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

NCT ID: NCT03583697

Last Updated: 2024-06-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 75 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-06-13
• Study Completion Date: 2022-01-26

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

Study Design

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

Study Groups

Active BMN111

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

Group Type: EXPERIMENTAL

BMN 111

Intervention Type: DRUG

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

Placebo

Daily subcutaneous injection of placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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

Interventions

BMN 111

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

Intervention Type: DRUG

Placebo

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

Intervention Type: DRUG

Other Intervention Names

Vosoritide; Modified recombinant human C-type natriuretic peptide

Eligibility Criteria

Inclusion Criteria

1. 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.

2. Age 0 to < 60 months, at study entry (Day 1)

3. 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.

4. 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

5. Willing and able to perform all study procedures as physically possible

6. Parent(s) or caregiver(s) are willing to administer daily injections to the subjects and complete the required training

1. Parent(s) or guardian(s) willing and able to provide signed informed consent after the nature of the study has been explained and prior to performance of any research-related procedure. Also, willing and able to provide written assent (if applicable) after the nature of the study has been explained and prior to performance of any research-related procedure.

2. Birth to <= 3 months of age at study entry.

3. Have ACH, documented by genetic testing

4. Are willing and able to perform all study procedures as physically possible

Exclusion Criteria

1. Have hypochondroplasia or short-stature condition other than achondroplasia (e.g., trisomy 21, pseudoachondroplasia, etc.)

2. Subject weighs < 5.0 kg (Cohort 1 and 2) or < 4.0 kg (Cohort 3)

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

4. 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
• Pulmonary hypertension
• Congenital heart disease with ongoing cardiac dysfunction
• Cerebrovascular disease
• Aortic insufficiency or other clinically significant valvular dysfunction
• Clinically significant atrial or ventricular arrhythmias

5. Have a clinically significant finding or arrhythmia that indicates abnormal cardiac function or conduction or Fridericia's corrected QT interval (QTc-F) >450 msec on screening ECG

6. Have evidence of cervicomedullary compression (CMC) likely to require surgical intervention within 60 days of Screening as determined by the Investigator based on the following assessments

• Physical exam (e.g., neurologic findings of clonus, opisthotonus, exaggerated reflexes, dilated facial veins)
• Polysomnography (e.g., severe central sleep apnea)
• MRI indicating presence of severe CMC or spinal cord damage

7. Have an unstable medical condition likely to require surgical intervention in the next 6 months, or planned spine or long-bone surgery (i.e., surgery involving significant disruption of bone cortex) during the study period

8. Have documented uncorrected Vitamin D deficiency: 25(OH)D <=15 ng/mL (37.5 nmol/L)

9. Require any other investigational product prior to completion of the study period

10. Have received another investigational product or investigational medical device within 30 days prior to the Screening visit

11. Have used any other investigational product or investigational medical device for the treatment of achondroplasia or short stature at any time

12. Require current chronic therapy with antihypertensive medication or any medication that, in the investigator's judgment, may compromise the safety or ability of the subject to participate in this clinical study (Table 9.3.5.1)

13. Have been treated with growth hormone, insulin-like growth factor 1 (IGF-1), or anabolic steroids in the 6 months prior to screening, or long-term treatment (>3 months) at any time

14. Have had regular long-term treatment (> 1 month) with oral corticosteroids (low-dose ongoing inhaled steroid for asthma, or intranasal steroids, are acceptable) in the 12 months prior to screening

15. Have ever had cervicomedullary decompression surgery (Cohorts 2 and 3 only), spine or long-bone surgery (i.e., surgery involving disruption of bone cortex) or have ever had bone-related surgery with chronic complications

NOTE: Subjects with prior cervicomedullary decompression may be allowed into Cohort 1 only after discussion and agreement with Medical Monitor.

16. Have ever had limb-lengthening surgery or plan to have limb-lengthening surgery during the study period

17. Have had a fracture of the long bones or spine within 6 months prior to screening

18. Have aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or total bilirubin greater than upper limit of normal (ULN) at screening (except for subjects with a known history of Gilberts or newborns entering screening in Cohort 3)

19. Have evidence of severe untreated sleep apnea; or have newly initiated sleep apnea treatment (eg, Continuous positive airway pressure (CPAP) or sleep apnea-mitigating surgery) in the 2 months prior to screening

20. Have current malignancy, history of malignancy, or currently under work-up for suspected malignancy

21. Have known hypersensitivity to BMN 111 or its excipients

22. Have a history of hip surgery or severe hip dysplasia

23. Have a history of clinically significant hip injury in the 30 days prior to screening

24. Have a history of slipped capital femoral epiphysis or avascular necrosis of the femoral head

25. Have abnormal findings on baseline clinical hip exam or imaging assessments that are determined to be clinically significant as determined by the Investigator

26. 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

27. Have any concurrent disease or condition that, in the view of the Investigator, would interfere with study participation or safety evaluations, for any reason

1. Have hypochondroplasia or short stature condition other than ACH (e.g., trisomy 21, pseudoachondroplasia)

2. Have any of the following disorders:

• Hypothyroidism
• Insulin-requiring diabetes mellitus
• Autoimmune inflammatory disease (including celiac disease, lupus (SLE), juvenile dermatomyositis, scleroderma, and others)
• Inflammatory bowel disease
• Autonomic neuropathy

3. Have an unstable clinical condition likely to lead to intervention during the course of the study, including progressive cervical medullary compression

4. Have a history of any of the following:

• Renal insufficiency
• Anemia

5. Have a history of cardiac or vascular disease, including the following:

• Cardiac dysfunction
• Hypertrophic cardiomyopathy
• Congenital heart disease
• Cerebrovascular disease, aortic insufficiency
• Clinically significant atrial or ventricular arrhythmias

6. Current treatment 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, drugs known to alter renal function that is expected to continue for the duration of the study

7. Have had regular long-term treatment (> 1 month) with oral corticosteroids (low-dose ongoing inhaled steroid for asthma is acceptable) in the previous 3 month

8. Concomitant medication that prolongs the QT/QTc interval within 14 days or 5 half-lives, whichever is longer, before the Screening visit

9. Have used any other investigational product or investigational medical device for the treatment of ACH or short stature

10. Planned or expected bone-related surgery (ie. surgery involving disruption of bone cortex), during the study period.

11. Planned or expected to have limb-lengthening surgery during the study period.

12. Have any condition that, in the view of the Investigator, places the subject at high risk of poor compliance with the visit schedule or of not completing the study.

13. Concurrent disease or condition that, in the view of the Investigator, would interfere with study participation

• Maximum Eligible Age: 59 Months
• 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

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Baylor College of Medicine

Houston, Texas, 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

Osaka University Hospital

Osaka, , Japan

Saitama Children's Medical Center

Saitama, , Japan

Tokushima University Hospital

Tokushima, , Japan

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; Japan; United Kingdom

References

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)

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.

Reference Type: DERIVED

PMID: 37984383 (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

Description NIH Genetic and Rare Diseases Information Center resources: Achondroplasia

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

U.S. FDA Resources

Other Identifiers

2016-003826-18

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

111-206

Identifier Type: -

Identifier Source: org_study_id