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

• Register: EUCTR
• Last refreshed on: 7 January 2019
• Main ID: EUCTR2017-002404-28-ES
• Date of registration: 23/11/2018
• Prospective Registration: No
• Primary sponsor: BioMarin Pharmaceutical Inc.
• Public title: A Phase 3 Long-Term Extension Study to Evaluate the Safety and Efficacy of BMN 111 in Children with Achondroplasia
• Scientific title: A Phase 3, Open-Label Long-Term Extension Study to Evaluate the Safety and Efficacy of BMN 111 in Children with Achondroplasia
• Date of first enrolment: 08/11/2018
• Target sample size: 110
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-002404-28
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: Placebo: Other:
• 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. Must have completed Study 111-301 (eligible to enroll in 302 within 3 months after completing 111-301 at the discretion of the principal investigator and medical monitor).
2. 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 majority are willing and able to provide written assent (if required by local regulations or the IRB/IEC) after the nature of the study has been explained and prior to performance of any research-related procedure. Subjects who reach the age of majority in their country while the study is ongoing will be asked to provide their own written consent again upon reaching the legal age of majority.
3. Females = 10 years old or who have begun menses must have a negative pregnancy test at the Baseline Visit and be willing to have additional pregnancy tests during the study
4. If sexually active, are willing to use contraception as specified in section 9.3.3 of the protocol,
5. Are willing and able to perform all study procedures as physically possible
Are the trial subjects under 18? yes
Number of subjects for this age range: 108
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. Permanently discontinued BMN 111 or placebo prior to completion of Study 111-301
2. Have a clinically significant finding or arrhythmia on Baseline electrocardiogram (ECG) that indicates abnormal cardiac function or conduction or QTc-F > 450 msec
3. Evidence of decreased growth velocity (AGV < 1.5 cm/year) as assessed over a period of at least 6 months or of growth plate closure (proximal tibia, distal femur) through bilateral lower extremity X-rays including both AP and lateral views
4. Require any investigational agent prior to completion of study period
5. 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
6. Planned or expected to have limb-lengthening surgery during the study period.
7. Planned or expected bone-related surgery (ie. surgery involving disruption of bone cortex (excluding tooth extraction), during the study period.
8. Have had a fracture of the long bones or spine within 6 months prior to 111-302 baseline visit
9. Pregnant or breastfeeding at the Baseline Visit or planning to become pregnant (self or partner) at any time during the study
10. Concurrent disease or condition that, in the view of the investigator, would interfere with study participation or safety evaluations, for any reason
11. 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


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-

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-

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Anthropometric measurements: 111-301 Week52/302 BL, Weeks 13, 26,39, 52, 65, 78, 91, 104, every 26 weeks up to 260

Clinical labs; Vital signs/AEs; Physical exam; ECG; Anti-BMN 111 immunogenicity; bone metabolism biomarkers: 111-301 Week 52/302 BL, Day 1, Weeks 13, 26, 39, 52, 65, 78, 91, 104, every 26 weeks up to 260

X-Ray/DXA: 111-301 Week 52/302 BL, Weeks 52, 104, 156, 208, 260

Clinical hip assessment: 111-301 Week 52/302 BL, Weeks 26, 52, 78, 104, every 26 weeks up to 260

Salivary cortisol; serum prolactin; FSH/LH: 111-301 Week 52/302 BL, 26, 52, 78, 26 weeks up to week 260

CBCL and WeeFIM: 111-301 Week 52/302 BL, 26, 52, 78, 104, every 26 weeks up to 260

BMN 111 activity biomarkers: 111-301 Week 52/302 BL, Day1, Weeks 26, 52, 78, 104, every 26 weeks up to 260

Main Objective: The primary objective of this extension study is to:
- Evaluate the long-term safety, tolerability, and efficacy for growth in children with ACH treated with BMN 111

Secondary Objective: The secondary objectives of the study are to:
- Evaluate the pharmacokinetics of BMN 111
- Evaluate changes in health-related quality of life as measured by quality of life questionnaires
- Evaluate changes in daily activity performance as measured by activity of daily living (ADL) questionnaires
- Evaluate change from baseline in bone metabolism biomarkers

Primary end point(s): The primary efficacy endpoint is the change from baseline in annualized growth velocity (AGV).

Safety will be evaluated by the incidence of AEs, SAEs, and clinically significant changes in vital signs, physical examination, Tanner stage, ECG, echocardiogram, bone morphology/quality assessed by X-rays/DXA, and laboratory test results (urinalysis, chemistry, hematology). Additionally, imaging, hip monitoring, immunogenicity, salivary cortisol, serum prolactin, and FSH/LH levels (FSH/LH will be monitored for all subjects >8 years of age, and for subjects at Tanner stage 2, whichever is earlier); and anxiety, motor and cognitive assessment with the Childhood Behavioral Checklist (CBCL) and WeeFIM will be utilized for safety-related reviews and analysis. Additional assessments will be conducted to evaluate changes from baseline in bone metabolism and BMN 111 activity biomarkers.

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.

PK sampling will be carried out over the study period.

Health-related Quality of Life (HRQoL) and ADL questionnaires will be administered to assess quality of life and daily activities performance of study subjects.

Timepoint(s) of evaluation of this end point: Anthropometric measurements: 111-301 Week 52/302 BL, Weeks 13, 26, 39, 52, 65, 78, 91, 104, every 26 weeks up to Week 260

PK: 301 Week 52/302 BL, Day 1, Week 26, Week 52, Week 78, Week 104, every 26 weeks up to Week 260

Health-related Quality of Life (HRQoL) and ADL questionnaires: 111-301 Week 52/302 BL, Week 26, Week 52, Week 78, Week 104, every 26 weeks up to 260

Secondary ID(s)

111-302

111299

Source(s) of Monetary Support

BioMarin Pharmaceutical Inc.