunction
      • Cerebrovascular disease
      • Aortic insufficiency
      • Clinically significant atrial or ventricular arrhythmias
  • Have an ECG showing any of the following:

    • Right or left atrial enlargement or ventricular hypertrophy
    • PR (period of time from the beginning of atrial depolarization until the beginning of ventricular depolarization) interval > 200 msec
    • QRS (The Q, R, and S heart waves that are measured on an electrocardiogram) interval > 110 msec
    • Corrected QTc-F (Measure of the corrected time between the start of the Q wave and end of the T wave in the heart's electrical cycle) > 450 msec
    • Second- or third-degree atrioventricular block
  • Documented Vitamin D deficiency
  • Require any investigational agent prior to completion of study period
  • Have received another investigational product or investigational medical device within 30 days before the Screening visit
  • Use of any other investigational product or investigational medical device for the treatment of ACH or short stature
  • Current chronic therapy 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, diuretics, or other drugs known to alter renal or tubular function
  • Treatment with growth hormone, IGF-1 (Insulin-like growth factor), or anabolic steroids in the previous 6 months or long-term treatment (> 3 months) at any time
  • Long-term treatment (> 1 month) with oral corticosteroids
  • Concomitant medication that prolongs the QT/QTc-F interval within 14 days or 5 half-lives, whichever is longer, before the Screening visit
  • Pregnant or breastfeeding at the Screening Visit or planning to become pregnant (self or partner) at any time during the study
  • Limb-lengthening or bone-related surgery < 18 months prior to study enrollment
  • Had a fracture of the long bones or spine within 6 months prior to screening (except for fracture of digits or toes)
  • AST (Aspartate Transaminase) or ALT (Alanine Transaminase) at least 3x upper limit of normal (ULN) or total bilirubin at least 2x ULN
  • Evidence of severe sleep apnea requiring surgery or new initiation of CPAP (Continuous positive airway pressure).
  • History of malignancy and chemotherapy/radiation or currently under work-up for suspected malignancy
  • Known hypersensitivity to BMN 111 or its excipients
  • 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
  • Concurrent disease or condition that would interfere with study participation or safety
  • Have abnormal findings on baseline clinical hip exam or imaging assessments that are determined to be clinically significant as determined by the PI.
  • 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.
  • History of slipped capital femoral epiphysis or avascular necrosis of the femoral head.
  • Are unable to lie flat when in prone position

Additional Exclusion Criteria for Optional, Open-label Extension Phase:

  • Use of restricted therapies during the initial 6 months of the study
  • Permanently discontinued BMN 111 during the initial 6 months of the study
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 5 Years to 14 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   France,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02055157
Other Study ID Numbers  ICMJE 111-202
2013-004137-32 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party BioMarin Pharmaceutical
Study Sponsor  ICMJE BioMarin Pharmaceutical
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director, MD BioMarin Pharmaceutical
PRS Account BioMarin Pharmaceutical
Verification Date December 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP