Clinical trial NCT03197766: A Study to Evaluate the Efficacy and Safety of BMN 111 in Children With Achondroplasia
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Achondroplasia
Keywords: Achondroplasia
Dwarfism
Bone Diseases
Bone Diseases, Developmental
ACH
Natriuretic Peptide, C-Type
Musculoskeletal Diseases
Natriuretic Agents
Physiological Effects of Drugs
Skeletal Dysplasias
Genetic Diseases, Inborn
Osteochondrodysplasias
Lead sponsor: BioMarin Pharmaceutical
Sponsor class: INDUSTRY
First posted: 2017-06-23
Enrollment: 121
Sex: ALL
Minimum age (years): 5
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change From Baseline in Annualized Growth Velocity (AGV) at Week 52
timeFrame: At Baseline and Week 52
Secondary outcomes:
measure: Change From Baseline in Height Z-score at Week 52
timeFrame: At baseline and Week 52
measure: Change From Baseline in Upper to Lower Segment Body Ratio at Week 52
timeFrame: At baseline and Week 52
measure: Summary of Subjects Experiencing Adverse Events (AEs) During Treatment
timeFrame: Up to Week 56
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: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Columbia
country: United States
facility: University of Missouri
state: Missouri
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
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: Magdeburg
country: Germany
facility: Otto-von-Guericke Universitaet, Universitaetskinderklinik
city: Münster
country: Germany
facility: Universitätsklinikum Münster
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: Barcelona
country: Spain
facility: Institut Catala de Traumatologica I Medicina de l'Esport
city: Barcelona
country: Spain
facility: Hospital Sant Joan de Deu
city: Málaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria
city: Istanbul
country: Turkey
facility: Acibadem University School of Medicine
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:
citation: Chan ML, Qi Y, Larimore K, Cherukuri A, Seid L, Jayaram K, Jeha G, Fisheleva E, Day J, Huntsman-Labed A, Savarirayan R, Irving M, Bacino CA, Hoover-Fong J, Ozono K, Mohnike K, Wilcox WR, Horton WA, Henshaw J. Pharmacokinetics and Exposure-Response of Vosoritide in Children with Achondroplasia. Clin Pharmacokinet. 2022 Feb;61(2):263-280. doi: 10.1007/s40262-021-01059-1. Epub 2021 Aug 25.