Achondroplasia
Conditions
Keywords
Achondroplasia, Dwarfism, Bone Diseases, Developmental, Bone Diseases
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.
Interventions
DRUGBMN 111
BMN 111 will be administered daily for 24 months in an open-label sequential dose adjustment fashion.
Sponsors
BioMarin Pharmaceutical
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
5 Years to 14 Years
Healthy volunteers
No
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
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Summary of Adverse Events During Initial 6-Month Period | Up to Month 6 ± 7 Days | 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). |
| Overall Summary of Adverse Events During Entire Study Period | Up to Month 25 ± 7 Days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Annualized Growth Velocity (AGV) During Entire Study Period - Cohort 1 and 2 Switchers | At month 24 | 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. |
| Change From Baseline in Height Z-Scores Using Centers for Disease Control and Prevention (CDC) Reference Standard During Initial 6-Months | At month 6 (Day 183) | 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). |
| Change From Baseline in Height Z-Scores Using CDC Reference Standard During Entire Study Period - Cohort 3 and 4 | At month 24 | 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). |
| Change From Baseline in Height Z-Scores Using CDC Reference Standard During Entire Study Period - Cohort 1 and 2 Switchers | At month 24 | 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). |
| Change From Baseline in Upper to Lower Body Ratios During Initial 6-Months | At month 6 (Day 183) | The Upper to Lower Body ratio prior to treatment, at baseline, and through 6 months is assessed on Sitting Height / (Standing Height - Sitting Height) |
| Change From Baseline in Upper to Lower Body Ratios During Entire Study Period - Cohort 3 and 4 | At month 24 | The Upper to Lower Body ratio prior to treatment, at baseline, and through 24 months is assessed on Sitting Height / (Standing Height - Sitting Height) |
| Change From Baseline in Upper Arm Length to Lower Arm (Forearm) Length Ratio During Initial 6-Months | At month 6 (Day 183) | 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. |
| Change From Baseline in Upper Arm to Lower Arm Length Ratio During Entire Study Period - Cohort 3 and 4 | At month 24 | 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. |
| Change From Baseline in Upper to Lower Body Ratios During Entire Study Period - Cohort 1 and 2 Switchers | At month 24 | The Upper to Lower Body ratio prior to treatment, at baseline, and through 24 months is assessed on Sitting Height / (Standing Height - Sitting Height) |
| Change From Baseline in Annualized Growth Velocity (AGV) During Initial 6-Month | At 6 month (Day 183) | 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. |
| Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Initial 6-months | At month 6 (Day 183) | 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. |
| Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Entire Study Period - Cohort 3 and 4 | At month 24 | 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. |
| Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers | At month 24 | 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. |
| Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Initial 6-months | At month 6 (Day 183) | 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. |
| Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Entire Study Period - Cohort 3 and 4 | At month 24 | 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. |
| Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers | At month 24 | 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. |
| Change From Baseline in Arm Span to Height Ratio During Initial 6-months | At month 6 (Day 183) | The Arm Span to Height Ratio prior to treatment, at baseline, and through 6 months is assessed by Arm Span / Standing Height. |
| Change From Baseline in Arm Span to Height Ratio During Entire Study Period - Cohort 3 and 4 | At month 24 | The Arm Span to Height Ratio prior to treatment, at baseline, and through 24 months is assessed by Arm Span / Standing Height. |
| Change From Baseline in Arm Span to Height Ratio During Entire Study Period - Cohort 1 and 2 Switchers | At month 24 | 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. |
| Change From Baseline in Upper Arm to Lower Arm Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers | At month 24 | 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. |
| Change From Baseline in Annualized Growth Velocity (AGV) During Entire Study Period - Cohort 3 and 4 | At month 24 | 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. |
Countries
Australia, France, United Kingdom, United States
Participant flow
Recruitment details
This study was conducted at nine study centers in United States, Australia, United Kingdom and France.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Initial 6 months: BMN 111 at 2.5 μg/kg daily subcutaneous injection, over a period of 6 months.
18-month extension: BMN 111 at 2.5 μg/kg daily subcutaneous injection, dose determined to be suboptimal after the end of the initial 6 months, 7 subjects escalated to 7.5 μg/kg daily subcutaneous injection, discontinued 1 subject escalating 6 subjects to BMN 111 at 15.0 μg/kg daily subcutaneous injection, over a period of 18 months. | 8 |
| Cohort 2 Initial 6 months: BMN 111 at 7.5 μg/kg daily subcutaneous injection, over a period of 6 months.
18-month extension: BMN 111 at 7.5 μg/kg daily subcutaneous injection, dose determined to be suboptimal after the end of the initial 6 months, discontinued 1 subject escalating 6 subjects to BMN 111 at 15.0 μg/kg daily subcutaneous injection, over a period of 18 months. | 8 |
| Cohort 3 Initial 6 months: BMN 111 at 15.0 μg/kg daily subcutaneous injection, over a period of 6 months.
18-month extension: BMN 111 at 15.0 μg/kg daily subcutaneous injection, over a period of 18 months. | 10 |
| Cohort 4 Initial 6 months: BMN 111 at 30.0 μg/kg daily subcutaneous injection, over a period of 6 months.
18-month extension: BMN 111 at 30.0 μg/kg daily subcutaneous injection, over a period of 18 months. | 9 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| 18-month Extension | Investigator decision | 0 | 1 | 0 | 0 |
| 18-month Extension | Subject discontinued due to NeedlePhobia | 1 | 0 | 0 | 0 |
| Initial 6 Months | Adverse Event | 0 | 0 | 0 | 1 |
| Initial 6 Months | Consent withdrawn by subject | 1 | 0 | 0 | 0 |
| Initial 6 Months | Subject discontinued due to NeedlePhobia | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort 1 | Total | Cohort 4 | Cohort 3 | Cohort 2 |
|---|---|---|---|---|---|
| Age, Continuous | 7.3 yrs STANDARD_DEVIATION 1.58 | 7.6 yrs STANDARD_DEVIATION 1.68 | 6.9 yrs STANDARD_DEVIATION 1.17 | 8.0 yrs STANDARD_DEVIATION 1.63 | 8.3 yrs STANDARD_DEVIATION 2.19 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 32 Participants | 7 Participants | 9 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 7 Participants | 3 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 7 Participants | 24 Participants | 6 Participants | 5 Participants | 6 Participants |
| Sex: Female, Male Female | 5 Participants | 19 Participants | 5 Participants | 6 Participants | 3 Participants |
| Sex: Female, Male Male | 3 Participants | 16 Participants | 4 Participants | 4 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 | 0 / 10 | 0 / 9 | 0 / 7 | 0 / 14 | 0 / 22 | 0 / 8 | 0 / 8 | 0 / 15 | 0 / 22 | 0 / 9 |
| other Total, other adverse events | 8 / 8 | 8 / 8 | 10 / 10 | 9 / 9 | 7 / 7 | 13 / 14 | 22 / 22 | 8 / 8 | 8 / 8 | 14 / 15 | 22 / 22 | 9 / 9 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 10 | 0 / 9 | 1 / 7 | 0 / 14 | 1 / 22 | 1 / 8 | 1 / 8 | 0 / 15 | 1 / 22 | 1 / 9 |
Outcome results
Primary
Overall Summary of Adverse Events During Entire Study Period
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.
Time frame: Up to Month 25 ± 7 Days
Population: Safety Analysis Population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 | Overall Summary of Adverse Events During Entire Study Period | Subjects Least Reported Study Drug-Related SAE | 0 Participants |
| Cohort 1 | Overall Summary of Adverse Events During Entire Study Period | Subjects Least Reported Study Drug-Related TEAE | 7 Participants |
| Cohort 1 | Overall Summary of Adverse Events During Entire Study Period | Subjects Who Died | 0 Participants |
| Cohort 1 | Overall Summary of Adverse Events During Entire Study Period | Subjects with at Least 1 Reported SAE | 1 Participants |
| Cohort 1 | Overall Summary of Adverse Events During Entire Study Period | Subjects with at Least 1 Reported TEAE | 8 Participants |
| Cohort 2 | Overall Summary of Adverse Events During Entire Study Period | Subjects with at Least 1 Reported SAE | 0 Participants |
| Cohort 2 | Overall Summary of Adverse Events During Entire Study Period | Subjects Least Reported Study Drug-Related SAE | 0 Participants |
| Cohort 2 | Overall Summary of Adverse Events During Entire Study Period | Subjects Who Died | 0 Participants |
| Cohort 2 | Overall Summary of Adverse Events During Entire Study Period | Subjects Least Reported Study Drug-Related TEAE | 8 Participants |
| Cohort 2 | Overall Summary of Adverse Events During Entire Study Period | Subjects with at Least 1 Reported TEAE | 8 Participants |
| Cohort 3 | Overall Summary of Adverse Events During Entire Study Period | Subjects with at Least 1 Reported SAE | 1 Participants |
| Cohort 3 | Overall Summary of Adverse Events During Entire Study Period | Subjects with at Least 1 Reported TEAE | 10 Participants |
| Cohort 3 | Overall Summary of Adverse Events During Entire Study Period | Subjects Least Reported Study Drug-Related TEAE | 9 Participants |
| Cohort 3 | Overall Summary of Adverse Events During Entire Study Period | Subjects Least Reported Study Drug-Related SAE | 0 Participants |
| Cohort 3 | Overall Summary of Adverse Events During Entire Study Period | Subjects Who Died | 0 Participants |
| Cohort 4 | Overall Summary of Adverse Events During Entire Study Period | Subjects Least Reported Study Drug-Related SAE | 0 Participants |
| Cohort 4 | Overall Summary of Adverse Events During Entire Study Period | Subjects Least Reported Study Drug-Related TEAE | 9 Participants |
| Cohort 4 | Overall Summary of Adverse Events During Entire Study Period | Subjects with at Least 1 Reported TEAE | 9 Participants |
| Cohort 4 | Overall Summary of Adverse Events During Entire Study Period | Subjects with at Least 1 Reported SAE | 1 Participants |
| Cohort 4 | Overall Summary of Adverse Events During Entire Study Period | Subjects Who Died | 0 Participants |
Primary
Overall Summary of Adverse Events During Initial 6-Month Period
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).
Time frame: Up to Month 6 ± 7 Days
Population: Safety Analysis Population includes all subjects who received at least one dose of study treatment and were used for safety analysis in the initial 6-month period and entire study period.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 | Overall Summary of Adverse Events During Initial 6-Month Period | Subjects Least Reported Study Drug-Related SAE | 0 Participants |
| Cohort 1 | Overall Summary of Adverse Events During Initial 6-Month Period | Subjects Least Reported Study Drug-Related TEAE | 7 Participants |
| Cohort 1 | Overall Summary of Adverse Events During Initial 6-Month Period | Subjects Who Died | 0 Participants |
| Cohort 1 | Overall Summary of Adverse Events During Initial 6-Month Period | Subjects with at Least 1 Reported SAE | 0 Participants |
| Cohort 1 | Overall Summary of Adverse Events During Initial 6-Month Period | Subjects with at Least 1 Reported TEAE | 8 Participants |
| Cohort 2 | Overall Summary of Adverse Events During Initial 6-Month Period | Subjects with at Least 1 Reported SAE | 0 Participants |
| Cohort 2 | Overall Summary of Adverse Events During Initial 6-Month Period | Subjects Least Reported Study Drug-Related SAE | 0 Participants |
| Cohort 2 | Overall Summary of Adverse Events During Initial 6-Month Period | Subjects Who Died | 0 Participants |
| Cohort 2 | Overall Summary of Adverse Events During Initial 6-Month Period | Subjects Least Reported Study Drug-Related TEAE | 8 Participants |
| Cohort 2 | Overall Summary of Adverse Events During Initial 6-Month Period | Subjects with at Least 1 Reported TEAE | 8 Participants |
| Cohort 3 | Overall Summary of Adverse Events During Initial 6-Month Period | Subjects with at Least 1 Reported SAE | 0 Participants |
| Cohort 3 | Overall Summary of Adverse Events During Initial 6-Month Period | Subjects with at Least 1 Reported TEAE | 10 Participants |
| Cohort 3 | Overall Summary of Adverse Events During Initial 6-Month Period | Subjects Least Reported Study Drug-Related TEAE | 9 Participants |
| Cohort 3 | Overall Summary of Adverse Events During Initial 6-Month Period | Subjects Least Reported Study Drug-Related SAE | 0 Participants |
| Cohort 3 | Overall Summary of Adverse Events During Initial 6-Month Period | Subjects Who Died | 0 Participants |
| Cohort 4 | Overall Summary of Adverse Events During Initial 6-Month Period | Subjects Least Reported Study Drug-Related SAE | 0 Participants |
| Cohort 4 | Overall Summary of Adverse Events During Initial 6-Month Period | Subjects Least Reported Study Drug-Related TEAE | 9 Participants |
| Cohort 4 | Overall Summary of Adverse Events During Initial 6-Month Period | Subjects with at Least 1 Reported TEAE | 9 Participants |
| Cohort 4 | Overall Summary of Adverse Events During Initial 6-Month Period | Subjects with at Least 1 Reported SAE | 0 Participants |
| Cohort 4 | Overall Summary of Adverse Events During Initial 6-Month Period | Subjects Who Died | 0 Participants |
Secondary
Change From Baseline in Annualized Growth Velocity (AGV) During Entire Study Period - Cohort 1 and 2 Switchers
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.
Time frame: At month 24
Population: Efficacy Analysis Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Annualized Growth Velocity (AGV) During Entire Study Period - Cohort 1 and 2 Switchers | Baseline | 3.629 cm/year | Standard Deviation 1.1586 |
| Cohort 1 | Change From Baseline in Annualized Growth Velocity (AGV) During Entire Study Period - Cohort 1 and 2 Switchers | Change from Baseline at >=12 Months on 15μg/kg | 1.846 cm/year | Standard Deviation 2.1466 |
| Cohort 2 | Change From Baseline in Annualized Growth Velocity (AGV) During Entire Study Period - Cohort 1 and 2 Switchers | Baseline | 3.510 cm/year | Standard Deviation 0.8327 |
| Cohort 2 | Change From Baseline in Annualized Growth Velocity (AGV) During Entire Study Period - Cohort 1 and 2 Switchers | Change from Baseline at >=12 Months on 15μg/kg | 2.245 cm/year | Standard Deviation 0.9176 |
Secondary
Change From Baseline in Annualized Growth Velocity (AGV) During Entire Study Period - Cohort 3 and 4
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.
Time frame: At month 24
Population: Efficacy Analysis Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Annualized Growth Velocity (AGV) During Entire Study Period - Cohort 3 and 4 | Baseline | 4.044 cm/year | Standard Deviation 2.2751 |
| Cohort 1 | Change From Baseline in Annualized Growth Velocity (AGV) During Entire Study Period - Cohort 3 and 4 | Change from Baseline to Month 24 | 1.744 cm/year | Standard Deviation 1.7974 |
| Cohort 2 | Change From Baseline in Annualized Growth Velocity (AGV) During Entire Study Period - Cohort 3 and 4 | Baseline | 4.492 cm/year | Standard Deviation 1.1889 |
| Cohort 2 | Change From Baseline in Annualized Growth Velocity (AGV) During Entire Study Period - Cohort 3 and 4 | Change from Baseline to Month 24 | 1.538 cm/year | Standard Deviation 1.3387 |
Secondary
Change From Baseline in Annualized Growth Velocity (AGV) During Initial 6-Month
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.
Time frame: At 6 month (Day 183)
Population: Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Annualized Growth Velocity (AGV) During Initial 6-Month | Baseline | 3.755 cm/year | Standard Deviation 1.1094 |
| Cohort 1 | Change From Baseline in Annualized Growth Velocity (AGV) During Initial 6-Month | Change from Baseline to Day 183 | -0.371 cm/year | Standard Deviation 1.592 |
| Cohort 2 | Change From Baseline in Annualized Growth Velocity (AGV) During Initial 6-Month | Change from Baseline to Day 183 | 1.276 cm/year | Standard Deviation 1.4387 |
| Cohort 2 | Change From Baseline in Annualized Growth Velocity (AGV) During Initial 6-Month | Baseline | 2.891 cm/year | Standard Deviation 1.392 |
| Cohort 3 | Change From Baseline in Annualized Growth Velocity (AGV) During Initial 6-Month | Baseline | 4.044 cm/year | Standard Deviation 2.2751 |
| Cohort 3 | Change From Baseline in Annualized Growth Velocity (AGV) During Initial 6-Month | Change from Baseline to Day 183 | 2.014 cm/year | Standard Deviation 1.999 |
| Cohort 4 | Change From Baseline in Annualized Growth Velocity (AGV) During Initial 6-Month | Baseline | 4.492 cm/year | Standard Deviation 1.1889 |
| Cohort 4 | Change From Baseline in Annualized Growth Velocity (AGV) During Initial 6-Month | Change from Baseline to Day 183 | 2.085 cm/year | Standard Deviation 2.1375 |
Secondary
Change From Baseline in Arm Span to Height Ratio During Entire Study Period - Cohort 1 and 2 Switchers
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.
Time frame: At month 24
Population: Efficacy Analysis Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Arm Span to Height Ratio During Entire Study Period - Cohort 1 and 2 Switchers | Baseline | 0.881 ratio | Standard Deviation 0.048 |
| Cohort 1 | Change From Baseline in Arm Span to Height Ratio During Entire Study Period - Cohort 1 and 2 Switchers | Change from Baseline to >=12 Months on 15ug/kg | -0.014 ratio | Standard Deviation 0.0179 |
Secondary
Change From Baseline in Arm Span to Height Ratio During Entire Study Period - Cohort 3 and 4
The Arm Span to Height Ratio prior to treatment, at baseline, and through 24 months is assessed by Arm Span / Standing Height.
Time frame: At month 24
Population: Efficacy Analysis Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Arm Span to Height Ratio During Entire Study Period - Cohort 3 and 4 | Baseline | 0.911 ratio | Standard Deviation 0.0119 |
| Cohort 1 | Change From Baseline in Arm Span to Height Ratio During Entire Study Period - Cohort 3 and 4 | Change from Baseline to Month 24 | 0.000 ratio | Standard Deviation 0.0123 |
| Cohort 2 | Change From Baseline in Arm Span to Height Ratio During Entire Study Period - Cohort 3 and 4 | Baseline | 0.900 ratio | Standard Deviation 0.0315 |
| Cohort 2 | Change From Baseline in Arm Span to Height Ratio During Entire Study Period - Cohort 3 and 4 | Change from Baseline to Month 24 | -0.006 ratio | Standard Deviation 0.029 |
Secondary
Change From Baseline in Arm Span to Height Ratio During Initial 6-months
The Arm Span to Height Ratio prior to treatment, at baseline, and through 6 months is assessed by Arm Span / Standing Height.
Time frame: At month 6 (Day 183)
Population: Efficacy Analysis Population~Arm span measurement was optional until July 2015. Therefore data was not collected for all subjects for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Arm Span to Height Ratio During Initial 6-months | Baseline | 0.901 ratio | Standard Deviation 0.0189 |
| Cohort 1 | Change From Baseline in Arm Span to Height Ratio During Initial 6-months | Change from Baseline to Day 183 | 0.012 ratio | Standard Deviation 0.0111 |
| Cohort 2 | Change From Baseline in Arm Span to Height Ratio During Initial 6-months | Change from Baseline to Day 183 | -0.005 ratio | Standard Deviation 0.0079 |
| Cohort 2 | Change From Baseline in Arm Span to Height Ratio During Initial 6-months | Baseline | 0.889 ratio | Standard Deviation 0.0906 |
| Cohort 3 | Change From Baseline in Arm Span to Height Ratio During Initial 6-months | Baseline | 0.913 ratio | Standard Deviation 0.0123 |
| Cohort 3 | Change From Baseline in Arm Span to Height Ratio During Initial 6-months | Change from Baseline to Day 183 | 0.007 ratio | Standard Deviation 0.0063 |
| Cohort 4 | Change From Baseline in Arm Span to Height Ratio During Initial 6-months | Baseline | 0.893 ratio | Standard Deviation 0.0284 |
| Cohort 4 | Change From Baseline in Arm Span to Height Ratio During Initial 6-months | Change from Baseline to Day 183 | 0.001 ratio | Standard Deviation 0.0143 |
Secondary
Change From Baseline in Height Z-Scores Using CDC Reference Standard During Entire Study Period - Cohort 1 and 2 Switchers
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).
Time frame: At month 24
Population: Efficacy Analysis Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Height Z-Scores Using CDC Reference Standard During Entire Study Period - Cohort 1 and 2 Switchers | Baseline | -6.064 z score | Standard Deviation 0.6932 |
| Cohort 1 | Change From Baseline in Height Z-Scores Using CDC Reference Standard During Entire Study Period - Cohort 1 and 2 Switchers | Change from Baseline to >=12 Months on 15ug/kg | 0.520 z score | Standard Deviation 0.295 |
| Cohort 2 | Change From Baseline in Height Z-Scores Using CDC Reference Standard During Entire Study Period - Cohort 1 and 2 Switchers | Baseline | -4.912 z score | Standard Deviation 0.7708 |
| Cohort 2 | Change From Baseline in Height Z-Scores Using CDC Reference Standard During Entire Study Period - Cohort 1 and 2 Switchers | Change from Baseline to >=12 Months on 15ug/kg | 0.259 z score | Standard Deviation 0.1887 |
Secondary
Change From Baseline in Height Z-Scores Using CDC Reference Standard During Entire Study Period - Cohort 3 and 4
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).
Time frame: At month 24
Population: Efficacy Analysis Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Height Z-Scores Using CDC Reference Standard During Entire Study Period - Cohort 3 and 4 | Baseline | -4.613 z score | Standard Deviation 1.1355 |
| Cohort 1 | Change From Baseline in Height Z-Scores Using CDC Reference Standard During Entire Study Period - Cohort 3 and 4 | Change from Baseline to Month 24 | 0.788 z score | Standard Deviation 0.2842 |
| Cohort 2 | Change From Baseline in Height Z-Scores Using CDC Reference Standard During Entire Study Period - Cohort 3 and 4 | Baseline | -5.193 z score | Standard Deviation 0.7486 |
| Cohort 2 | Change From Baseline in Height Z-Scores Using CDC Reference Standard During Entire Study Period - Cohort 3 and 4 | Change from Baseline to Month 24 | 0.896 z score | Standard Deviation 0.301 |
Secondary
Change From Baseline in Height Z-Scores Using Centers for Disease Control and Prevention (CDC) Reference Standard During Initial 6-Months
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).
Time frame: At month 6 (Day 183)
Population: Efficacy Analysis Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Height Z-Scores Using Centers for Disease Control and Prevention (CDC) Reference Standard During Initial 6-Months | Baseline | -6.056 z score | Standard Deviation 0.6331 |
| Cohort 1 | Change From Baseline in Height Z-Scores Using Centers for Disease Control and Prevention (CDC) Reference Standard During Initial 6-Months | Change from Baseline to Day 183 | -0.008 z score | Standard Deviation 0.1788 |
| Cohort 2 | Change From Baseline in Height Z-Scores Using Centers for Disease Control and Prevention (CDC) Reference Standard During Initial 6-Months | Change from Baseline to Day 183 | 0.078 z score | Standard Deviation 0.144 |
| Cohort 2 | Change From Baseline in Height Z-Scores Using Centers for Disease Control and Prevention (CDC) Reference Standard During Initial 6-Months | Baseline | -5.145 z score | Standard Deviation 0.853 |
| Cohort 3 | Change From Baseline in Height Z-Scores Using Centers for Disease Control and Prevention (CDC) Reference Standard During Initial 6-Months | Baseline | -4.613 z score | Standard Deviation 1.1355 |
| Cohort 3 | Change From Baseline in Height Z-Scores Using Centers for Disease Control and Prevention (CDC) Reference Standard During Initial 6-Months | Change from Baseline to Day 183 | 0.229 z score | Standard Deviation 0.1505 |
| Cohort 4 | Change From Baseline in Height Z-Scores Using Centers for Disease Control and Prevention (CDC) Reference Standard During Initial 6-Months | Baseline | -5.193 z score | Standard Deviation 0.7486 |
| Cohort 4 | Change From Baseline in Height Z-Scores Using Centers for Disease Control and Prevention (CDC) Reference Standard During Initial 6-Months | Change from Baseline to Day 183 | 0.265 z score | Standard Deviation 0.1869 |
Secondary
Change From Baseline in Upper Arm Length to Lower Arm (Forearm) Length Ratio During Initial 6-Months
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.
Time frame: At month 6 (Day 183)
Population: Efficacy Analysis Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Upper Arm Length to Lower Arm (Forearm) Length Ratio During Initial 6-Months | Baseline | 1.130 ratio | Standard Deviation 0.1168 |
| Cohort 1 | Change From Baseline in Upper Arm Length to Lower Arm (Forearm) Length Ratio During Initial 6-Months | Change from Baseline to Day 183 | -0.019 ratio | Standard Deviation 0.0623 |
| Cohort 2 | Change From Baseline in Upper Arm Length to Lower Arm (Forearm) Length Ratio During Initial 6-Months | Change from Baseline to Day 183 | 0.001 ratio | Standard Deviation 0.0521 |
| Cohort 2 | Change From Baseline in Upper Arm Length to Lower Arm (Forearm) Length Ratio During Initial 6-Months | Baseline | 1.143 ratio | Standard Deviation 0.0924 |
| Cohort 3 | Change From Baseline in Upper Arm Length to Lower Arm (Forearm) Length Ratio During Initial 6-Months | Baseline | 1.130 ratio | Standard Deviation 0.119 |
| Cohort 3 | Change From Baseline in Upper Arm Length to Lower Arm (Forearm) Length Ratio During Initial 6-Months | Change from Baseline to Day 183 | -0.048 ratio | Standard Deviation 0.1002 |
| Cohort 4 | Change From Baseline in Upper Arm Length to Lower Arm (Forearm) Length Ratio During Initial 6-Months | Baseline | 1.106 ratio | Standard Deviation 0.0816 |
| Cohort 4 | Change From Baseline in Upper Arm Length to Lower Arm (Forearm) Length Ratio During Initial 6-Months | Change from Baseline to Day 183 | 0.003 ratio | Standard Deviation 0.0869 |
Secondary
Change From Baseline in Upper Arm to Lower Arm Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers
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.
Time frame: At month 24
Population: Efficacy Analysis Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Upper Arm to Lower Arm Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers | Baseline | 1.131 ratio | Standard Deviation 0.128 |
| Cohort 1 | Change From Baseline in Upper Arm to Lower Arm Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers | Change from Baseline to >=12 Months on 15ug/kg | 0.009 ratio | Standard Deviation 0.0056 |
| Cohort 2 | Change From Baseline in Upper Arm to Lower Arm Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers | Baseline | 1.114 ratio | Standard Deviation 0.052 |
| Cohort 2 | Change From Baseline in Upper Arm to Lower Arm Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers | Change from Baseline to >=12 Months on 15ug/kg | -0.004 ratio | Standard Deviation 0.1181 |
Secondary
Change From Baseline in Upper Arm to Lower Arm Length Ratio During Entire Study Period - Cohort 3 and 4
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.
Time frame: At month 24
Population: Efficacy Analysis Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Upper Arm to Lower Arm Length Ratio During Entire Study Period - Cohort 3 and 4 | Baseline | 1.130 ratio | Standard Deviation 0.119 |
| Cohort 1 | Change From Baseline in Upper Arm to Lower Arm Length Ratio During Entire Study Period - Cohort 3 and 4 | Change from Baseline to Month 24 | 0.037 ratio | Standard Deviation 0.0673 |
| Cohort 2 | Change From Baseline in Upper Arm to Lower Arm Length Ratio During Entire Study Period - Cohort 3 and 4 | Baseline | 1.106 ratio | Standard Deviation 0.0816 |
| Cohort 2 | Change From Baseline in Upper Arm to Lower Arm Length Ratio During Entire Study Period - Cohort 3 and 4 | Change from Baseline to Month 24 | -0.027 ratio | Standard Deviation 0.0504 |
Secondary
Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers
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.
Time frame: At month 24
Population: Efficacy Analysis Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers | Baseline | 0.659 ratio | Standard Deviation 0.0541 |
| Cohort 1 | Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers | Change from Baseline to >=12 Months on 15ug/kg | 0.002 ratio | Standard Deviation 0.0228 |
| Cohort 2 | Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers | Baseline | 0.673 ratio | Standard Deviation 0.0579 |
| Cohort 2 | Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers | Change from Baseline to >=12 Months on 15ug/kg | 0.006 ratio | Standard Deviation 0.0618 |
Secondary
Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Entire Study Period - Cohort 3 and 4
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.
Time frame: At month 24
Population: Efficacy Analysis Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Entire Study Period - Cohort 3 and 4 | Baseline | 0.687 ratio | Standard Deviation 0.0268 |
| Cohort 1 | Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Entire Study Period - Cohort 3 and 4 | Change from Baseline to Month 24 | 0.010 ratio | Standard Deviation 0.0503 |
| Cohort 2 | Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Entire Study Period - Cohort 3 and 4 | Baseline | 0.691 ratio | Standard Deviation 0.0847 |
| Cohort 2 | Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Entire Study Period - Cohort 3 and 4 | Change from Baseline to Month 24 | -0.033 ratio | Standard Deviation 0.1065 |
Secondary
Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Initial 6-months
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.
Time frame: At month 6 (Day 183)
Population: Efficacy Analysis Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Initial 6-months | Baseline | 0.672 ratio | Standard Deviation 0.06 |
| Cohort 1 | Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Initial 6-months | Change from Baseline to Day 183 | -0.002 ratio | Standard Deviation 0.0401 |
| Cohort 2 | Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Initial 6-months | Change from Baseline to Day 183 | -0.006 ratio | Standard Deviation 0.0462 |
| Cohort 2 | Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Initial 6-months | Baseline | 0.662 ratio | Standard Deviation 0.0585 |
| Cohort 3 | Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Initial 6-months | Baseline | 0.687 ratio | Standard Deviation 0.0268 |
| Cohort 3 | Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Initial 6-months | Change from Baseline to Day 183 | 0.007 ratio | Standard Deviation 0.0411 |
| Cohort 4 | Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Initial 6-months | Baseline | 0.691 ratio | Standard Deviation 0.0847 |
| Cohort 4 | Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Initial 6-months | Change from Baseline to Day 183 | -0.006 ratio | Standard Deviation 0.081 |
Secondary
Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers
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.
Time frame: At month 24
Population: Efficacy Analysis Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers | Baseline | 1.080 ratio | Standard Deviation 0.1139 |
| Cohort 1 | Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers | Change from Baseline to >=12 Months on 15ug/kg | -0.020 ratio | Standard Deviation 0.0297 |
| Cohort 2 | Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers | Baseline | 1.100 ratio | Standard Deviation 0.1447 |
| Cohort 2 | Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers | Change from Baseline to >=12 Months on 15ug/kg | 0.018 ratio | Standard Deviation 0.1602 |
Secondary
Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Entire Study Period - Cohort 3 and 4
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.
Time frame: At month 24
Population: Efficacy Analysis Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Entire Study Period - Cohort 3 and 4 | Baseline | 1.107 ratio | Standard Deviation 0.0607 |
| Cohort 1 | Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Entire Study Period - Cohort 3 and 4 | Change from Baseline to Month 24 | 0.014 ratio | Standard Deviation 0.0888 |
| Cohort 2 | Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Entire Study Period - Cohort 3 and 4 | Baseline | 1.061 ratio | Standard Deviation 0.1341 |
| Cohort 2 | Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Entire Study Period - Cohort 3 and 4 | Change from Baseline to Month 24 | -0.012 ratio | Standard Deviation 0.1477 |
Secondary
Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Initial 6-months
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.
Time frame: At month 6 (Day 183)
Population: Efficacy Analysis Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Initial 6-months | Baseline | 1.089 ratio | Standard Deviation 0.1067 |
| Cohort 1 | Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Initial 6-months | Change from Baseline to Day 183 | 0.001 ratio | Standard Deviation 0.0774 |
| Cohort 2 | Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Initial 6-months | Change from Baseline to Day 183 | 0.007 ratio | Standard Deviation 0.0863 |
| Cohort 2 | Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Initial 6-months | Baseline | 1.074 ratio | Standard Deviation 0.135 |
| Cohort 3 | Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Initial 6-months | Baseline | 1.107 ratio | Standard Deviation 0.0607 |
| Cohort 3 | Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Initial 6-months | Change from Baseline to Day 183 | 0.034 ratio | Standard Deviation 0.1048 |
| Cohort 4 | Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Initial 6-months | Baseline | 1.061 ratio | Standard Deviation 0.1341 |
| Cohort 4 | Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Initial 6-months | Change from Baseline to Day 183 | 0.015 ratio | Standard Deviation 0.1571 |
Secondary
Change From Baseline in Upper to Lower Body Ratios During Entire Study Period - Cohort 1 and 2 Switchers
The Upper to Lower Body ratio prior to treatment, at baseline, and through 24 months is assessed on Sitting Height / (Standing Height - Sitting Height)
Time frame: At month 24
Population: Efficacy Analysis Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Upper to Lower Body Ratios During Entire Study Period - Cohort 1 and 2 Switchers | Baseline | 2.119 ratio | Standard Deviation 0.0812 |
| Cohort 1 | Change From Baseline in Upper to Lower Body Ratios During Entire Study Period - Cohort 1 and 2 Switchers | Change from Baseline to >=12 Months on 15ug/kg | -0.078 ratio | Standard Deviation 0.0452 |
| Cohort 2 | Change From Baseline in Upper to Lower Body Ratios During Entire Study Period - Cohort 1 and 2 Switchers | Baseline | 2.053 ratio | Standard Deviation 0.1746 |
| Cohort 2 | Change From Baseline in Upper to Lower Body Ratios During Entire Study Period - Cohort 1 and 2 Switchers | Change from Baseline to >=12 Months on 15ug/kg | -0.078 ratio | Standard Deviation 0.1271 |
Secondary
Change From Baseline in Upper to Lower Body Ratios During Entire Study Period - Cohort 3 and 4
The Upper to Lower Body ratio prior to treatment, at baseline, and through 24 months is assessed on Sitting Height / (Standing Height - Sitting Height)
Time frame: At month 24
Population: Efficacy Analysis Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Upper to Lower Body Ratios During Entire Study Period - Cohort 3 and 4 | Baseline | 1.911 ratio | Standard Deviation 0.2286 |
| Cohort 1 | Change From Baseline in Upper to Lower Body Ratios During Entire Study Period - Cohort 3 and 4 | Change from Baseline to Month 24 | -0.067 ratio | Standard Deviation 0.0451 |
| Cohort 2 | Change From Baseline in Upper to Lower Body Ratios During Entire Study Period - Cohort 3 and 4 | Baseline | 1.962 ratio | Standard Deviation 0.1822 |
| Cohort 2 | Change From Baseline in Upper to Lower Body Ratios During Entire Study Period - Cohort 3 and 4 | Change from Baseline to Month 24 | -0.121 ratio | Standard Deviation 0.1058 |
Secondary
Change From Baseline in Upper to Lower Body Ratios During Initial 6-Months
The Upper to Lower Body ratio prior to treatment, at baseline, and through 6 months is assessed on Sitting Height / (Standing Height - Sitting Height)
Time frame: At month 6 (Day 183)
Population: Efficacy Analysis Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Upper to Lower Body Ratios During Initial 6-Months | Baseline | 2.094 Ratio | Standard Deviation 0.0984 |
| Cohort 1 | Change From Baseline in Upper to Lower Body Ratios During Initial 6-Months | Change from Baseline to Day 183 | -0.021 Ratio | Standard Deviation 0.0626 |
| Cohort 2 | Change From Baseline in Upper to Lower Body Ratios During Initial 6-Months | Change from Baseline to Day 183 | 0.003 Ratio | Standard Deviation 0.051 |
| Cohort 2 | Change From Baseline in Upper to Lower Body Ratios During Initial 6-Months | Baseline | 2.027 Ratio | Standard Deviation 0.1793 |
| Cohort 3 | Change From Baseline in Upper to Lower Body Ratios During Initial 6-Months | Baseline | 1.911 Ratio | Standard Deviation 0.2286 |
| Cohort 3 | Change From Baseline in Upper to Lower Body Ratios During Initial 6-Months | Change from Baseline to Day 183 | -0.024 Ratio | Standard Deviation 0.0369 |
| Cohort 4 | Change From Baseline in Upper to Lower Body Ratios During Initial 6-Months | Baseline | 1.962 Ratio | Standard Deviation 0.1822 |
| Cohort 4 | Change From Baseline in Upper to Lower Body Ratios During Initial 6-Months | Change from Baseline to Day 183 | -0.030 Ratio | Standard Deviation 0.0811 |