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

Achondroplasia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03197766
• Other study ID #: 111-301
• Secondary ID: 2015-003836-11
• Status: Completed
• Phase: Phase 3
• Start date: December 12, 2016
• Est. completion date: October 30, 2019

Study information

• Verified date: February 2022
• Source: BioMarin Pharmaceutical
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 121
• Est. completion date: October 30, 2019
• Est. primary completion date: October 30, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 5 Years to 18 Years

Eligibility

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

Related Conditions & MeSH terms

• Achondroplasia

Intervention

Drug:
• BMN 111
Subcutaneous injection of 15 µg/kg of BMN 111 daily
• Placebo
Subcutaneous injection of 15 µg/kg of placebo daily

Locations

Country	Name	City	State
Australia	Murdoch Children's Research Institute	Parkville	Victoria
Australia	The Children's Hospital at Westmead	Westmead	New South Wales
Germany	Otto-von-Guericke Universitaet, Universitaetskinderklinik	Magdeburg
Germany	Universitätsklinikum Münster	Münster
Japan	Osaka University Hospital	Osaka
Japan	Saitama Children's Medical Center	Saitama
Japan	Tokushima University Hospital	Tokushima
Spain	Hospital Sant Joan de Deu	Barcelona
Spain	Institut Catala de Traumatologica I Medicina de l'Esport	Barcelona
Spain	Hospital Universitario Virgen de la Victoria	Málaga
Turkey	Acibadem University School of Medicine	Istanbul
United Kingdom	Guy's and St. Thomas NHS Foundation Trust Evelina Children's Hospital	London
United Kingdom	Sheffield Children's NHS Foundation Trust	Sheffield
United States	Johns Hopkins University	Baltimore	Maryland
United States	Ann and Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	University of Missouri	Columbia	Missouri
United States	Emory University	Decatur	Georgia
United States	Baylor College of Medicine	Houston	Texas
United States	Medical College of Wisconsin, Children's Hospital	Milwaukee	Wisconsin
United States	Children's Hospital & Research Center Oakland	Oakland	California
United States	Seattle Children's Hospital	Seattle	Washington
United States	Harbor - UCLA Medical Center	Torrance	California
United States	Alfred I. duPont Hospital for Children	Wilmington	Delaware

Sponsors (1)

Lead Sponsor	Collaborator
BioMarin Pharmaceutical

Countries where clinical trial is conducted

United States,  Australia,  Germany,  Japan,  Spain,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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

External Links

•   NIH Genetic and Rare Diseases Information Center resources: Achondroplasia
•   NIH Genetics Home Reference related topics: Achondroplasia
•   U.S. FDA Resources