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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
This is a Phase 2, open-label, sequential cohort dose-escalation study of BMN 111 in children with achondroplasia. The primary objective is to assess the safety and tolerability of daily BMN 111 administered to children with achondroplasia.
Trial website
https://clinicaltrials.gov/study/NCT02055157
Trial related presentations / publications
Chan ML, Qi Y, Larimore K, Cherukuri A, Seid L, Jayaram K, Jeha G, Fisheleva E, Day J, Huntsman-Labed A, Savarirayan R, Irving M, Bacino CA, Hoover-Fong J, Ozono K, Mohnike K, Wilcox WR, Horton WA, Henshaw J. Pharmacokinetics and Exposure-Response of Vosoritide in Children with Achondroplasia. Clin Pharmacokinet. 2022 Feb;61(2):263-280. doi: 10.1007/s40262-021-01059-1. Epub 2021 Aug 25.
Savarirayan R, Irving M, Bacino CA, Bostwick B, Charrow J, Cormier-Daire V, Le Quan Sang KH, Dickson P, Harmatz P, Phillips J, Owen N, Cherukuri A, Jayaram K, Jeha GS, Larimore K, Chan ML, Huntsman Labed A, Day J, Hoover-Fong J. C-Type Natriuretic Peptide Analogue Therapy in Children with Achondroplasia. N Engl J Med. 2019 Jul 4;381(1):25-35. doi: 10.1056/NEJMoa1813446. Epub 2019 Jun 18.
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



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT02055157