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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT02055157




Registration number
NCT02055157
Ethics application status
Date submitted
18/04/2013
Date registered
5/02/2014
Date last updated
15/01/2021

Titles & IDs
Public title
A Phase 2 Study of BMN 111 to Evaluate Safety, Tolerability, and Efficacy in Children With Achondroplasia
Scientific title
A Phase 2, Open-label, Sequential Cohort Dose-escalation Study of BMN 111 in Children With Achondroplasia
Secondary ID [1] 0 0
2013-004137-32
Secondary ID [2] 0 0
111-202
Universal Trial Number (UTN)
Trial acronym
ACH
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Achondroplasia 0 0
Condition category
Condition code
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders
Musculoskeletal 0 0 0 0
Other muscular and skeletal disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - BMN 111

Experimental: Cohort 1 - Cohort 1: 2.5 ug/kg

Experimental: Cohort 2 - Cohort 2: 7.5 ug/kg,

Experimental: Cohort 3 - Cohort 3: 15 ug/Kg

Experimental: Cohort 4 - Cohort 4: 30 ug/kg


Treatment: Drugs: BMN 111
BMN 111 will be administered daily for 24 months in an open-label sequential dose adjustment fashion.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Overall Summary of Adverse Events During Initial 6-Month Period
Timepoint [1] 0 0
Up to Month 6 ± 7 Days
Primary outcome [2] 0 0
Overall Summary of Adverse Events During Entire Study Period
Timepoint [2] 0 0
Up to Month 25 ± 7 Days
Secondary outcome [1] 0 0
Change From Baseline in Annualized Growth Velocity (AGV) During Initial 6-Month
Timepoint [1] 0 0
At 6 month (Day 183)
Secondary outcome [2] 0 0
Change From Baseline in Annualized Growth Velocity (AGV) During Entire Study Period - Cohort 3 and 4
Timepoint [2] 0 0
At month 24
Secondary outcome [3] 0 0
Change From Baseline in Annualized Growth Velocity (AGV) During Entire Study Period - Cohort 1 and 2 Switchers
Timepoint [3] 0 0
At month 24
Secondary outcome [4] 0 0
Change From Baseline in Height Z-Scores Using Centers for Disease Control and Prevention (CDC) Reference Standard During Initial 6-Months
Timepoint [4] 0 0
At month 6 (Day 183)
Secondary outcome [5] 0 0
Change From Baseline in Height Z-Scores Using CDC Reference Standard During Entire Study Period - Cohort 3 and 4
Timepoint [5] 0 0
At month 24
Secondary outcome [6] 0 0
Change From Baseline in Height Z-Scores Using CDC Reference Standard During Entire Study Period - Cohort 1 and 2 Switchers
Timepoint [6] 0 0
At month 24
Secondary outcome [7] 0 0
Change From Baseline in Upper to Lower Body Ratios During Initial 6-Months
Timepoint [7] 0 0
At month 6 (Day 183)
Secondary outcome [8] 0 0
Change From Baseline in Upper to Lower Body Ratios During Entire Study Period - Cohort 3 and 4
Timepoint [8] 0 0
At month 24
Secondary outcome [9] 0 0
Change From Baseline in Upper Arm Length to Lower Arm (Forearm) Length Ratio During Initial 6-Months
Timepoint [9] 0 0
At month 6 (Day 183)
Secondary outcome [10] 0 0
Change From Baseline in Upper Arm to Lower Arm Length Ratio During Entire Study Period - Cohort 3 and 4
Timepoint [10] 0 0
At month 24
Secondary outcome [11] 0 0
Change From Baseline in Upper to Lower Body Ratios During Entire Study Period - Cohort 1 and 2 Switchers
Timepoint [11] 0 0
At month 24
Secondary outcome [12] 0 0
Change From Baseline in Upper Arm to Lower Arm Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers
Timepoint [12] 0 0
At month 24
Secondary outcome [13] 0 0
Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Initial 6-months
Timepoint [13] 0 0
At month 6 (Day 183)
Secondary outcome [14] 0 0
Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Entire Study Period - Cohort 3 and 4
Timepoint [14] 0 0
At month 24
Secondary outcome [15] 0 0
Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers
Timepoint [15] 0 0
At month 24
Secondary outcome [16] 0 0
Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Initial 6-months
Timepoint [16] 0 0
At month 6 (Day 183)
Secondary outcome [17] 0 0
Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Entire Study Period - Cohort 3 and 4
Timepoint [17] 0 0
At month 24
Secondary outcome [18] 0 0
Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers
Timepoint [18] 0 0
At month 24
Secondary outcome [19] 0 0
Change From Baseline in Arm Span to Height Ratio During Initial 6-months
Timepoint [19] 0 0
At month 6 (Day 183)
Secondary outcome [20] 0 0
Change From Baseline in Arm Span to Height Ratio During Entire Study Period - Cohort 3 and 4
Timepoint [20] 0 0
At month 24
Secondary outcome [21] 0 0
Change From Baseline in Arm Span to Height Ratio During Entire Study Period - Cohort 1 and 2 Switchers
Timepoint [21] 0 0
At month 24

Eligibility
Key inclusion criteria
* Parent(s) or guardian(s) are willing and able to provide written, signed informed consent
* 5 to 14 years old at end of study
* ACH, documented by clinical grounds, confirmed by genetic testing
* At least 6-month of pretreatment growth assessment in Study 111-901 before study entry, and one standing height at least 6 months prior to screening for 111-202
* Negative pregnancy test at the Screening Visit for females = 10 years old or who have begun menses
* If sexually active, willing to use a highly effective method of contraception while participating in the study
* Ambulatory, able to stand without assistance
* Willing and able to perform all study procedures as physically possible
* Parents/caregivers willing to administer daily injections to the subjects

Additional inclusion Criteria Optional, Open-label Extension Phase:

* Appropriate written informed consent
Minimum age
5 Years
Maximum age
14 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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
* Recent acute illness associated with volume dehydration not completely resolved prior to the first dose of study drug
* Unstable condition requiring surgical intervention during the study
* Growth plates have fused
* Have a history of any of the following:

* Renal insufficiency, defined as creatinine > 2 mg/dl
* Anemia
* Baseline systolic BP < 75 mm Hg or recurrent symptomatic hypotension or recurrent symptomatic hypotension, recurrent symptomatic orthostatic hypotension
* Cardiac or vascular disease, including the following:

* Cardiac dysfunction (abnormal echocardiogram [ECHO] including left ventricle [LV] mass) at Screening Visit
* Hypertrophic cardiomyopathy
* Pulmonary Hypertension
* Congenital heart disease with ongoing cardiac dysfunction
* Cerebrovascular disease
* Aortic insufficiency
* Clinically significant atrial or ventricular arrhythmias
* Have an ECG showing any of the following:

* Right or left atrial enlargement or ventricular hypertrophy
* PR (period of time from the beginning of atrial depolarization until the beginning of ventricular depolarization) interval > 200 msec
* QRS (The Q, R, and S heart waves that are measured on an electrocardiogram) interval > 110 msec
* Corrected QTc-F (Measure of the corrected time between the start of the Q wave and end of the T wave in the heart's electrical cycle) > 450 msec
* Second- or third-degree atrioventricular block
* Documented Vitamin D deficiency
* Require any investigational agent prior to completion of study period
* Have received another investigational product or investigational medical device within 30 days before the Screening visit
* Use of any other investigational product or investigational medical device for the treatment of ACH or short stature
* Current chronic therapy 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, diuretics, or other drugs known to alter renal or tubular function
* Treatment with growth hormone, IGF-1 (Insulin-like growth factor), or anabolic steroids in the previous 6 months or long-term treatment (> 3 months) at any time
* Long-term treatment (> 1 month) with oral corticosteroids
* Concomitant medication that prolongs the QT/QTc-F interval within 14 days or 5 half-lives, whichever is longer, before the Screening visit
* Pregnant or breastfeeding at the Screening Visit or planning to become pregnant (self or partner) at any time during the study
* Limb-lengthening or bone-related surgery < 18 months prior to study enrollment
* Had a fracture of the long bones or spine within 6 months prior to screening (except for fracture of digits or toes)
* AST (Aspartate Transaminase) or ALT (Alanine Transaminase) at least 3x upper limit of normal (ULN) or total bilirubin at least 2x ULN
* Evidence of severe sleep apnea requiring surgery or new initiation of CPAP (Continuous positive airway pressure).
* History of malignancy and chemotherapy/radiation or currently under work-up for suspected malignancy
* Known hypersensitivity to BMN 111 or its excipients
* 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
* Concurrent disease or condition that would interfere with study participation or safety
* Have abnormal findings on baseline clinical hip exam or imaging assessments that are determined to be clinically significant as determined by the PI.
* Have a history of hip surgery or severe hip dysplasia
* Have a 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.
* Are unable to lie flat when in prone position

Additional Exclusion Criteria for Optional, Open-label Extension Phase:

* Use of restricted therapies during the initial 6 months of the study
* Permanently discontinued BMN 111 during the initial 6 months of the study

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
13/01/2014
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
2/10/2017
Sample size
Target
Accrual to date
Final
35
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
Murdoch Children's Research Institute - Parkville
Recruitment postcode(s) [1] 0 0
3052 - Parkville
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Illinois
Country [3] 0 0
United States of America
State/province [3] 0 0
Maryland
Country [4] 0 0
United States of America
State/province [4] 0 0
Tennessee
Country [5] 0 0
United States of America
State/province [5] 0 0
Texas
Country [6] 0 0
France
State/province [6] 0 0
Paris
Country [7] 0 0
United Kingdom
State/province [7] 0 0
London

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
BioMarin Pharmaceutical
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director, MD
Address 0 0
BioMarin Pharmaceutical
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

No information has been provided regarding IPD availability


What supporting documents are/will be available?




Results publications and other study-related documents

No documents have been uploaded by study researchers.

Results are available at https://clinicaltrials.gov/study/NCT02055157