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A Phase 2 Study of BMN 111 to Evaluate Safety, Tolerability, and Efficacy in Children With Achondroplasia (ACH)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02055157
Recruitment Status : Completed
First Posted : February 5, 2014
Results First Posted : January 15, 2021
Last Update Posted : January 15, 2021
Sponsor:
Information provided by (Responsible Party):
BioMarin Pharmaceutical

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Sequential Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Achondroplasia
Intervention Drug: BMN 111
Enrollment 35
Recruitment Details This study was conducted at nine study centers in United States, Australia, United Kingdom and France.
Pre-assignment Details  
Arm/Group Title Cohort 1 Cohort 2 Cohort 3 Cohort 4
Hide Arm/Group Description

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.

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.

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.

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.

Period Title: Initial 6 Months
Started 8 8 10 9
Completed 7 7 10 8
Not Completed 1 1 0 1
Reason Not Completed
Subject discontinued due to NeedlePhobia             0             1             0             0
Adverse Event             0             0             0             1
Consent withdrawn by subject             1             0             0             0
Period Title: 18-month Extension
Started 7 7 10 8
Completed 6 6 10 8
Not Completed 1 1 0 0
Reason Not Completed
Investigator decision             0             1             0             0
Subject discontinued due to NeedlePhobia             1             0             0             0
Arm/Group Title Cohort 1 Cohort 2 Cohort 3 Cohort 4 Total
Hide Arm/Group Description

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.

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.

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.

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.

Total of all reporting groups
Overall Number of Baseline Participants 8 8 10 9 35
Hide Baseline Analysis Population Description
Safety Analysis Population consists of 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.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Yrs
Number Analyzed 8 participants 8 participants 10 participants 9 participants 35 participants
7.3  (1.58) 8.3  (2.19) 8.0  (1.63) 6.9  (1.17) 7.6  (1.68)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 8 participants 8 participants 10 participants 9 participants 35 participants
Female
5
  62.5%
3
  37.5%
6
  60.0%
5
  55.6%
19
  54.3%
Male
3
  37.5%
5
  62.5%
4
  40.0%
4
  44.4%
16
  45.7%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 8 participants 8 participants 10 participants 9 participants 35 participants
Hispanic or Latino
0
   0.0%
0
   0.0%
1
  10.0%
1
  11.1%
2
   5.7%
Not Hispanic or Latino
8
 100.0%
8
 100.0%
9
  90.0%
7
  77.8%
32
  91.4%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
1
  11.1%
1
   2.9%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 8 participants 8 participants 10 participants 9 participants 35 participants
White
7
  87.5%
6
  75.0%
5
  50.0%
6
  66.7%
24
  68.6%
Asian
0
   0.0%
1
  12.5%
3
  30.0%
3
  33.3%
7
  20.0%
Black or African American
1
  12.5%
0
   0.0%
1
  10.0%
0
   0.0%
2
   5.7%
Other
0
   0.0%
1
  12.5%
1
  10.0%
0
   0.0%
2
   5.7%
1.Primary Outcome
Title Overall Summary of Adverse Events During Initial 6-Month Period
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Cohort 1 Cohort 2 Cohort 3 Cohort 4
Hide Arm/Group Description:

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.

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.

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.

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.

Overall Number of Participants Analyzed 8 8 10 9
Measure Type: Count of Participants
Unit of Measure: Participants
Subjects with at Least 1 Reported TEAE
8
 100.0%
8
 100.0%
10
 100.0%
9
 100.0%
Subjects Least Reported Study Drug-Related TEAE
7
  87.5%
8
 100.0%
9
  90.0%
9
 100.0%
Subjects with at Least 1 Reported SAE
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Subjects Least Reported Study Drug-Related SAE
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Subjects Who Died
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
2.Primary Outcome
Title Overall Summary of Adverse Events During Entire Study Period
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Analysis Population.
Arm/Group Title Cohort 1 Cohort 2 Cohort 3 Cohort 4
Hide Arm/Group Description:

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.

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.

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.

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.

Overall Number of Participants Analyzed 8 8 10 9
Measure Type: Count of Participants
Unit of Measure: Participants
Subjects with at Least 1 Reported TEAE
8
 100.0%
8
 100.0%
10
 100.0%
9
 100.0%
Subjects Least Reported Study Drug-Related TEAE
7
  87.5%
8
 100.0%
9
  90.0%
9
 100.0%
Subjects with at Least 1 Reported SAE
1
  12.5%
0
   0.0%
1
  10.0%
1
  11.1%
Subjects Least Reported Study Drug-Related SAE
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Subjects Who Died
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
3.Secondary Outcome
Title Change From Baseline in Annualized Growth Velocity (AGV) During Initial 6-Month
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Cohort 1 Cohort 2 Cohort 3 Cohort 4
Hide Arm/Group Description:

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.

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.

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.

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.

Overall Number of Participants Analyzed 8 8 10 8
Mean (Standard Deviation)
Unit of Measure: cm/year
Baseline Number Analyzed 8 participants 8 participants 10 participants 8 participants
3.755  (1.1094) 2.891  (1.3920) 4.044  (2.2751) 4.492  (1.1889)
Change from Baseline to Day 183 Number Analyzed 7 participants 8 participants 10 participants 8 participants
-0.371  (1.5920) 1.276  (1.4387) 2.014  (1.9990) 2.085  (2.1375)
4.Secondary Outcome
Title Change From Baseline in Annualized Growth Velocity (AGV) During Entire Study Period - Cohort 3 and 4
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy Analysis Population
Arm/Group Title Cohort 3 Cohort 4
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 10 8
Mean (Standard Deviation)
Unit of Measure: cm/year
Baseline 4.044  (2.2751) 4.492  (1.1889)
Change from Baseline to Month 24 1.744  (1.7974) 1.538  (1.3387)
5.Secondary Outcome
Title Change From Baseline in Annualized Growth Velocity (AGV) During Entire Study Period - Cohort 1 and 2 Switchers
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy Analysis Population
Arm/Group Title Cohort 1 Cohort 2
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 6 6
Mean (Standard Deviation)
Unit of Measure: cm/year
Baseline Number Analyzed 6 participants 6 participants
3.629  (1.1586) 3.510  (0.8327)
Change from Baseline at >=12 Months on 15μg/kg Number Analyzed 3 participants 6 participants
1.846  (2.1466) 2.245  (0.9176)
6.Secondary Outcome
Title Change From Baseline in Height Z-Scores Using Centers for Disease Control and Prevention (CDC) Reference Standard During Initial 6-Months
Hide Description

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)
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy Analysis Population
Arm/Group Title Cohort 1 Cohort 2 Cohort 3 Cohort 4
Hide Arm/Group Description:

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.

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.

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.

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.

Overall Number of Participants Analyzed 8 8 10 8
Mean (Standard Deviation)
Unit of Measure: z score
Baseline Number Analyzed 7 participants 8 participants 10 participants 8 participants
-6.056  (0.6331) -5.145  (0.8530) -4.613  (1.1355) -5.193  (0.7486)
Change from Baseline to Day 183 Number Analyzed 7 participants 8 participants 10 participants 8 participants
-0.008  (0.1788) 0.078  (0.1440) 0.229  (0.1505) 0.265  (0.1869)
7.Secondary Outcome
Title Change From Baseline in Height Z-Scores Using CDC Reference Standard During Entire Study Period - Cohort 3 and 4
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy Analysis Population
Arm/Group Title Cohort 3 Cohort 4
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 10 8
Mean (Standard Deviation)
Unit of Measure: z score
Baseline -4.613  (1.1355) -5.193  (0.7486)
Change from Baseline to Month 24 0.788  (0.2842) 0.896  (0.3010)
8.Secondary Outcome
Title Change From Baseline in Height Z-Scores Using CDC Reference Standard During Entire Study Period - Cohort 1 and 2 Switchers
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy Analysis Population
Arm/Group Title Cohort 1 Cohort 2
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 6 6
Mean (Standard Deviation)
Unit of Measure: z score
Baseline Number Analyzed 6 participants 6 participants
-6.064  (0.6932) -4.912  (0.7708)
Change from Baseline to >=12 Months on 15ug/kg Number Analyzed 3 participants 6 participants
0.520  (0.2950) 0.259  (0.1887)
9.Secondary Outcome
Title Change From Baseline in Upper to Lower Body Ratios During Initial 6-Months
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy Analysis Population
Arm/Group Title Cohort 1 Cohort 2 Cohort 3 Cohort 4
Hide Arm/Group Description:

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.

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.

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.

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.

Overall Number of Participants Analyzed 8 8 10 8
Mean (Standard Deviation)
Unit of Measure: Ratio
Baseline Number Analyzed 7 participants 8 participants 10 participants 8 participants
2.094  (0.0984) 2.027  (0.1793) 1.911  (0.2286) 1.962  (0.1822)
Change from Baseline to Day 183 Number Analyzed 7 participants 8 participants 10 participants 8 participants
-0.021  (0.0626) 0.003  (0.0510) -0.024  (0.0369) -0.030  (0.0811)
10.Secondary Outcome
Title Change From Baseline in Upper to Lower Body Ratios During Entire Study Period - Cohort 3 and 4
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy Analysis Population
Arm/Group Title Cohort 3 Cohort 4
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 10 8
Mean (Standard Deviation)
Unit of Measure: ratio
Baseline 1.911  (0.2286) 1.962  (0.1822)
Change from Baseline to Month 24 -0.067  (0.0451) -0.121  (0.1058)
11.Secondary Outcome
Title Change From Baseline in Upper Arm Length to Lower Arm (Forearm) Length Ratio During Initial 6-Months
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy Analysis Population
Arm/Group Title Cohort 1 Cohort 2 Cohort 3 Cohort 4
Hide Arm/Group Description:

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.

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.

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.

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.

Overall Number of Participants Analyzed 8 8 10 8
Mean (Standard Deviation)
Unit of Measure: ratio
Baseline Number Analyzed 7 participants 8 participants 10 participants 8 participants
1.130  (0.1168) 1.143  (0.0924) 1.130  (0.1190) 1.106  (0.0816)
Change from Baseline to Day 183 Number Analyzed 8 participants 8 participants 10 participants 8 participants
-0.019  (0.0623) 0.001  (0.0521) -0.048  (0.1002) 0.003  (0.0869)
12.Secondary Outcome
Title Change From Baseline in Upper Arm to Lower Arm Length Ratio During Entire Study Period - Cohort 3 and 4
Hide Description 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
Hide Outcome Measure Data
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Efficacy Analysis Population
Arm/Group Title Cohort 3 Cohort 4
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 10 8
Mean (Standard Deviation)
Unit of Measure: ratio
Baseline 1.130  (0.1190) 1.106  (0.0816)
Change from Baseline to Month 24 0.037  (0.0673) -0.027  (0.0504)
13.Secondary Outcome
Title Change From Baseline in Upper to Lower Body Ratios During Entire Study Period - Cohort 1 and 2 Switchers
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy Analysis Population
Arm/Group Title Cohort 1 Cohort 2
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 6 6
Mean (Standard Deviation)
Unit of Measure: ratio
Baseline Number Analyzed 6 participants 6 participants
2.119  (0.0812) 2.053  (0.1746)
Change from Baseline to >=12 Months on 15ug/kg Number Analyzed 3 participants 6 participants
-0.078  (0.0452) -0.078  (0.1271)
14.Secondary Outcome
Title Change From Baseline in Upper Arm to Lower Arm Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy Analysis Population
Arm/Group Title Cohort 1 Cohort 2
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 6 6
Mean (Standard Deviation)
Unit of Measure: ratio
Baseline Number Analyzed 6 participants 6 participants
1.131  (0.1280) 1.114  (0.0520)
Change from Baseline to >=12 Months on 15ug/kg Number Analyzed 3 participants 6 participants
0.009  (0.0056) -0.004  (0.1181)
15.Secondary Outcome
Title Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Initial 6-months
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy Analysis Population
Arm/Group Title Cohort 1 Cohort 2 Cohort 3 Cohort 4
Hide Arm/Group Description:

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.

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.

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.

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.

Overall Number of Participants Analyzed 8 8 10 8
Mean (Standard Deviation)
Unit of Measure: ratio
Baseline Number Analyzed 7 participants 8 participants 10 participants 8 participants
0.672  (0.0600) 0.662  (0.0585) 0.687  (0.0268) 0.691  (0.0847)
Change from Baseline to Day 183 Number Analyzed 7 participants 8 participants 10 participants 8 participants
-0.002  (0.0401) -0.006  (0.0462) 0.007  (0.0411) -0.006  (0.0810)
16.Secondary Outcome
Title Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Entire Study Period - Cohort 3 and 4
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy Analysis Population
Arm/Group Title Cohort 3 Cohort 4
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 10 8
Mean (Standard Deviation)
Unit of Measure: ratio
Baseline 0.687  (0.0268) 0.691  (0.0847)
Change from Baseline to Month 24 0.010  (0.0503) -0.033  (0.1065)
17.Secondary Outcome
Title Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy Analysis Population
Arm/Group Title Cohort 1 Cohort 2
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 6 6
Mean (Standard Deviation)
Unit of Measure: ratio
Baseline Number Analyzed 6 participants 6 participants
0.659  (0.0541) 0.673  (0.0579)
Change from Baseline to >=12 Months on 15ug/kg Number Analyzed 3 participants 6 participants
0.002  (0.0228) 0.006  (0.0618)
18.Secondary Outcome
Title Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Initial 6-months
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy Analysis Population
Arm/Group Title Cohort 1 Cohort 2 Cohort 3 Cohort 4
Hide Arm/Group Description:

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.

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.

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.

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.

Overall Number of Participants Analyzed 8 8 10 8
Mean (Standard Deviation)
Unit of Measure: ratio
Baseline Number Analyzed 7 participants 8 participants 10 participants 8 participants
1.089  (0.1067) 1.074  (0.1350) 1.107  (0.0607) 1.061  (0.1341)
Change from Baseline to Day 183 Number Analyzed 7 participants 8 participants 10 participants 8 participants
0.001  (0.0774) 0.007  (0.0863) 0.034  (0.1048) 0.015  (0.1571)
19.Secondary Outcome
Title Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Entire Study Period - Cohort 3 and 4
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy Analysis Population
Arm/Group Title Cohort 3 Cohort 4
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 10 8
Mean (Standard Deviation)
Unit of Measure: ratio
Baseline 1.107  (0.0607) 1.061  (0.1341)
Change from Baseline to Month 24 0.014  (0.0888) -0.012  (0.1477)
20.Secondary Outcome
Title Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy Analysis Population
Arm/Group Title Cohort 1 Cohort 2
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 6 6
Mean (Standard Deviation)
Unit of Measure: ratio
Baseline Number Analyzed 6 participants 6 participants
1.080  (0.1139) 1.100  (0.1447)
Change from Baseline to >=12 Months on 15ug/kg Number Analyzed 3 participants 6 participants
-0.020  (0.0297) 0.018  (0.1602)
21.Secondary Outcome
Title Change From Baseline in Arm Span to Height Ratio During Initial 6-months
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description

Efficacy Analysis Population

Arm span measurement was optional until July 2015. Therefore data was not collected for all subjects for this outcome measure.

Arm/Group Title Cohort 1 Cohort 2 Cohort 3 Cohort 4
Hide Arm/Group Description:

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.

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.

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.

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.

Overall Number of Participants Analyzed 4 2 4 7
Mean (Standard Deviation)
Unit of Measure: ratio
Baseline 0.901  (0.0189) 0.889  (0.0906) 0.913  (0.0123) 0.893  (0.0284)
Change from Baseline to Day 183 0.012  (0.0111) -0.005  (0.0079) 0.007  (0.0063) 0.001  (0.0143)
22.Secondary Outcome
Title Change From Baseline in Arm Span to Height Ratio During Entire Study Period - Cohort 3 and 4
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy Analysis Population
Arm/Group Title Cohort 3 Cohort 4
Hide Arm/Group Description:

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.

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.

Overall Number of Participants Analyzed 5 8
Mean (Standard Deviation)
Unit of Measure: ratio
Baseline 0.911  (0.0119) 0.900  (0.0315)
Change from Baseline to Month 24 0.000  (0.0123) -0.006  (0.0290)
23.Secondary Outcome
Title Change From Baseline in Arm Span to Height Ratio During Entire Study Period - Cohort 1 and 2 Switchers
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
Efficacy Analysis Population
Arm/Group Title Cohort 2
Hide Arm/Group Description:

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.

Overall Number of Participants Analyzed 6
Mean (Standard Deviation)
Unit of Measure: ratio
Baseline Number Analyzed 5 participants
0.881  (0.0480)
Change from Baseline to >=12 Months on 15ug/kg Number Analyzed 6 participants
-0.014  (0.0179)
Time Frame Up to Month 25 ± 7 Days
Adverse Event Reporting Description

Safety Analysis Population consists of 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.

Extension Safety Analysis Population consists of all subjects who received at least one dose of study treatment in the extension period and were used for safety analysis in the extension period.

 
Arm/Group Title Initial 6-Months Period 2.5 µg/kg. Initial 6-Months Period 7.5 µg/kg. Initial 6-Months Period 15 µg/kg. Initial 6-Months Period 30 µg/kg. Extension Period 2.5 µg/kg. Extension Period 7.5 µg/kg. Extension Period 15 µg/kg. Extension Period 30 µg/kg. Entire Study Period 2.5 µg/kg. Entire Study Period 7.5 µg/kg. Entire Study Period 15 µg/kg. Entire Study Period 30 µg/kg.
Hide Arm/Group Description BMN 111 at 2.5 μg/kg subcutaneous injection, once daily in the morning for initial 6-month period. BMN 111 at 7.5 μg/kg subcutaneous injection, once daily in the morning for initial 6-month period. BMN 111 at 15 μg/kg subcutaneous injection, once daily in the morning for initial 6-month period. BMN 111 at 30 μg/kg subcutaneous injection, once daily in the morning for initial 6-month period. BMN 111 at 2.5 μg/kg subcutaneous injection, once daily in the morning for mean duration of 135.4 days. BMN 111 at 7.5 μg/kg subcutaneous injection, once daily in the morning for mean duration of 83.1 days. BMN 111 at 15 μg/kg subcutaneous injection, once daily in the morning for mean duration of 464.7 days. BMN 111 at 30 μg/kg subcutaneous injection, once daily in the morning for mean duration of 546.4 days. BMN 111 at 2.5 μg/kg subcutaneous injection, once daily in the morning for mean duration of 298.8 days. BMN 111 at 7.5 μg/kg subcutaneous injection, once daily in the morning for mean duration of 175.5 days. BMN 111 at 15 μg/kg subcutaneous injection, once daily in the morning for mean duration of 549.6 days. BMN 111 at 30 μg/kg subcutaneous injection, once daily in the morning for mean duration of 650.9 days.
All-Cause Mortality
Initial 6-Months Period 2.5 µg/kg. Initial 6-Months Period 7.5 µg/kg. Initial 6-Months Period 15 µg/kg. Initial 6-Months Period 30 µg/kg. Extension Period 2.5 µg/kg. Extension Period 7.5 µg/kg. Extension Period 15 µg/kg. Extension Period 30 µg/kg. Entire Study Period 2.5 µg/kg. Entire Study Period 7.5 µg/kg. Entire Study Period 15 µg/kg. Entire Study Period 30 µg/kg.
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/8 (0.00%)   0/8 (0.00%)   0/10 (0.00%)   0/9 (0.00%)   0/7 (0.00%)   0/14 (0.00%)   0/22 (0.00%)   0/8 (0.00%)   0/8 (0.00%)   0/15 (0.00%)   0/22 (0.00%)   0/9 (0.00%) 
Hide Serious Adverse Events
Initial 6-Months Period 2.5 µg/kg. Initial 6-Months Period 7.5 µg/kg. Initial 6-Months Period 15 µg/kg. Initial 6-Months Period 30 µg/kg. Extension Period 2.5 µg/kg. Extension Period 7.5 µg/kg. Extension Period 15 µg/kg. Extension Period 30 µg/kg. Entire Study Period 2.5 µg/kg. Entire Study Period 7.5 µg/kg. Entire Study Period 15 µg/kg. Entire Study Period 30 µg/kg.
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/8 (0.00%)   0/8 (0.00%)   0/10 (0.00%)   0/9 (0.00%)   1/7 (14.29%)   0/14 (0.00%)   1/22 (4.55%)   1/8 (12.50%)   1/8 (12.50%)   0/15 (0.00%)   1/22 (4.55%)   1/9 (11.11%) 
Congenital, familial and genetic disorders                         
Thyroglossal cyst  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  1/8 (12.50%)  0/8 (0.00%)  0/15 (0.00%)  0/22 (0.00%)  1/9 (11.11%) 
Respiratory, thoracic and mediastinal disorders                         
Sleep apnoea syndrome  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  1/7 (14.29%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  0/22 (0.00%)  0/9 (0.00%) 
Tonsillar hypertrophy  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
1
Term from vocabulary, MedDRA (19.1)
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Initial 6-Months Period 2.5 µg/kg. Initial 6-Months Period 7.5 µg/kg. Initial 6-Months Period 15 µg/kg. Initial 6-Months Period 30 µg/kg. Extension Period 2.5 µg/kg. Extension Period 7.5 µg/kg. Extension Period 15 µg/kg. Extension Period 30 µg/kg. Entire Study Period 2.5 µg/kg. Entire Study Period 7.5 µg/kg. Entire Study Period 15 µg/kg. Entire Study Period 30 µg/kg.
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   8/8 (100.00%)   8/8 (100.00%)   10/10 (100.00%)   9/9 (100.00%)   7/7 (100.00%)   13/14 (92.86%)   22/22 (100.00%)   8/8 (100.00%)   8/8 (100.00%)   14/15 (93.33%)   22/22 (100.00%)   9/9 (100.00%) 
Blood and lymphatic system disorders                         
Lymphadenopathy  1  1/8 (12.50%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Neutropenia  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  2/22 (9.09%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  2/22 (9.09%)  0/9 (0.00%) 
Cardiac disorders                         
Cyanosis  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  1/9 (11.11%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  0/22 (0.00%)  1/9 (11.11%) 
Wolff-Parkinson-White syndrome  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  1/9 (11.11%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  0/22 (0.00%)  1/9 (11.11%) 
Congenital, familial and genetic disorders                         
Thyroglossal cyst  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  1/8 (12.50%)  0/8 (0.00%)  0/15 (0.00%)  0/22 (0.00%)  1/9 (11.11%) 
Ear and labyrinth disorders                         
Ear pain  1  1/8 (12.50%)  2/8 (25.00%)  1/10 (10.00%)  1/9 (11.11%)  1/7 (14.29%)  2/14 (14.29%)  3/22 (13.64%)  1/8 (12.50%)  2/8 (25.00%)  3/15 (20.00%)  3/22 (13.64%)  1/9 (11.11%) 
Ear swelling  1  1/8 (12.50%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Otorrhoea  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  2/22 (9.09%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  2/22 (9.09%)  0/9 (0.00%) 
Middle ear effusion  1  0/8 (0.00%)  1/8 (12.50%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  1/15 (6.67%)  0/22 (0.00%)  0/9 (0.00%) 
Tympanic membrane hyperaemia  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Endocrine disorders                         
Hypothyroidism  1  2/8 (25.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  2/8 (25.00%)  0/15 (0.00%)  0/22 (0.00%)  0/9 (0.00%) 
Eye disorders                         
Eye pain  1  1/8 (12.50%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Eye discharge  1  1/8 (12.50%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  0/22 (0.00%)  0/9 (0.00%) 
Eye inflammation  1  0/8 (0.00%)  0/8 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Eye irritation  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  1/9 (11.11%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  0/22 (0.00%)  1/9 (11.11%) 
Hypermetropia  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Gastrointestinal disorders                         
Vomiting  1  2/8 (25.00%)  1/8 (12.50%)  1/10 (10.00%)  1/9 (11.11%)  0/7 (0.00%)  1/14 (7.14%)  3/22 (13.64%)  3/8 (37.50%)  2/8 (25.00%)  2/15 (13.33%)  4/22 (18.18%)  3/9 (33.33%) 
Nausea  1  0/8 (0.00%)  1/8 (12.50%)  0/10 (0.00%)  1/9 (11.11%)  0/7 (0.00%)  0/14 (0.00%)  3/22 (13.64%)  1/8 (12.50%)  0/8 (0.00%)  1/15 (6.67%)  3/22 (13.64%)  1/9 (11.11%) 
Abdominal pain upper  1  1/8 (12.50%)  1/8 (12.50%)  0/10 (0.00%)  1/9 (11.11%)  0/7 (0.00%)  0/14 (0.00%)  4/22 (18.18%)  0/8 (0.00%)  1/8 (12.50%)  1/15 (6.67%)  4/22 (18.18%)  1/9 (11.11%) 
Diarrhoea  1  0/8 (0.00%)  1/8 (12.50%)  1/10 (10.00%)  2/9 (22.22%)  0/7 (0.00%)  1/14 (7.14%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  2/15 (13.33%)  1/22 (4.55%)  2/9 (22.22%) 
Abdominal pain  1  0/8 (0.00%)  0/8 (0.00%)  1/10 (10.00%)  1/9 (11.11%)  0/7 (0.00%)  0/14 (0.00%)  2/22 (9.09%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  2/22 (9.09%)  1/9 (11.11%) 
Dental caries  1  2/8 (25.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  1/7 (14.29%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  3/8 (37.50%)  0/15 (0.00%)  0/22 (0.00%)  0/9 (0.00%) 
Dyspepsia  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  1/15 (6.67%)  0/22 (0.00%)  0/9 (0.00%) 
Faeces discoloured  1  1/8 (12.50%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  0/22 (0.00%)  0/9 (0.00%) 
Malpositioned teeth  1  0/8 (0.00%)  1/8 (12.50%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  1/15 (6.67%)  0/22 (0.00%)  0/9 (0.00%) 
Mouth ulceration  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  1/9 (11.11%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  0/22 (0.00%)  1/9 (11.11%) 
Toothache  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  1/7 (14.29%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  0/22 (0.00%)  0/9 (0.00%) 
Aphthous ulcer  1  1/8 (12.50%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  0/22 (0.00%)  0/9 (0.00%) 
Gastritis  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  1/8 (12.50%)  0/8 (0.00%)  0/15 (0.00%)  0/22 (0.00%)  1/9 (11.11%) 
Gingival bleeding  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Oral pain  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Parotid gland enlargement  1  0/8 (0.00%)  0/8 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
General disorders                         
Injection site reaction  1  2/8 (25.00%)  6/8 (75.00%)  8/10 (80.00%)  9/9 (100.00%)  2/7 (28.57%)  5/14 (35.71%)  15/22 (68.18%)  6/8 (75.00%)  2/8 (25.00%)  8/15 (53.33%)  17/22 (77.27%)  9/9 (100.00%) 
Injection site erythema  1  4/8 (50.00%)  7/8 (87.50%)  9/10 (90.00%)  9/9 (100.00%)  1/7 (14.29%)  5/14 (35.71%)  11/22 (50.00%)  6/8 (75.00%)  4/8 (50.00%)  7/15 (46.67%)  14/22 (63.64%)  9/9 (100.00%) 
Injection site swelling  1  4/8 (50.00%)  2/8 (25.00%)  4/10 (40.00%)  2/9 (22.22%)  0/7 (0.00%)  0/14 (0.00%)  8/22 (36.36%)  1/8 (12.50%)  4/8 (50.00%)  2/15 (13.33%)  8/22 (36.36%)  2/9 (22.22%) 
Injection site urticaria  1  1/8 (12.50%)  1/8 (12.50%)  2/10 (20.00%)  3/9 (33.33%)  1/7 (14.29%)  1/14 (7.14%)  3/22 (13.64%)  1/8 (12.50%)  1/8 (12.50%)  2/15 (13.33%)  3/22 (13.64%)  4/9 (44.44%) 
Injection site pain  1  0/8 (0.00%)  0/8 (0.00%)  1/10 (10.00%)  2/9 (22.22%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  2/8 (25.00%)  0/8 (0.00%)  0/15 (0.00%)  2/22 (9.09%)  3/9 (33.33%) 
Pyrexia  1  4/8 (50.00%)  1/8 (12.50%)  3/10 (30.00%)  2/9 (22.22%)  0/7 (0.00%)  1/14 (7.14%)  5/22 (22.73%)  1/8 (12.50%)  4/8 (50.00%)  2/15 (13.33%)  7/22 (31.82%)  2/9 (22.22%) 
Injection site bruising  1  1/8 (12.50%)  2/8 (25.00%)  0/10 (0.00%)  0/9 (0.00%)  1/7 (14.29%)  0/14 (0.00%)  0/22 (0.00%)  1/8 (12.50%)  1/8 (12.50%)  2/15 (13.33%)  0/22 (0.00%)  1/9 (11.11%) 
Fatigue  1  0/8 (0.00%)  1/8 (12.50%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  2/22 (9.09%)  0/8 (0.00%)  0/8 (0.00%)  1/15 (6.67%)  2/22 (9.09%)  0/9 (0.00%) 
Injection site pruritus  1  0/8 (0.00%)  0/8 (0.00%)  2/10 (20.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  1/8 (12.50%)  0/8 (0.00%)  0/15 (0.00%)  3/22 (13.64%)  1/9 (11.11%) 
Injection site haemorrhage  1  0/8 (0.00%)  0/8 (0.00%)  1/10 (10.00%)  1/9 (11.11%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  2/22 (9.09%)  1/9 (11.11%) 
Application site erythema  1  1/8 (12.50%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  0/22 (0.00%)  0/9 (0.00%) 
Cyst  1  1/8 (12.50%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  0/22 (0.00%)  0/9 (0.00%) 
Influenza like illness  1  0/8 (0.00%)  0/8 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Injection site discolouration  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  1/9 (11.11%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  0/22 (0.00%)  1/9 (11.11%) 
Injection site induration  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  1/8 (12.50%)  0/8 (0.00%)  0/15 (0.00%)  0/22 (0.00%)  1/9 (11.11%) 
Malaise  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Medical device site reaction  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  1/15 (6.67%)  0/22 (0.00%)  0/9 (0.00%) 
Pain  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  1/7 (14.29%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  0/22 (0.00%)  0/9 (0.00%) 
Immune system disorders                         
Drug hypersensitivity  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  1/7 (14.29%)  1/14 (7.14%)  1/22 (4.55%)  0/8 (0.00%)  1/8 (12.50%)  1/15 (6.67%)  1/22 (4.55%)  0/9 (0.00%) 
Hypersensitivity  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  1/8 (12.50%)  0/8 (0.00%)  0/15 (0.00%)  0/22 (0.00%)  1/9 (11.11%) 
Seasonal allergy  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  1/8 (12.50%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  1/9 (11.11%) 
Infections and infestations                         
Nasopharyngitis  1  1/8 (12.50%)  3/8 (37.50%)  3/10 (30.00%)  1/9 (11.11%)  0/7 (0.00%)  1/14 (7.14%)  4/22 (18.18%)  2/8 (25.00%)  1/8 (12.50%)  3/15 (20.00%)  7/22 (31.82%)  2/9 (22.22%) 
Ear infection  1  0/8 (0.00%)  3/8 (37.50%)  2/10 (20.00%)  2/9 (22.22%)  1/7 (14.29%)  1/14 (7.14%)  4/22 (18.18%)  2/8 (25.00%)  1/8 (12.50%)  4/15 (26.67%)  6/22 (27.27%)  2/9 (22.22%) 
Upper respiratory tract infection  1  0/8 (0.00%)  1/8 (12.50%)  3/10 (30.00%)  2/9 (22.22%)  0/7 (0.00%)  0/14 (0.00%)  3/22 (13.64%)  1/8 (12.50%)  0/8 (0.00%)  1/15 (6.67%)  5/22 (22.73%)  2/9 (22.22%) 
Otitis media  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  2/9 (22.22%)  1/7 (14.29%)  0/14 (0.00%)  3/22 (13.64%)  2/8 (25.00%)  1/8 (12.50%)  0/15 (0.00%)  3/22 (13.64%)  3/9 (33.33%) 
Viral upper respiratory tract infection  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  1/9 (11.11%)  0/7 (0.00%)  0/14 (0.00%)  3/22 (13.64%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  3/22 (13.64%)  1/9 (11.11%) 
Gastroenteritis viral  1  0/8 (0.00%)  1/8 (12.50%)  0/10 (0.00%)  1/9 (11.11%)  1/7 (14.29%)  2/14 (14.29%)  0/22 (0.00%)  1/8 (12.50%)  1/8 (12.50%)  3/15 (20.00%)  0/22 (0.00%)  2/9 (22.22%) 
Viral infection  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  5/22 (22.73%)  1/8 (12.50%)  0/8 (0.00%)  0/15 (0.00%)  5/22 (22.73%)  1/9 (11.11%) 
Gastroenteritis  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  1/22 (4.55%)  1/8 (12.50%)  0/8 (0.00%)  1/15 (6.67%)  1/22 (4.55%)  1/9 (11.11%) 
Bronchitis  1  1/8 (12.50%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  1/22 (4.55%)  0/8 (0.00%)  1/8 (12.50%)  1/15 (6.67%)  1/22 (4.55%)  0/9 (0.00%) 
Sinusitis  1  1/8 (12.50%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  2/22 (9.09%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  2/22 (9.09%)  0/9 (0.00%) 
Conjunctivitis  1  1/8 (12.50%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Influenza  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  1/9 (11.11%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  1/8 (12.50%)  0/8 (0.00%)  0/15 (0.00%)  0/22 (0.00%)  2/9 (22.22%) 
Otitis externa  1  1/8 (12.50%)  0/8 (0.00%)  0/10 (0.00%)  1/9 (11.11%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  0/22 (0.00%)  1/9 (11.11%) 
Pharyngitis streptococcal  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  2/22 (9.09%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  2/22 (9.09%)  0/9 (0.00%) 
Rhinitis  1  0/8 (0.00%)  0/8 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Acute sinusitis  1  1/8 (12.50%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  0/22 (0.00%)  0/9 (0.00%) 
Atypical pneumonia  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Croup infectious  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  1/9 (11.11%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  0/22 (0.00%)  1/9 (11.11%) 
Eye abscess  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Gastrointestinal viral infection  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  1/8 (12.50%)  0/8 (0.00%)  0/15 (0.00%)  0/22 (0.00%)  1/9 (11.11%) 
Incision site infection  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Onychomycosis  1  0/8 (0.00%)  0/8 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Pharyngitis  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  1/8 (12.50%)  0/8 (0.00%)  0/15 (0.00%)  0/22 (0.00%)  1/9 (11.11%) 
Rash pustular  1  0/8 (0.00%)  0/8 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Respiratory tract infection  1  0/8 (0.00%)  0/8 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Scarlet fever  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  1/8 (12.50%)  0/8 (0.00%)  0/15 (0.00%)  0/22 (0.00%)  1/9 (11.11%) 
Tonsillitis  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Tooth abscess  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  1/7 (14.29%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  0/22 (0.00%)  0/9 (0.00%) 
Varicella  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Injury, poisoning and procedural complications                         
Arthropod bite  1  1/8 (12.50%)  2/8 (25.00%)  1/10 (10.00%)  0/9 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  3/22 (13.64%)  1/8 (12.50%)  1/8 (12.50%)  2/15 (13.33%)  3/22 (13.64%)  1/9 (11.11%) 
Fall  1  1/8 (12.50%)  0/8 (0.00%)  1/10 (10.00%)  1/9 (11.11%)  1/7 (14.29%)  1/14 (7.14%)  2/22 (9.09%)  1/8 (12.50%)  2/8 (25.00%)  1/15 (6.67%)  3/22 (13.64%)  2/9 (22.22%) 
Contusion  1  1/8 (12.50%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  1/7 (14.29%)  0/14 (0.00%)  2/22 (9.09%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  2/22 (9.09%)  0/9 (0.00%) 
Procedural anxiety  1  1/8 (12.50%)  1/8 (12.50%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  1/8 (12.50%)  1/15 (6.67%)  1/22 (4.55%)  0/9 (0.00%) 
Limb injury  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  1/8 (12.50%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  1/9 (11.11%) 
Procedural pain  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  2/7 (28.57%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  2/8 (25.00%)  0/15 (0.00%)  0/22 (0.00%)  0/9 (0.00%) 
Skin abrasion  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  1/9 (11.11%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  1/8 (12.50%)  0/8 (0.00%)  0/15 (0.00%)  0/22 (0.00%)  2/9 (22.22%) 
Thermal burn  1  1/8 (12.50%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Excoriation  1  0/8 (0.00%)  1/8 (12.50%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  1/15 (6.67%)  0/22 (0.00%)  0/9 (0.00%) 
Joint injury  1  1/8 (12.50%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  0/22 (0.00%)  0/9 (0.00%) 
Laceration  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  1/9 (11.11%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  0/22 (0.00%)  1/9 (11.11%) 
Meniscus injury  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Muscle strain  1  0/8 (0.00%)  1/8 (12.50%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  1/15 (6.67%)  0/22 (0.00%)  0/9 (0.00%) 
Post-traumatic pain  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  1/15 (6.67%)  0/22 (0.00%)  0/9 (0.00%) 
Soft tissue injury  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  1/8 (12.50%)  0/8 (0.00%)  0/15 (0.00%)  0/22 (0.00%)  1/9 (11.11%) 
Sunburn  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  1/8 (12.50%)  0/8 (0.00%)  0/15 (0.00%)  0/22 (0.00%)  1/9 (11.11%) 
Wound  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Investigations                         
Body temperature increased  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  1/9 (11.11%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  1/8 (12.50%)  0/8 (0.00%)  0/15 (0.00%)  0/22 (0.00%)  1/9 (11.11%) 
Eosinophil count increased  1  0/8 (0.00%)  0/8 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  2/22 (9.09%)  0/9 (0.00%) 
Electrocardiogram QT prolonged  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Vitamin D decreased  1  0/8 (0.00%)  0/8 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  2/22 (9.09%)  0/9 (0.00%) 
Blood immunoglobulin E increased  1  0/8 (0.00%)  0/8 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Respiratory rate increased  1  1/8 (12.50%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  0/22 (0.00%)  0/9 (0.00%) 
Sleep study abnormal  1  0/8 (0.00%)  0/8 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Metabolism and nutrition disorders                         
Hyperglycaemia  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Vitamin D deficiency  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Musculoskeletal and connective tissue disorders                         
Pain in extremity  1  1/8 (12.50%)  0/8 (0.00%)  0/10 (0.00%)  1/9 (11.11%)  0/7 (0.00%)  0/14 (0.00%)  2/22 (9.09%)  4/8 (50.00%)  1/8 (12.50%)  0/15 (0.00%)  2/22 (9.09%)  4/9 (44.44%) 
Arthralgia  1  1/8 (12.50%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  3/22 (13.64%)  1/8 (12.50%)  1/8 (12.50%)  0/15 (0.00%)  3/22 (13.64%)  1/9 (11.11%) 
Back pain  1  1/8 (12.50%)  1/8 (12.50%)  1/10 (10.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  2/22 (9.09%)  0/8 (0.00%)  1/8 (12.50%)  1/15 (6.67%)  3/22 (13.64%)  0/9 (0.00%) 
Neck pain  1  1/8 (12.50%)  0/8 (0.00%)  0/10 (0.00%)  1/9 (11.11%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  1/22 (4.55%)  1/9 (11.11%) 
Groin pain  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  1/7 (14.29%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Joint range of motion decreased  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  1/8 (12.50%)  0/8 (0.00%)  0/15 (0.00%)  0/22 (0.00%)  1/9 (11.11%) 
Bone pain  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  1/7 (14.29%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  0/22 (0.00%)  0/9 (0.00%) 
Muscle spasms  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Musculoskeletal chest pain  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  1/15 (6.67%)  0/22 (0.00%)  0/9 (0.00%) 
Myalgia  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  1/8 (12.50%)  0/8 (0.00%)  0/15 (0.00%)  0/22 (0.00%)  1/9 (11.11%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                         
Skin papilloma  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  1/8 (12.50%)  0/8 (0.00%)  0/15 (0.00%)  0/22 (0.00%)  1/9 (11.11%) 
Nervous system disorders                         
Headache  1  4/8 (50.00%)  2/8 (25.00%)  2/10 (20.00%)  3/9 (33.33%)  1/7 (14.29%)  1/14 (7.14%)  5/22 (22.73%)  0/8 (0.00%)  4/8 (50.00%)  3/15 (20.00%)  6/22 (27.27%)  3/9 (33.33%) 
Dizziness  1  1/8 (12.50%)  1/8 (12.50%)  1/10 (10.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  1/8 (12.50%)  1/15 (6.67%)  2/22 (9.09%)  0/9 (0.00%) 
Presyncope  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  2/22 (9.09%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  2/22 (9.09%)  0/9 (0.00%) 
Syncope  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Tremor  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  1/9 (11.11%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  0/22 (0.00%)  1/9 (11.11%) 
Sinus headache  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  1/7 (14.29%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  0/22 (0.00%)  0/9 (0.00%) 
Psychiatric disorders                         
Emotional disorder  1  0/8 (0.00%)  1/8 (12.50%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  1/15 (6.67%)  0/22 (0.00%)  0/9 (0.00%) 
Irritability  1  1/8 (12.50%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  0/22 (0.00%)  0/8 (0.00%)  1/8 (12.50%)  1/15 (6.67%)  0/22 (0.00%)  0/9 (0.00%) 
Aggression  1  0/8 (0.00%)  1/8 (12.50%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  1/15 (6.67%)  0/22 (0.00%)  0/9 (0.00%) 
Attention deficit/hyperactivity disorder  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Enuresis  1  1/8 (12.50%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  0/22 (0.00%)  0/9 (0.00%) 
Frustration tolerance decreased  1  0/8 (0.00%)  1/8 (12.50%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  1/15 (6.67%)  0/22 (0.00%)  0/9 (0.00%) 
Renal and urinary disorders                         
Pollakiuria  1  0/8 (0.00%)  1/8 (12.50%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  1/15 (6.67%)  0/22 (0.00%)  0/9 (0.00%) 
Respiratory, thoracic and mediastinal disorders                         
Cough  1  4/8 (50.00%)  0/8 (0.00%)  2/10 (20.00%)  4/9 (44.44%)  0/7 (0.00%)  2/14 (14.29%)  4/22 (18.18%)  1/8 (12.50%)  4/8 (50.00%)  2/15 (13.33%)  6/22 (27.27%)  4/9 (44.44%) 
Oropharyngeal pain  1  1/8 (12.50%)  2/8 (25.00%)  2/10 (20.00%)  0/9 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  3/22 (13.64%)  0/8 (0.00%)  1/8 (12.50%)  2/15 (13.33%)  4/22 (18.18%)  0/9 (0.00%) 
Nasal congestion  1  1/8 (12.50%)  2/8 (25.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  1/22 (4.55%)  2/8 (25.00%)  1/8 (12.50%)  2/15 (13.33%)  1/22 (4.55%)  2/9 (22.22%) 
Rhinorrhoea  1  1/8 (12.50%)  1/8 (12.50%)  0/10 (0.00%)  1/9 (11.11%)  1/7 (14.29%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  2/8 (25.00%)  1/15 (6.67%)  0/22 (0.00%)  1/9 (11.11%) 
Epistaxis  1  0/8 (0.00%)  1/8 (12.50%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  0/8 (0.00%)  1/15 (6.67%)  1/22 (4.55%)  0/9 (0.00%) 
Sleep apnoea syndrome  1  0/8 (0.00%)  0/8 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  1/7 (14.29%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  2/22 (9.09%)  0/9 (0.00%) 
Sneezing  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  1/8 (12.50%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  1/9 (11.11%) 
Tonsillar hypertrophy  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  2/22 (9.09%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  2/22 (9.09%)  0/9 (0.00%) 
Asthma  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Nasal dryness  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  1/7 (14.29%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  0/22 (0.00%)  0/9 (0.00%) 
Rhinitis allergic  1  1/8 (12.50%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  0/22 (0.00%)  0/9 (0.00%) 
Snoring  1  0/8 (0.00%)  0/8 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Wheezing  1  0/8 (0.00%)  0/8 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Skin and subcutaneous tissue disorders                         
Rash  1  0/8 (0.00%)  2/8 (25.00%)  0/10 (0.00%)  1/9 (11.11%)  1/7 (14.29%)  0/14 (0.00%)  3/22 (13.64%)  0/8 (0.00%)  1/8 (12.50%)  2/15 (13.33%)  3/22 (13.64%)  1/9 (11.11%) 
Dermatitis  1  0/8 (0.00%)  0/8 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  2/22 (9.09%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  2/22 (9.09%)  0/9 (0.00%) 
Dry skin  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  2/22 (9.09%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  2/22 (9.09%)  0/9 (0.00%) 
Pruritus  1  1/8 (12.50%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  1/8 (12.50%)  1/8 (12.50%)  0/15 (0.00%)  1/22 (4.55%)  1/9 (11.11%) 
Erythema  1  1/8 (12.50%)  0/8 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Rash generalised  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  1/7 (14.29%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Rash pruritic  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  1/8 (12.50%)  0/8 (0.00%)  0/15 (0.00%)  0/22 (0.00%)  1/9 (11.11%) 
Acne  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Miliaria  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Skin exfoliation  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  1/9 (11.11%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  0/22 (0.00%)  1/9 (11.11%) 
Skin striae  1  0/8 (0.00%)  1/8 (12.50%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  1/15 (6.67%)  0/22 (0.00%)  0/9 (0.00%) 
Surgical and medical procedures                         
Ear tube insertion  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  2/22 (9.09%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  2/22 (9.09%)  0/9 (0.00%) 
Tooth extraction  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  1/7 (14.29%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  0/22 (0.00%)  0/9 (0.00%) 
Vascular disorders                         
Hypotension  1  3/8 (37.50%)  4/8 (50.00%)  4/10 (40.00%)  2/9 (22.22%)  1/7 (14.29%)  1/14 (7.14%)  3/22 (13.64%)  2/8 (25.00%)  4/8 (50.00%)  5/15 (33.33%)  7/22 (31.82%)  2/9 (22.22%) 
Haematoma  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Haemorrhage  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/22 (4.55%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  1/22 (4.55%)  0/9 (0.00%) 
Hypertension  1  1/8 (12.50%)  0/8 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  1/8 (12.50%)  0/15 (0.00%)  0/22 (0.00%)  0/9 (0.00%) 
Pallor  1  0/8 (0.00%)  0/8 (0.00%)  0/10 (0.00%)  1/9 (11.11%)  0/7 (0.00%)  0/14 (0.00%)  0/22 (0.00%)  0/8 (0.00%)  0/8 (0.00%)  0/15 (0.00%)  0/22 (0.00%)  1/9 (11.11%) 
1
Term from vocabulary, MedDRA (19.1)
Indicates events were collected by systematic assessment
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Alice Hunstman-Labed
Organization: BioMarin Pharmaceutical Inc.
Phone: +44 207 4203392
EMail: alice.huntsmanlabed@bmrn.com
Layout table for additonal information
Responsible Party: BioMarin Pharmaceutical
ClinicalTrials.gov Identifier: NCT02055157    
Other Study ID Numbers: 111-202
2013-004137-32 ( EudraCT Number )
First Submitted: April 18, 2013
First Posted: February 5, 2014
Results First Submitted: September 18, 2020
Results First Posted: January 15, 2021
Last Update Posted: January 15, 2021