A Phase 3 Study to Evaluate the Safety and Efficacy of BMN 111 in Children with Achondroplasia

• Register: EUCTR
• Last refreshed on: 30 April 2019
• Main ID: EUCTR2015-003836-11-GB
• Date of registration: 20/10/2016
• Prospective Registration: Yes
• Primary sponsor: BioMarin Pharmaceutical Inc.
• Public title: A Phase 3 Study to Evaluate the Safety and Efficacy of BMN 111 in Children with Achondroplasia
• Scientific title: A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of BMN 111 in Children with Achondroplasia.
• Date of first enrolment: 20/01/2017
• Target sample size: 110
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-003836-11
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

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

Contacts

• Name: Clinical Trials Information
• Affiliation: BioMarin Pharmaceutical Inc.

• Name: Clinical Trials Information
• Affiliation: BioMarin Pharmaceutical Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
1. Parent(s) or guardian(s) 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. Also, subjects under the age of 18 are willing and able to provide written assent (if required by local regulations or the IRB/EC) after the nature of the study has been explained and prior to performance of any research-related procedure. Subjects who reach the age of 18 years while the study is ongoing will be asked to provide their own written consent.
2. 5 to < 18 years old at study entry
3. Have ACH, documented by clinical grounds and confirmed by genetic testing
4. Have at least a 6-month period of pretreatment growth assessments, including standing height, and are currently active participants in 111-901.
5. Females = 10 years old or who have begun menses must have a negative pregnancy test at the Screening Visit and be willing to have additional pregnancy tests during the study
6. If sexually active, willing to use a highly effective method of contraception while participating in the study
7. Are ambulatory and able to stand without assistance
8. Are willing and able to perform all study procedures as physically possible
9. Caregivers are willing to administer daily injections to the subjects and complete the required training
Are the trial subjects under 18? yes
Number of subjects for this age range: 110
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 2
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. Have hypochondroplasia or short stature condition other than ACH (e.g., trisomy 21, pseudoachondroplasia)
2. Have any of the following: Hypothyroidism or hyperthyroidism; Insulin-requiring diabetes mellitus; Autoimmune
inflammatory disease (including celiac disease, lupus (SLE), juvenile dermatomyositis, scleroderma, and others); Inflammatory bowel disease; Autonomic neuropathy
3. Have a 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 i.e., dizziness, fainting) or recurrent symptomatic orthostatic hypotension; Cardiac or vascular disease (including Cardiac dysfunction (abnormal echocardiogram) at Screening Visit; Hypertrophic cardiomyopathy; Pulmonary hypertension; Congenital heart disease; Cerebrovascular disease; Aortic insufficiency or other clin significant valvular dysfunction; Clinically significant atrial or ventricular arrhythmias)
4. Have a clinically significant finding or arrhythmia on screening electrocardiogram (ECG) that indicates abnormal cardiac function or conduction or QTc-F > 450 msec
5. Have an unstable condition likely to require surgical intervention during the study (including progressive cervical medullary compression or severe untreated sleep apnea)
6. Evidence of decreased growth velocity (AGV<1.5 cm/y) as assessed over a period of at least 6 mths or of growth plate closure (proximal tibia, distal femur) through bilateral lower extremity X-rays including both AP and lateral views
7. Documented Vitamin D deficiency (concentration of blood 25-hydroxy-vitamin D <12 ng/mL or <30 nmol/L)
8. Require any investigational agent prior to completion of study period9. Have received another investigational product or investigational medical device within 6 mths before the Screening Visit
10. Have used any investigational product or investigational medical device for the treatment of ACH or short stature at any time, including BMN 111
11. Current therapy with antihypertensive medications, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, diuretics, beta-blockers, calcium-channel blockers, cardiac glycosides, systemic anticholinergic agents, GnRH agonists, any medication that may impair or enhance compensatory tachycardia, diuretics, or other drugs known to alter renal or tubular function
12. Have been 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
13. Have had > 1 month treatment with oral corticosteroids (low-dose ongoing inhaled steroid for asthma, or intranasal steroids, are acceptable) in the previous 12 months
14. 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 screening and healing is complete without sequelae.
15. Planned or expected bone-related surgery (ie. surgery involving disruption of bone cortex, excluding tooth extraction), during the study period.

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

achondroplasia
MedDRA version: 20.0 Level: LLT Classification code 10000452 Term: Achondroplasia System Organ Class: 100000004850

Therapeutic area: Body processes [G] - Bones and nerves physological processes [G11]

Intervention(s)

Product Name: modified recombinant human C-type natriuretic peptide
Product Code: BMN 111
Pharmaceutical Form: Lyophilisate for solution for injection
INN or Proposed INN: Vosoritide
CAS Number: 1480724-61-5
Current Sponsor code: BMN 111
Other descriptive name: MODIFIED RHCNP
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 0.8-
Pharmaceutical form of the placebo: Lyophilisate and solvent for solution for injection
Route of administration of the placebo: Subcutaneous use

Product Name: modified recombinant human C-type natriuretic peptide
Product Code: BMN 111
Pharmaceutical Form: Lyophilisate for solution for injection
INN or Proposed INN: Vosoritide
CAS Number: 1480724-61-5
Current Sponsor code: BMN 111
Other descriptive name: MODIFIED RHCNP
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 2-
Pharmaceutical form of the placebo: Lyophilisate and solvent for solution for injection
Route of administration of the placebo: Subcutaneous use

Product Name: modified recombinant human C-type natriuretic peptide
Product Code: BMN 111
Pharmaceutical Form: Lyophilisate for solution for injection
INN or Proposed INN: Vosoritide
CAS Number: 1480724-61-5
Current Sponsor code: BMN 111
Other descriptive name: MODIFIED RHCNP
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-
Pharmaceut

Primary Outcome(s)

Primary end point(s): The primary efficacy endpoint is the change from baseline in annualized growth velocity (AGV) at Week 52 (12- month).

Timepoint(s) of evaluation of this end point: Anthropometric measurements: Screen, Day 1, Week 13, Week 26, Week 39, Week 52

Secondary Objective: •Evaluate change from baseline in height Z-score in subjects treated with BMN 111 compared with control subjects in the placebo group at 52 weeks
•Evaluate change from baseline in upper:lower segment body ratio in subjects treated with BMN 111 compared with control subjects in the placebo group at 52 weeks
•Evaluate safety and tolerability of BMN 111 in children with ACH
•Evaluate the pharmacokinetics of BMN 111
•Evaluate change from baseline in bone metabolism biomarkers

Main Objective: Evaluate change from baseline in annualized growth velocity at 52 weeks in subjectstreated with BMN 111 compared with control subjects in the placebo group

Secondary Outcome(s)

Secondary end point(s): The secondary efficacy endpoints include the change from baseline in height Z-score and the change from baseline in upper:lower body segment ratio.

Safety will be evaluated by assessment of AEs, SAEs, laboratory test results (urinalysis, chemistry, hematology), changes in vital signs, physical examination, ECG, X-rays/DXA, clinical hip assessment, and anti-BMN 111 immunogenicity assessments.

PK sampling will be carried out over the 12-month study period in subjects randomized to BMN 111 or placebo.

Timepoint(s) of evaluation of this end point: Anthropometric measurements: Screen, Day 1, Week 13, Week 26, Week 39, Week 52

Clinical labs (urinalysis, chemistry, hematology): Screen, Day 1, Day 10, Week 6, Week 13, Week 26, Week 39, Week 52, Week 54

Vital signs and AEs: Screen, Day 1, Day 2, Day 3, Day 10, Week 6, Week 26, Week 39, Week 52, Week 54 (follow-up)

Physical exam: Screen, Day 1, Day 10, Week 6, Week 13, Week 26, Week 39, Week 52, Week 54 (follow-up)

ECG: Screen, Day 1, Day 10, Week 13, Week 26, Week 39, Week 52, Week 54 (follow-up)

X-Ray/DXA: Screen, Week 26, Week 52

Clinical hip assessment: Screen, Week 26, Week 52

Anti-BMN 111 immunogenicity: Day 1, Week 13, Week 26, Week 39, Week 52, Week 54 (follow-up)

PK: Day 1 (full), Week 13 (partial), Week 26 (full), Week 39 (partial), Week 52 (full)

Secondary ID(s)

111-301

Source(s) of Monetary Support

BioMarin Pharmaceutical Inc.

Ethics review

Status: Approved
Approval date:
Contact: