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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/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
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Scientific title
A Phase 2, Open-label, Sequential Cohort Dose-escalation Study of BMN 111 in Children With Achondroplasia
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Secondary ID [1]
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2013-004137-32
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Secondary ID [2]
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111-202
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Universal Trial Number (UTN)
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Trial acronym
ACH
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Achondroplasia
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Condition category
Condition code
Human Genetics and Inherited Disorders
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Other human genetics and inherited disorders
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Musculoskeletal
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Other muscular and skeletal disorders
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Intervention/exposure
Study type
Interventional
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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.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Overall Summary of Adverse Events During Initial 6-Month Period
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Assessment method [1]
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A treatment-emergent Adverse Events (TEAE) is any Adverse Events that newly appeared, increased in frequency or worsened in severity following initiation of study drug administration.
Serious adverse event (SAE).
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Timepoint [1]
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Up to Month 6 ± 7 Days
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Primary outcome [2]
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Overall Summary of Adverse Events During Entire Study Period
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Assessment method [2]
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A treatment-emergent Adverse Events (TEAE) is any Adverse Events that newly appeared, increased in frequency or worsened in severity following initiation of study drug administration.
TEAE - Treatment-emergent adverse event. SAE - Serious adverse event.
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Timepoint [2]
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Up to Month 25 ± 7 Days
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Secondary outcome [1]
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Change From Baseline in Annualized Growth Velocity (AGV) During Initial 6-Month
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Assessment method [1]
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Annualized Growth Velocity at Day 183 is assessed on standing height as ((Height at Day 183 Visit - Height at Baseline Visit)/(Date at Day 183 Visit - Baseline Visit Date)) x 365.25.
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Timepoint [1]
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At 6 month (Day 183)
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Secondary outcome [2]
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Change From Baseline in Annualized Growth Velocity (AGV) During Entire Study Period - Cohort 3 and 4
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Assessment method [2]
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Annualized Growth Velocity at Day 183 visit is assessed on standing height as ((Height at Day 183 Visit - Height at Baseline Visit)/(Date at Day 183 Visit - Baseline Visit Date)) x 365.25.
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Timepoint [2]
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At month 24
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Secondary outcome [3]
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Change From Baseline in Annualized Growth Velocity (AGV) During Entire Study Period - Cohort 1 and 2 Switchers
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Assessment method [3]
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Annualized Growth Velocity at 1st visit with >= 12 months on 15ug/kg is assessed on standing height as ((Height at 1st Visit with >= 12 Months on 15 µg/kg - Height at 1st Visit on 15 µg/kg)/(Date of the 1st Visit with >= 12 months on 15 µg/kg - Date of at 1st Visit on 15 µg/kg)) x 365.25.
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Timepoint [3]
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At month 24
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Secondary outcome [4]
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Change From Baseline in Height Z-Scores Using Centers for Disease Control and Prevention (CDC) Reference Standard During Initial 6-Months
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Assessment method [4]
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Height Z scores indicates how far a particular child is from the average height for children of the same sex and age. A positive height Z score indicates the child's height is above average whilst a negative Z score indicates the child's height is below average. Height Z scores below -2 Standard Deviation Scores (SDs) indicate a child's height is no longer within normal height range for average stature children of the same sex and age.
Z-scores are derived using non-ACH age-sex-specific reference data (means and standard deviations) per Centers for Disease Control and Prevention (CDC).
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Timepoint [4]
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At month 6 (Day 183)
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Secondary outcome [5]
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Change From Baseline in Height Z-Scores Using CDC Reference Standard During Entire Study Period - Cohort 3 and 4
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Assessment method [5]
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Height Z scores indicates how far a particular child is from the average height for children of the same sex and age. A positive height Z score indicates the child's height is above average whilst a negative Z score indicates the child's height is below average. Height Z scores below -2 SDs indicate a child's height is no longer within normal height range for average stature children of the same sex and age.
Z-scores are derived using non-ACH age-sex-specific reference data (means and standard deviations) per Centers for Disease Control and Prevention (CDC).
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Timepoint [5]
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At month 24
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Secondary outcome [6]
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Change From Baseline in Height Z-Scores Using CDC Reference Standard During Entire Study Period - Cohort 1 and 2 Switchers
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Assessment method [6]
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Height Z scores indicates how far a particular child is from the average height for children of the same sex and age. A positive height Z score indicates the child's height is above average whilst a negative Z score indicates the child's height is below average. Height Z scores below -2 SDs indicate a child's height is no longer within normal height range for average stature children of the same sex and age.
Z-scores are derived using non-ACH age-sex-specific reference data (means and standard deviations) per Centers for Disease Control and Prevention (CDC).
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Timepoint [6]
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At month 24
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Secondary outcome [7]
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Change From Baseline in Upper to Lower Body Ratios During Initial 6-Months
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Assessment method [7]
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The Upper to Lower Body ratio prior to treatment, at baseline, and through 6 months is assessed on Sitting Height / (Standing Height - Sitting Height)
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Timepoint [7]
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At month 6 (Day 183)
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Secondary outcome [8]
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Change From Baseline in Upper to Lower Body Ratios During Entire Study Period - Cohort 3 and 4
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Assessment method [8]
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The Upper to Lower Body ratio prior to treatment, at baseline, and through 24 months is assessed on Sitting Height / (Standing Height - Sitting Height)
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Timepoint [8]
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At month 24
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Secondary outcome [9]
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Change From Baseline in Upper Arm Length to Lower Arm (Forearm) Length Ratio During Initial 6-Months
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Assessment method [9]
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The Upper Arm Length to Lower Arm (Forearm) Length ratio prior to treatment, at baseline, and through 6 months is assessed on Upper Arm Length / Lower Arm (Forearm) Length.
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Timepoint [9]
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At month 6 (Day 183)
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Secondary outcome [10]
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Change From Baseline in Upper Arm to Lower Arm Length Ratio During Entire Study Period - Cohort 3 and 4
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Assessment method [10]
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The Upper Arm Length to Lower Arm (Forearm) Length ratio prior to treatment, at baseline, and through 24 months is assessed on Upper Arm Length / Lower Arm (Forearm) Length.
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Timepoint [10]
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At month 24
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Secondary outcome [11]
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Change From Baseline in Upper to Lower Body Ratios During Entire Study Period - Cohort 1 and 2 Switchers
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Assessment method [11]
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The Upper to Lower Body ratio prior to treatment, at baseline, and through 24 months is assessed on Sitting Height / (Standing Height - Sitting Height)
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Timepoint [11]
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At month 24
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Secondary outcome [12]
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Change From Baseline in Upper Arm to Lower Arm Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers
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Assessment method [12]
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The Upper Arm Length to Lower Arm (Forearm) Length ratio prior to treatment, at baseline, and through 24 months is assessed on Upper Arm Length / Lower Arm (Forearm) Length.
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Timepoint [12]
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At month 24
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Secondary outcome [13]
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Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Initial 6-months
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Assessment method [13]
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The Upper Leg Length (Thigh) to Knee to Heel Length Ratio prior to treatment, at baseline, and through 6 months is assessed on Upper Leg Length (Thigh) / Knee to Heel Length.
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Timepoint [13]
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At month 6 (Day 183)
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Secondary outcome [14]
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Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Entire Study Period - Cohort 3 and 4
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Assessment method [14]
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The Upper Leg Length (Thigh) to Knee to Heel Length Ratio prior to treatment, at baseline, and through 24 months is assessed by Upper Leg Length (Thigh) / Knee to Heel Length.
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Timepoint [14]
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At month 24
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Secondary outcome [15]
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Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers
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Assessment method [15]
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The Upper Leg Length (Thigh) to Knee to Heel Length Ratio prior to treatment, at baseline, and through 24 months is assessed by Upper Leg Length (Thigh) / Knee to Heel Length.
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Timepoint [15]
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At month 24
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Secondary outcome [16]
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Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Initial 6-months
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Assessment method [16]
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The Upper Leg Length (Thigh) to Tibial Length Ratio prior to treatment, at baseline, and through 6 months is assessed by Upper Leg Length (Thigh)/ Tibial Leg Length.
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Timepoint [16]
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At month 6 (Day 183)
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Secondary outcome [17]
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Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Entire Study Period - Cohort 3 and 4
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Assessment method [17]
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The Upper Leg Length (Thigh) to Tibial Length Ratio prior to treatment, at baseline, and through 24 months is assessed by Upper Leg Length (Thigh)/ Tibial Leg Length.
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Timepoint [17]
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At month 24
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Secondary outcome [18]
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Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers
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Assessment method [18]
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The Upper Leg Length (Thigh) to Tibial Length Ratio prior to treatment, at baseline, and through 24 months is assessed by Upper Leg Length (Thigh)/ Tibial Leg Length.
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Timepoint [18]
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At month 24
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Secondary outcome [19]
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Change From Baseline in Arm Span to Height Ratio During Initial 6-months
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Assessment method [19]
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The Arm Span to Height Ratio prior to treatment, at baseline, and through 6 months is assessed by Arm Span / Standing Height.
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Timepoint [19]
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At month 6 (Day 183)
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Secondary outcome [20]
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Change From Baseline in Arm Span to Height Ratio During Entire Study Period - Cohort 3 and 4
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Assessment method [20]
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The Arm Span to Height Ratio prior to treatment, at baseline, and through 24 months is assessed by Arm Span / Standing Height.
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Timepoint [20]
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At month 24
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Secondary outcome [21]
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Change From Baseline in Arm Span to Height Ratio During Entire Study Period - Cohort 1 and 2 Switchers
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Assessment method [21]
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The Arm Span to Height Ratio prior to treatment, at baseline, and through 24 months is assessed by Arm Span / Standing Height.
Values are not available for participants in cohort 1 switchers for Change from Baseline to >=12 Months on 15ug/kg.
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Timepoint [21]
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At month 24
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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
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Minimum age
5
Years
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Maximum age
14
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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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
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Other
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Other design features
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Phase
Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
13/01/2014
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
2/10/2017
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Sample size
Target
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Accrual to date
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Final
35
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Recruitment in Australia
Recruitment state(s)
VIC
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Recruitment hospital [1]
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Murdoch Children's Research Institute - Parkville
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Recruitment postcode(s) [1]
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3052 - Parkville
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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California
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Country [2]
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United States of America
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State/province [2]
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Illinois
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Country [3]
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United States of America
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State/province [3]
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Maryland
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Country [4]
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United States of America
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State/province [4]
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Tennessee
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Country [5]
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United States of America
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State/province [5]
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Texas
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Country [6]
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France
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State/province [6]
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Paris
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Country [7]
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United Kingdom
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State/province [7]
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London
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
BioMarin Pharmaceutical
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Address
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Country
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Ethics approval
Ethics application status
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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.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT02055157
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Medical Director, MD
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Address
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BioMarin Pharmaceutical
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT02055157
Download to PDF