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

NCT ID: NCT03197766

Last Updated: 2022-03-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 121 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-12-12
• Study Completion Date: 2019-10-30

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.

Conditions

Achondroplasia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Active BMN 111

Daily subcutaneous injection of 15 micrograms per kilogram BMN111

Group Type: EXPERIMENTAL

BMN 111

Intervention Type: DRUG

Subcutaneous injection of 15 μg/kg of BMN 111 daily

Placebo

Daily subcutaneous injection of placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Subcutaneous injection of 15 μg/kg of placebo daily

Interventions

BMN 111

Subcutaneous injection of 15 μg/kg of BMN 111 daily

Intervention Type: DRUG

Placebo

Subcutaneous injection of 15 μg/kg of placebo daily

Intervention Type: DRUG

Other Intervention Names

Vosoritide; Modified recombinant human C-type natriuretic peptide

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

• Minimum Eligible Age: 5 Years
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

BioMarin Pharmaceutical

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director, MD

Role: STUDY_DIRECTOR

BioMarin Pharmaceutical

Locations

Children's Hospital & Research Center Oakland

Oakland, California, United States

Harbor - UCLA Medical Center

Torrance, California, United States

Alfred I. duPont Hospital for Children

Wilmington, Delaware, United States

Emory University

Decatur, Georgia, United States

Ann and Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, United States

Johns Hopkins University

Baltimore, Maryland, United States

University of Missouri

Columbia, Missouri, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Baylor College of Medicine

Houston, Texas, United States

Seattle Children's Hospital

Seattle, Washington, United States

Medical College of Wisconsin, Children's Hospital

Milwaukee, Wisconsin, United States

The Children's Hospital at Westmead

Westmead, New South Wales, Australia

Murdoch Children's Research Institute

Parkville, Victoria, Australia

Otto-von-Guericke Universitaet, Universitaetskinderklinik

Magdeburg, , Germany

Universitätsklinikum Münster

Münster, , Germany

Osaka University Hospital

Osaka, , Japan

Saitama Children's Medical Center

Saitama, , Japan

Tokushima University Hospital

Tokushima, , Japan

Institut Catala de Traumatologica I Medicina de l'Esport

Barcelona, , Spain

Hospital Sant Joan de Deu

Barcelona, , Spain

Hospital Universitario Virgen de la Victoria

Málaga, , Spain

Acibadem University School of Medicine

Istanbul, , Turkey (Türkiye)

Guy's and St. Thomas NHS Foundation Trust Evelina Children's Hospital

London, , United Kingdom

Sheffield Children's NHS Foundation Trust

Sheffield, , United Kingdom

Countries

United States; Australia; Germany; Japan; Spain; Turkey (Türkiye); United Kingdom

References

Savarirayan R, Irving M, Wilcox WR, Bacino CA, Hoover-Fong JE, Harmatz P, Polgreen LE, Palm K, Prada CE, Kubota T, Arundel P, Kotani Y, Leiva-Gea A, Bober MB, Hecht JT, Legare JM, Lawrinson S, Low A, Sabir I, Huntsman-Labed A, Day JRS. Sustained growth-promoting effects of vosoritide in children with achondroplasia from an ongoing phase 3 extension study. Med. 2025 May 9;6(5):100566. doi: 10.1016/j.medj.2024.11.019. Epub 2024 Dec 30.

Reference Type: DERIVED

PMID: 39740666 (View on PubMed)

Savarirayan R, Irving M, Wilcox WR, Bacino CA, Hoover-Fong JE, Harmatz P, Polgreen LE, Mohnike K, Prada CE, Kubota T, Arundel P, Leiva-Gea A, Rowell R, Low A, Sabir I, Huntsman-Labed A, Day J. Persistent growth-promoting effects of vosoritide in children with achondroplasia are accompanied by improvements in physical and social aspects of health-related quality of life. Genet Med. 2024 Dec;26(12):101274. doi: 10.1016/j.gim.2024.101274. Epub 2024 Sep 18.

Reference Type: DERIVED

PMID: 39305160 (View on PubMed)

Qi Y, Chan ML, Mould DR, Larimore K, Fisheleva E, Cherukuri A, Day J, Savarirayan R, Irving M, Bacino CA, Hoover-Fong J, Ozono K, Mohnike K, Wilcox WR, Bober MB, Henshaw J. Development of a Weight-Band Dosing Approach for Vosoritide in Children with Achondroplasia Using a Population Pharmacokinetic Model. Clin Pharmacokinet. 2024 May;63(5):707-719. doi: 10.1007/s40262-024-01371-6. Epub 2024 Apr 23.

Reference Type: DERIVED

PMID: 38649657 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34431071 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://ghr.nlm.nih.gov/condition/achondroplasia

NIH Genetics Home Reference related topics: Achondroplasia

https://rarediseases.info.nih.gov/diseases/8173/achondroplasia

NIH Genetic and Rare Diseases Information Center resources: Achondroplasia

https://clinicaltrials.gov/ct2/info/fdalinks

U.S. FDA Resources

Other Identifiers

2015-003836-11

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

111-301

Identifier Type: -

Identifier Source: org_study_id