A Clinical Trial to Evaluate the Safety and Efficacy of BMN 111 in Infants and Young Children With Achondroplasia

NCT03583697 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 111-2062016-003826-18
• Study Type: interventional
• Target: 75
• Locations: 4 countries
• Sites: 16

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.

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

Outcome Measures

Primary Outcomes (2)

• Number of Participants With Adverse Events (AEs) by Severity Grade and Study Drug Treatment-emergent Adverse Events (TEAEs)

  A treatment-emergent Adverse Events (TEAE) is any Adverse Events that newly appeared, increased in frequency or worsened in severity following initiation of study drug administration. A severity grade was defined by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. As per CTCAE, Grade 1 scales as Mild; Grade 2 scales as Moderate; Grade 3 scales as severe or medically significant but not immediately life threatening; Grade 4 scales as life-threatening consequences; and Grade 5 scales as death related to AE. Safety Population includes all sentinel and randomized participants in the FAS who received at least one dose of vosoritide or placebo in this study. Serious adverse event (SAE)

  Up to Week 56 (Safety Follow-Up +/-7d)

• 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. standard deviation score (SDS). The primary efficacy analysis population was the subset of randomized participants in the FAS.

  Baseline to Week 52

Secondary Outcomes (53)

• Change From Baseline in Height at Week 52

  Baseline to Week 52

• Change From Baseline in Annualized Growth Velocity (AGV) at Week 52

  Baseline to Week 52

• Change From Baseline in Upper to Lower Body Segment Ratio at Week 52

  Baseline to Week 52

• 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

  Baseline to Week 52

• 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

  Baseline to Week 52

Study Arms (2)

Active BMN111

EXPERIMENTAL

Subcutaneous injection of 15 μg/kg/day and/or 30 μg/kg/day of BMN111 daily.

Drug: BMN 111

Placebo

PLACEBO COMPARATOR

Daily subcutaneous injection of placebo

Drug: Placebo

Interventions

BMN 111 DRUG

Subcutaneous injection of 15 μg/kg/day and/or 30 μg/kg/day of BMN 111 daily, subject to adjustment per protocol

Also known as: Vosoritide, Modified recombinant human C-type natriuretic peptide

Active BMN111

Placebo DRUG

Subcutaneous injection of 15 μg/kg of placebo daily, Subject to adjustment per protocol

Placebo

Eligibility Criteria

• Age: Up to 59 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

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

You may not qualify if:

• Have hypochondroplasia or short-stature condition other than achondroplasia (e.g., trisomy 21, pseudoachondroplasia, etc.)
• Subject weighs \< 5.0 kg (Cohort 1 and 2) or \< 4.0 kg (Cohort 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
• 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

Sponsors & Collaborators

• BioMarin Pharmaceutical: lead

Study Sites (16)

Children's Hospital & Research Center Oakland

Oakland, California, 94609, United States

Location

Harbor - UCLA Medical Center

Torrance, California, 90509, United States

Location

Alfred I. duPont Hospital for Children

Wilmington, Delaware, 19803, United States

Location

Emory University

Decatur, Georgia, 30033, United States

Location

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

Chicago, Illinois, 60611, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232-2578, United States

Location

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

Medical College of Wisconsin, Children's Hospital

Milwaukee, Wisconsin, 53226, United States

Location

The Children's Hospital at Westmead

Westmead, New South Wales, 2145, Australia

Location

Murdoch Children's Research Institute

Parkville, Victoria, 3052, Australia

Location

Osaka University Hospital

Osaka, Japan

Location

Saitama Children's Medical Center

Saitama, Japan

Location

Tokushima University Hospital

Tokushima, Japan

Location

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

London, SE1 9RT, United Kingdom

Location

Sheffield Children's NHS Foundation Trust

Sheffield, S10 2TH, United Kingdom

Location

Related Publications (2)

• 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.

  PMID: 38649657 DERIVED

• Savarirayan R, Wilcox WR, Harmatz P, Phillips J 3rd, Polgreen LE, Tofts L, Ozono K, Arundel P, Irving M, Bacino CA, Basel D, Bober MB, Charrow J, Mochizuki H, Kotani Y, Saal HM, Army C, Jeha G, Qi Y, Han L, Fisheleva E, Huntsman-Labed A, Day J. Vosoritide therapy in children with achondroplasia aged 3-59 months: a multinational, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Child Adolesc Health. 2024 Jan;8(1):40-50. doi: 10.1016/S2352-4642(23)00265-1. Epub 2023 Nov 18.

  PMID: 37984383 DERIVED

Related Links

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

MeSH Terms

Conditions

Achondroplasia; Dwarfism; Bone Diseases; Bone Diseases, Developmental; Musculoskeletal Diseases; Genetic Diseases, Inborn; Osteochondrodysplasias

Interventions

vosoritide

Condition Hierarchy (Ancestors)

Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Endocrine System Diseases

Results Point of Contact

• Title: Alice Huntsman Labed
• Organization: BioMarin Pharmaceutical Inc.

alice.huntsmanlabed@bmrn.com

+44 792-756-5104

Study Officials

• Medical Director, MD

  BioMarin Pharmaceutical

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 14, 2018
• First Posted: July 11, 2018
• Study Start: June 13, 2018
• Primary Completion: January 26, 2022
• Study Completion: January 26, 2022
• Last Updated: June 13, 2024
• Results First Posted: June 13, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

AU (2); JP (3); GB (2); US (9)