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

• Sponsor: BioMarin Pharmaceutical (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02055157
• Collaborator: (none)
• Enrollment: 35
• Locations: 9
• Arms: 4
• Actual Duration (Months): 44.6
• Patients Per Site: 3.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Achondroplasia	Drug: BMN 111	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 35 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Open-label, Sequential Cohort Dose-escalation Study of BMN 111 in Children With Achondroplasia
• Actual Study Start Date: Jan 13, 2014
• Actual Primary Completion Date: Oct 2, 2017
• Actual Study Completion Date: Oct 2, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1 Cohort 1: 2.5 ug/kg	Drug: BMN 111; BMN 111 will be administered daily for 24 months in an open-label sequential dose adjustment fashion.; Other Names: Modified recombinant human C-type natriuretic peptide Vosoritide
Experimental: Cohort 2 Cohort 2: 7.5 ug/kg,	Drug: BMN 111; BMN 111 will be administered daily for 24 months in an open-label sequential dose adjustment fashion.; Other Names: Modified recombinant human C-type natriuretic peptide Vosoritide
Experimental: Cohort 3 Cohort 3: 15 ug/Kg	Drug: BMN 111; BMN 111 will be administered daily for 24 months in an open-label sequential dose adjustment fashion.; Other Names: Modified recombinant human C-type natriuretic peptide Vosoritide
Experimental: Cohort 4 Cohort 4: 30 ug/kg	Drug: BMN 111; BMN 111 will be administered daily for 24 months in an open-label sequential dose adjustment fashion.; Other Names: Modified recombinant human C-type natriuretic peptide Vosoritide

Outcome Measures

Primary Outcome Measures

1. 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).

2. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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).

5. 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).

6. 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).

7. 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)

8. 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)

9. 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.

10. 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.

11. 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)

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

19. 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.

20. 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.

21. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 5 Years to 14 Years
• Sexes Eligible for Study: All
• Accepts 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 Exclusion Criteria for Optional, Open-label Extension Phase:

• Use of restricted therapies during the initial 6 months of the study

• Permanently discontinued BMN 111 during the initial 6 months of the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital & Research Center Oakland	Oakland	California	United States	94609
2	Harbor - UCLA Medical Center	Torrance	California	United States	90509
3	Ann and Robert H. Lurie Childrens Hospital of Chicago	Chicago	Illinois	United States	60611
4	Johns Hopkins McKusick - Institute of Genetic Medicine	Baltimore	Maryland	United States	21287
5	Vanderbilt University	Nashville	Tennessee	United States	37232-2578
6	Baylor College of Medicine	Houston	Texas	United States	77030
7	Murdoch Children's Research Institute	Parkville	Victoria	Australia	3052
8	Institut Necker	Paris		France	75015
9	Guys & St. Thomas NHS Foundation Trust Evelina Hospital	London		United Kingdom	SE1 9RT

Sponsors and Collaborators

• BioMarin Pharmaceutical

Investigators

• Study Director: Medical Director, MD, BioMarin Pharmaceutical

Study Documents (Full-Text)

• Study Protocol - Aug 22, 2016
• Statistical Analysis Plan - Jun 11, 2018

More Information

Publications

None provided.

• Responsible Party: BioMarin Pharmaceutical
• ClinicalTrials.gov Identifier: NCT02055157
• Other Study ID Numbers: 111-202; 2013-004137-32
• First Posted: Feb 5, 2014
• Last Update Posted: Jan 15, 2021
• Last Verified: Dec 1, 2020

• Keywords provided by BioMarin Pharmaceutical: Achondroplasia; Dwarfism; Bone Diseases, Developmental; Bone Diseases
• Additional relevant MeSH terms: Achondroplasia; Natriuretic Peptide, C-Type

Study Results

Participant Flow

Recruitment Details	This study was conducted at nine study centers in United States, Australia, United Kingdom and France.

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4
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
Period Title: Initial 6 Months
STARTED	7	7	10	8
COMPLETED	6	6	10	8
NOT COMPLETED	1	1	0	0

Baseline Characteristics

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Total
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 Participants	8	8	10	9	35
Age (yrs) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [yrs]	7.3 (1.58)	8.3 (2.19)	8.0 (1.63)	6.9 (1.17)	7.6 (1.68)
Sex: Female, Male (Count of Participants)
Female	5 62.5%	3 37.5%	6 60%	5 55.6%	19 54.3%
Male	3 37.5%	5 62.5%	4 40%	4 44.4%	16 45.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	1 10%	1 11.1%	2 5.7%
Not Hispanic or Latino	8 100%	8 100%	9 90%	7 77.8%	32 91.4%
Unknown or Not Reported	0 0%	0 0%	0 0%	1 11.1%	1 2.9%
Race/Ethnicity, Customized (Count of Participants)
White	7 87.5%	6 75%	5 50%	6 66.7%	24 68.6%
Asian	0 0%	1 12.5%	3 30%	3 33.3%	7 20%
Black or African American	1 12.5%	0 0%	1 10%	0 0%	2 5.7%
Other	0 0%	1 12.5%	1 10%	0 0%	2 5.7%

Outcome Measures

1. Primary Outcome

Title	Overall Summary of Adverse Events During Initial 6-Month Period
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

Outcome Measure Data

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
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.
Measure Participants	8	8	10	9
Subjects with at Least 1 Reported TEAE	8 100%	8 100%	10 100%	9 100%
Subjects Least Reported Study Drug-Related TEAE	7 87.5%	8 100%	9 90%	9 100%
Subjects with at Least 1 Reported SAE	0 0%	0 0%	0 0%	0 0%
Subjects Least Reported Study Drug-Related SAE	0 0%	0 0%	0 0%	0 0%
Subjects Who Died	0 0%	0 0%	0 0%	0 0%

2. Primary Outcome

Title	Overall Summary of Adverse Events During Entire Study Period
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

Outcome Measure Data

Analysis Population Description

Safety Analysis Population.

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4
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.
Measure Participants	8	8	10	9
Subjects with at Least 1 Reported TEAE	8 100%	8 100%	10 100%	9 100%
Subjects Least Reported Study Drug-Related TEAE	7 87.5%	8 100%	9 90%	9 100%
Subjects with at Least 1 Reported SAE	1 12.5%	0 0%	1 10%	1 11.1%
Subjects Least Reported Study Drug-Related SAE	0 0%	0 0%	0 0%	0 0%
Subjects Who Died	0 0%	0 0%	0 0%	0 0%

3. Secondary Outcome

Title	Change From Baseline in Annualized Growth Velocity (AGV) During Initial 6-Month
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)

Outcome Measure Data

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
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.
Measure Participants	8	8	10	8
Baseline	3.755 (1.1094)	2.891 (1.3920)	4.044 (2.2751)	4.492 (1.1889)
Change from Baseline to Day 183	-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
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

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Population

Arm/Group Title	Cohort 3	Cohort 4
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.
Measure Participants	10	8
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
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

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Population

Arm/Group Title	Cohort 1	Cohort 2
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.
Measure Participants	6	6
Baseline	3.629 (1.1586)	3.510 (0.8327)
Change from Baseline at >=12 Months on 15μg/kg	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
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)

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Population

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4
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.
Measure Participants	8	8	10	8
Baseline	-6.056 (0.6331)	-5.145 (0.8530)	-4.613 (1.1355)	-5.193 (0.7486)
Change from Baseline to Day 183	-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
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

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Population

Arm/Group Title	Cohort 3	Cohort 4
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.
Measure Participants	10	8
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
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

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Population

Arm/Group Title	Cohort 1	Cohort 2
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.
Measure Participants	6	6
Baseline	-6.064 (0.6932)	-4.912 (0.7708)
Change from Baseline to >=12 Months on 15ug/kg	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
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)

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Population

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4
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.
Measure Participants	8	8	10	8
Baseline	2.094 (0.0984)	2.027 (0.1793)	1.911 (0.2286)	1.962 (0.1822)
Change from Baseline to Day 183	-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
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

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Population

Arm/Group Title	Cohort 3	Cohort 4
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.
Measure Participants	10	8
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
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)

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Population

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4
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.
Measure Participants	8	8	10	8
Baseline	1.130 (0.1168)	1.143 (0.0924)	1.130 (0.1190)	1.106 (0.0816)
Change from Baseline to Day 183	-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
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

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Population

Arm/Group Title	Cohort 3	Cohort 4
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.
Measure Participants	10	8
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
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

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Population

Arm/Group Title	Cohort 1	Cohort 2
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.
Measure Participants	6	6
Baseline	2.119 (0.0812)	2.053 (0.1746)
Change from Baseline to >=12 Months on 15ug/kg	-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
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

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Population

Arm/Group Title	Cohort 1	Cohort 2
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.
Measure Participants	6	6
Baseline	1.131 (0.1280)	1.114 (0.0520)
Change from Baseline to >=12 Months on 15ug/kg	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
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)

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Population

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4
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.
Measure Participants	8	8	10	8
Baseline	0.672 (0.0600)	0.662 (0.0585)	0.687 (0.0268)	0.691 (0.0847)
Change from Baseline to Day 183	-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
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

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Population

Arm/Group Title	Cohort 3	Cohort 4
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.
Measure Participants	10	8
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
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

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Population

Arm/Group Title	Cohort 1	Cohort 2
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.
Measure Participants	6	6
Baseline	0.659 (0.0541)	0.673 (0.0579)
Change from Baseline to >=12 Months on 15ug/kg	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
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)

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Population

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4
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.
Measure Participants	8	8	10	8
Baseline	1.089 (0.1067)	1.074 (0.1350)	1.107 (0.0607)	1.061 (0.1341)
Change from Baseline to Day 183	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
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

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Population

Arm/Group Title	Cohort 3	Cohort 4
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.
Measure Participants	10	8
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
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

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Population

Arm/Group Title	Cohort 1	Cohort 2
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.
Measure Participants	6	6
Baseline	1.080 (0.1139)	1.100 (0.1447)
Change from Baseline to >=12 Months on 15ug/kg	-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
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)

Outcome Measure Data

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
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.
Measure Participants	4	2	4	7
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
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

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Population

Arm/Group Title	Cohort 3	Cohort 4
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.
Measure Participants	5	8
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
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

Outcome Measure Data

Analysis Population Description

Efficacy Analysis Population

Arm/Group Title	Cohort 2
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.
Measure Participants	6
Baseline	0.881 (0.0480)
Change from Baseline to >=12 Months on 15ug/kg	-0.014 (0.0179)

Adverse Events

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.
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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		0/22 (0%)		0/9 (0%)
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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		1/7 (14.3%)		0/14 (0%)		1/22 (4.5%)		1/8 (12.5%)		1/8 (12.5%)		0/15 (0%)		1/22 (4.5%)		1/9 (11.1%)
Congenital, familial and genetic disorders
Thyroglossal cyst	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		1/8 (12.5%)		0/8 (0%)		0/15 (0%)		0/22 (0%)		1/9 (11.1%)
Respiratory, thoracic and mediastinal disorders
Sleep apnoea syndrome	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		1/7 (14.3%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		0/22 (0%)		0/9 (0%)
Tonsillar hypertrophy	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Other (Not Including 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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/8 (100%)		8/8 (100%)		10/10 (100%)		9/9 (100%)		7/7 (100%)		13/14 (92.9%)		22/22 (100%)		8/8 (100%)		8/8 (100%)		14/15 (93.3%)		22/22 (100%)		9/9 (100%)
Blood and lymphatic system disorders
Lymphadenopathy	1/8 (12.5%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Neutropenia	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		2/22 (9.1%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		2/22 (9.1%)		0/9 (0%)
Cardiac disorders
Cyanosis	0/8 (0%)		0/8 (0%)		0/10 (0%)		1/9 (11.1%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		0/22 (0%)		1/9 (11.1%)
Wolff-Parkinson-White syndrome	0/8 (0%)		0/8 (0%)		0/10 (0%)		1/9 (11.1%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		0/22 (0%)		1/9 (11.1%)
Congenital, familial and genetic disorders
Thyroglossal cyst	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		1/8 (12.5%)		0/8 (0%)		0/15 (0%)		0/22 (0%)		1/9 (11.1%)
Ear and labyrinth disorders
Ear pain	1/8 (12.5%)		2/8 (25%)		1/10 (10%)		1/9 (11.1%)		1/7 (14.3%)		2/14 (14.3%)		3/22 (13.6%)		1/8 (12.5%)		2/8 (25%)		3/15 (20%)		3/22 (13.6%)		1/9 (11.1%)
Ear swelling	1/8 (12.5%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Otorrhoea	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		2/22 (9.1%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		2/22 (9.1%)		0/9 (0%)
Middle ear effusion	0/8 (0%)		1/8 (12.5%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		1/15 (6.7%)		0/22 (0%)		0/9 (0%)
Tympanic membrane hyperaemia	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Endocrine disorders
Hypothyroidism	2/8 (25%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		2/8 (25%)		0/15 (0%)		0/22 (0%)		0/9 (0%)
Eye disorders
Eye pain	1/8 (12.5%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Eye discharge	1/8 (12.5%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		0/22 (0%)		0/9 (0%)
Eye inflammation	0/8 (0%)		0/8 (0%)		1/10 (10%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Eye irritation	0/8 (0%)		0/8 (0%)		0/10 (0%)		1/9 (11.1%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		0/22 (0%)		1/9 (11.1%)
Hypermetropia	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Gastrointestinal disorders
Vomiting	2/8 (25%)		1/8 (12.5%)		1/10 (10%)		1/9 (11.1%)		0/7 (0%)		1/14 (7.1%)		3/22 (13.6%)		3/8 (37.5%)		2/8 (25%)		2/15 (13.3%)		4/22 (18.2%)		3/9 (33.3%)
Nausea	0/8 (0%)		1/8 (12.5%)		0/10 (0%)		1/9 (11.1%)		0/7 (0%)		0/14 (0%)		3/22 (13.6%)		1/8 (12.5%)		0/8 (0%)		1/15 (6.7%)		3/22 (13.6%)		1/9 (11.1%)
Abdominal pain upper	1/8 (12.5%)		1/8 (12.5%)		0/10 (0%)		1/9 (11.1%)		0/7 (0%)		0/14 (0%)		4/22 (18.2%)		0/8 (0%)		1/8 (12.5%)		1/15 (6.7%)		4/22 (18.2%)		1/9 (11.1%)
Diarrhoea	0/8 (0%)		1/8 (12.5%)		1/10 (10%)		2/9 (22.2%)		0/7 (0%)		1/14 (7.1%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		2/15 (13.3%)		1/22 (4.5%)		2/9 (22.2%)
Abdominal pain	0/8 (0%)		0/8 (0%)		1/10 (10%)		1/9 (11.1%)		0/7 (0%)		0/14 (0%)		2/22 (9.1%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		2/22 (9.1%)		1/9 (11.1%)
Dental caries	2/8 (25%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		1/7 (14.3%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		3/8 (37.5%)		0/15 (0%)		0/22 (0%)		0/9 (0%)
Dyspepsia	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		1/14 (7.1%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		1/15 (6.7%)		0/22 (0%)		0/9 (0%)
Faeces discoloured	1/8 (12.5%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		0/22 (0%)		0/9 (0%)
Malpositioned teeth	0/8 (0%)		1/8 (12.5%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		1/15 (6.7%)		0/22 (0%)		0/9 (0%)
Mouth ulceration	0/8 (0%)		0/8 (0%)		0/10 (0%)		1/9 (11.1%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		0/22 (0%)		1/9 (11.1%)
Toothache	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		1/7 (14.3%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		0/22 (0%)		0/9 (0%)
Aphthous ulcer	1/8 (12.5%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		0/22 (0%)		0/9 (0%)
Gastritis	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		1/8 (12.5%)		0/8 (0%)		0/15 (0%)		0/22 (0%)		1/9 (11.1%)
Gingival bleeding	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Oral pain	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Parotid gland enlargement	0/8 (0%)		0/8 (0%)		1/10 (10%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
General disorders
Injection site reaction	2/8 (25%)		6/8 (75%)		8/10 (80%)		9/9 (100%)		2/7 (28.6%)		5/14 (35.7%)		15/22 (68.2%)		6/8 (75%)		2/8 (25%)		8/15 (53.3%)		17/22 (77.3%)		9/9 (100%)
Injection site erythema	4/8 (50%)		7/8 (87.5%)		9/10 (90%)		9/9 (100%)		1/7 (14.3%)		5/14 (35.7%)		11/22 (50%)		6/8 (75%)		4/8 (50%)		7/15 (46.7%)		14/22 (63.6%)		9/9 (100%)
Injection site swelling	4/8 (50%)		2/8 (25%)		4/10 (40%)		2/9 (22.2%)		0/7 (0%)		0/14 (0%)		8/22 (36.4%)		1/8 (12.5%)		4/8 (50%)		2/15 (13.3%)		8/22 (36.4%)		2/9 (22.2%)
Injection site urticaria	1/8 (12.5%)		1/8 (12.5%)		2/10 (20%)		3/9 (33.3%)		1/7 (14.3%)		1/14 (7.1%)		3/22 (13.6%)		1/8 (12.5%)		1/8 (12.5%)		2/15 (13.3%)		3/22 (13.6%)		4/9 (44.4%)
Injection site pain	0/8 (0%)		0/8 (0%)		1/10 (10%)		2/9 (22.2%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		2/8 (25%)		0/8 (0%)		0/15 (0%)		2/22 (9.1%)		3/9 (33.3%)
Pyrexia	4/8 (50%)		1/8 (12.5%)		3/10 (30%)		2/9 (22.2%)		0/7 (0%)		1/14 (7.1%)		5/22 (22.7%)		1/8 (12.5%)		4/8 (50%)		2/15 (13.3%)		7/22 (31.8%)		2/9 (22.2%)
Injection site bruising	1/8 (12.5%)		2/8 (25%)		0/10 (0%)		0/9 (0%)		1/7 (14.3%)		0/14 (0%)		0/22 (0%)		1/8 (12.5%)		1/8 (12.5%)		2/15 (13.3%)		0/22 (0%)		1/9 (11.1%)
Fatigue	0/8 (0%)		1/8 (12.5%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		2/22 (9.1%)		0/8 (0%)		0/8 (0%)		1/15 (6.7%)		2/22 (9.1%)		0/9 (0%)
Injection site pruritus	0/8 (0%)		0/8 (0%)		2/10 (20%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		1/8 (12.5%)		0/8 (0%)		0/15 (0%)		3/22 (13.6%)		1/9 (11.1%)
Injection site haemorrhage	0/8 (0%)		0/8 (0%)		1/10 (10%)		1/9 (11.1%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		2/22 (9.1%)		1/9 (11.1%)
Application site erythema	1/8 (12.5%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		0/22 (0%)		0/9 (0%)
Cyst	1/8 (12.5%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		0/22 (0%)		0/9 (0%)
Influenza like illness	0/8 (0%)		0/8 (0%)		1/10 (10%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Injection site discolouration	0/8 (0%)		0/8 (0%)		0/10 (0%)		1/9 (11.1%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		0/22 (0%)		1/9 (11.1%)
Injection site induration	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		1/8 (12.5%)		0/8 (0%)		0/15 (0%)		0/22 (0%)		1/9 (11.1%)
Malaise	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Medical device site reaction	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		1/14 (7.1%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		1/15 (6.7%)		0/22 (0%)		0/9 (0%)
Pain	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		1/7 (14.3%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		0/22 (0%)		0/9 (0%)
Immune system disorders
Drug hypersensitivity	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		1/7 (14.3%)		1/14 (7.1%)		1/22 (4.5%)		0/8 (0%)		1/8 (12.5%)		1/15 (6.7%)		1/22 (4.5%)		0/9 (0%)
Hypersensitivity	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		1/8 (12.5%)		0/8 (0%)		0/15 (0%)		0/22 (0%)		1/9 (11.1%)
Seasonal allergy	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		1/8 (12.5%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		1/9 (11.1%)
Infections and infestations
Nasopharyngitis	1/8 (12.5%)		3/8 (37.5%)		3/10 (30%)		1/9 (11.1%)		0/7 (0%)		1/14 (7.1%)		4/22 (18.2%)		2/8 (25%)		1/8 (12.5%)		3/15 (20%)		7/22 (31.8%)		2/9 (22.2%)
Ear infection	0/8 (0%)		3/8 (37.5%)		2/10 (20%)		2/9 (22.2%)		1/7 (14.3%)		1/14 (7.1%)		4/22 (18.2%)		2/8 (25%)		1/8 (12.5%)		4/15 (26.7%)		6/22 (27.3%)		2/9 (22.2%)
Upper respiratory tract infection	0/8 (0%)		1/8 (12.5%)		3/10 (30%)		2/9 (22.2%)		0/7 (0%)		0/14 (0%)		3/22 (13.6%)		1/8 (12.5%)		0/8 (0%)		1/15 (6.7%)		5/22 (22.7%)		2/9 (22.2%)
Otitis media	0/8 (0%)		0/8 (0%)		0/10 (0%)		2/9 (22.2%)		1/7 (14.3%)		0/14 (0%)		3/22 (13.6%)		2/8 (25%)		1/8 (12.5%)		0/15 (0%)		3/22 (13.6%)		3/9 (33.3%)
Viral upper respiratory tract infection	0/8 (0%)		0/8 (0%)		0/10 (0%)		1/9 (11.1%)		0/7 (0%)		0/14 (0%)		3/22 (13.6%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		3/22 (13.6%)		1/9 (11.1%)
Gastroenteritis viral	0/8 (0%)		1/8 (12.5%)		0/10 (0%)		1/9 (11.1%)		1/7 (14.3%)		2/14 (14.3%)		0/22 (0%)		1/8 (12.5%)		1/8 (12.5%)		3/15 (20%)		0/22 (0%)		2/9 (22.2%)
Viral infection	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		5/22 (22.7%)		1/8 (12.5%)		0/8 (0%)		0/15 (0%)		5/22 (22.7%)		1/9 (11.1%)
Gastroenteritis	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		1/14 (7.1%)		1/22 (4.5%)		1/8 (12.5%)		0/8 (0%)		1/15 (6.7%)		1/22 (4.5%)		1/9 (11.1%)
Bronchitis	1/8 (12.5%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		1/14 (7.1%)		1/22 (4.5%)		0/8 (0%)		1/8 (12.5%)		1/15 (6.7%)		1/22 (4.5%)		0/9 (0%)
Sinusitis	1/8 (12.5%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		2/22 (9.1%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		2/22 (9.1%)		0/9 (0%)
Conjunctivitis	1/8 (12.5%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Influenza	0/8 (0%)		0/8 (0%)		0/10 (0%)		1/9 (11.1%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		1/8 (12.5%)		0/8 (0%)		0/15 (0%)		0/22 (0%)		2/9 (22.2%)
Otitis externa	1/8 (12.5%)		0/8 (0%)		0/10 (0%)		1/9 (11.1%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		0/22 (0%)		1/9 (11.1%)
Pharyngitis streptococcal	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		2/22 (9.1%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		2/22 (9.1%)		0/9 (0%)
Rhinitis	0/8 (0%)		0/8 (0%)		1/10 (10%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Acute sinusitis	1/8 (12.5%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		0/22 (0%)		0/9 (0%)
Atypical pneumonia	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Croup infectious	0/8 (0%)		0/8 (0%)		0/10 (0%)		1/9 (11.1%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		0/22 (0%)		1/9 (11.1%)
Eye abscess	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Gastrointestinal viral infection	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		1/8 (12.5%)		0/8 (0%)		0/15 (0%)		0/22 (0%)		1/9 (11.1%)
Incision site infection	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Onychomycosis	0/8 (0%)		0/8 (0%)		1/10 (10%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Pharyngitis	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		1/8 (12.5%)		0/8 (0%)		0/15 (0%)		0/22 (0%)		1/9 (11.1%)
Rash pustular	0/8 (0%)		0/8 (0%)		1/10 (10%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Respiratory tract infection	0/8 (0%)		0/8 (0%)		1/10 (10%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Scarlet fever	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		1/8 (12.5%)		0/8 (0%)		0/15 (0%)		0/22 (0%)		1/9 (11.1%)
Tonsillitis	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Tooth abscess	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		1/7 (14.3%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		0/22 (0%)		0/9 (0%)
Varicella	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Injury, poisoning and procedural complications
Arthropod bite	1/8 (12.5%)		2/8 (25%)		1/10 (10%)		0/9 (0%)		0/7 (0%)		1/14 (7.1%)		3/22 (13.6%)		1/8 (12.5%)		1/8 (12.5%)		2/15 (13.3%)		3/22 (13.6%)		1/9 (11.1%)
Fall	1/8 (12.5%)		0/8 (0%)		1/10 (10%)		1/9 (11.1%)		1/7 (14.3%)		1/14 (7.1%)		2/22 (9.1%)		1/8 (12.5%)		2/8 (25%)		1/15 (6.7%)		3/22 (13.6%)		2/9 (22.2%)
Contusion	1/8 (12.5%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		1/7 (14.3%)		0/14 (0%)		2/22 (9.1%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		2/22 (9.1%)		0/9 (0%)
Procedural anxiety	1/8 (12.5%)		1/8 (12.5%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		1/8 (12.5%)		1/15 (6.7%)		1/22 (4.5%)		0/9 (0%)
Limb injury	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		1/8 (12.5%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		1/9 (11.1%)
Procedural pain	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		2/7 (28.6%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		2/8 (25%)		0/15 (0%)		0/22 (0%)		0/9 (0%)
Skin abrasion	0/8 (0%)		0/8 (0%)		0/10 (0%)		1/9 (11.1%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		1/8 (12.5%)		0/8 (0%)		0/15 (0%)		0/22 (0%)		2/9 (22.2%)
Thermal burn	1/8 (12.5%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Excoriation	0/8 (0%)		1/8 (12.5%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		1/15 (6.7%)		0/22 (0%)		0/9 (0%)
Joint injury	1/8 (12.5%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		0/22 (0%)		0/9 (0%)
Laceration	0/8 (0%)		0/8 (0%)		0/10 (0%)		1/9 (11.1%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		0/22 (0%)		1/9 (11.1%)
Meniscus injury	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Muscle strain	0/8 (0%)		1/8 (12.5%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		1/15 (6.7%)		0/22 (0%)		0/9 (0%)
Post-traumatic pain	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		1/14 (7.1%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		1/15 (6.7%)		0/22 (0%)		0/9 (0%)
Soft tissue injury	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		1/8 (12.5%)		0/8 (0%)		0/15 (0%)		0/22 (0%)		1/9 (11.1%)
Sunburn	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		1/8 (12.5%)		0/8 (0%)		0/15 (0%)		0/22 (0%)		1/9 (11.1%)
Wound	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Investigations
Body temperature increased	0/8 (0%)		0/8 (0%)		0/10 (0%)		1/9 (11.1%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		1/8 (12.5%)		0/8 (0%)		0/15 (0%)		0/22 (0%)		1/9 (11.1%)
Eosinophil count increased	0/8 (0%)		0/8 (0%)		1/10 (10%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		2/22 (9.1%)		0/9 (0%)
Electrocardiogram QT prolonged	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Vitamin D decreased	0/8 (0%)		0/8 (0%)		1/10 (10%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		2/22 (9.1%)		0/9 (0%)
Blood immunoglobulin E increased	0/8 (0%)		0/8 (0%)		1/10 (10%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Respiratory rate increased	1/8 (12.5%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		0/22 (0%)		0/9 (0%)
Sleep study abnormal	0/8 (0%)		0/8 (0%)		1/10 (10%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Metabolism and nutrition disorders
Hyperglycaemia	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Vitamin D deficiency	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Musculoskeletal and connective tissue disorders
Pain in extremity	1/8 (12.5%)		0/8 (0%)		0/10 (0%)		1/9 (11.1%)		0/7 (0%)		0/14 (0%)		2/22 (9.1%)		4/8 (50%)		1/8 (12.5%)		0/15 (0%)		2/22 (9.1%)		4/9 (44.4%)
Arthralgia	1/8 (12.5%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		3/22 (13.6%)		1/8 (12.5%)		1/8 (12.5%)		0/15 (0%)		3/22 (13.6%)		1/9 (11.1%)
Back pain	1/8 (12.5%)		1/8 (12.5%)		1/10 (10%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		2/22 (9.1%)		0/8 (0%)		1/8 (12.5%)		1/15 (6.7%)		3/22 (13.6%)		0/9 (0%)
Neck pain	1/8 (12.5%)		0/8 (0%)		0/10 (0%)		1/9 (11.1%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		1/22 (4.5%)		1/9 (11.1%)
Groin pain	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		1/7 (14.3%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Joint range of motion decreased	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		1/8 (12.5%)		0/8 (0%)		0/15 (0%)		0/22 (0%)		1/9 (11.1%)
Bone pain	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		1/7 (14.3%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		0/22 (0%)		0/9 (0%)
Muscle spasms	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Musculoskeletal chest pain	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		1/14 (7.1%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		1/15 (6.7%)		0/22 (0%)		0/9 (0%)
Myalgia	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		1/8 (12.5%)		0/8 (0%)		0/15 (0%)		0/22 (0%)		1/9 (11.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		1/8 (12.5%)		0/8 (0%)		0/15 (0%)		0/22 (0%)		1/9 (11.1%)
Nervous system disorders
Headache	4/8 (50%)		2/8 (25%)		2/10 (20%)		3/9 (33.3%)		1/7 (14.3%)		1/14 (7.1%)		5/22 (22.7%)		0/8 (0%)		4/8 (50%)		3/15 (20%)		6/22 (27.3%)		3/9 (33.3%)
Dizziness	1/8 (12.5%)		1/8 (12.5%)		1/10 (10%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		1/8 (12.5%)		1/15 (6.7%)		2/22 (9.1%)		0/9 (0%)
Presyncope	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		2/22 (9.1%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		2/22 (9.1%)		0/9 (0%)
Syncope	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Tremor	0/8 (0%)		0/8 (0%)		0/10 (0%)		1/9 (11.1%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		0/22 (0%)		1/9 (11.1%)
Sinus headache	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		1/7 (14.3%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		0/22 (0%)		0/9 (0%)
Psychiatric disorders
Emotional disorder	0/8 (0%)		1/8 (12.5%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		1/15 (6.7%)		0/22 (0%)		0/9 (0%)
Irritability	1/8 (12.5%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		1/14 (7.1%)		0/22 (0%)		0/8 (0%)		1/8 (12.5%)		1/15 (6.7%)		0/22 (0%)		0/9 (0%)
Aggression	0/8 (0%)		1/8 (12.5%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		1/15 (6.7%)		0/22 (0%)		0/9 (0%)
Attention deficit/hyperactivity disorder	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Enuresis	1/8 (12.5%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		0/22 (0%)		0/9 (0%)
Frustration tolerance decreased	0/8 (0%)		1/8 (12.5%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		1/15 (6.7%)		0/22 (0%)		0/9 (0%)
Renal and urinary disorders
Pollakiuria	0/8 (0%)		1/8 (12.5%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		1/15 (6.7%)		0/22 (0%)		0/9 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	4/8 (50%)		0/8 (0%)		2/10 (20%)		4/9 (44.4%)		0/7 (0%)		2/14 (14.3%)		4/22 (18.2%)		1/8 (12.5%)		4/8 (50%)		2/15 (13.3%)		6/22 (27.3%)		4/9 (44.4%)
Oropharyngeal pain	1/8 (12.5%)		2/8 (25%)		2/10 (20%)		0/9 (0%)		0/7 (0%)		1/14 (7.1%)		3/22 (13.6%)		0/8 (0%)		1/8 (12.5%)		2/15 (13.3%)		4/22 (18.2%)		0/9 (0%)
Nasal congestion	1/8 (12.5%)		2/8 (25%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		1/14 (7.1%)		1/22 (4.5%)		2/8 (25%)		1/8 (12.5%)		2/15 (13.3%)		1/22 (4.5%)		2/9 (22.2%)
Rhinorrhoea	1/8 (12.5%)		1/8 (12.5%)		0/10 (0%)		1/9 (11.1%)		1/7 (14.3%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		2/8 (25%)		1/15 (6.7%)		0/22 (0%)		1/9 (11.1%)
Epistaxis	0/8 (0%)		1/8 (12.5%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		0/8 (0%)		1/15 (6.7%)		1/22 (4.5%)		0/9 (0%)
Sleep apnoea syndrome	0/8 (0%)		0/8 (0%)		1/10 (10%)		0/9 (0%)		1/7 (14.3%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		2/22 (9.1%)		0/9 (0%)
Sneezing	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		1/8 (12.5%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		1/9 (11.1%)
Tonsillar hypertrophy	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		2/22 (9.1%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		2/22 (9.1%)		0/9 (0%)
Asthma	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Nasal dryness	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		1/7 (14.3%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		0/22 (0%)		0/9 (0%)
Rhinitis allergic	1/8 (12.5%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		0/22 (0%)		0/9 (0%)
Snoring	0/8 (0%)		0/8 (0%)		1/10 (10%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Wheezing	0/8 (0%)		0/8 (0%)		1/10 (10%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Skin and subcutaneous tissue disorders
Rash	0/8 (0%)		2/8 (25%)		0/10 (0%)		1/9 (11.1%)		1/7 (14.3%)		0/14 (0%)		3/22 (13.6%)		0/8 (0%)		1/8 (12.5%)		2/15 (13.3%)		3/22 (13.6%)		1/9 (11.1%)
Dermatitis	0/8 (0%)		0/8 (0%)		1/10 (10%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		2/22 (9.1%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		2/22 (9.1%)		0/9 (0%)
Dry skin	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		2/22 (9.1%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		2/22 (9.1%)		0/9 (0%)
Pruritus	1/8 (12.5%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		1/8 (12.5%)		1/8 (12.5%)		0/15 (0%)		1/22 (4.5%)		1/9 (11.1%)
Erythema	1/8 (12.5%)		0/8 (0%)		1/10 (10%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Rash generalised	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		1/7 (14.3%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Rash pruritic	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		1/8 (12.5%)		0/8 (0%)		0/15 (0%)		0/22 (0%)		1/9 (11.1%)
Acne	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Miliaria	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Skin exfoliation	0/8 (0%)		0/8 (0%)		0/10 (0%)		1/9 (11.1%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		0/22 (0%)		1/9 (11.1%)
Skin striae	0/8 (0%)		1/8 (12.5%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		1/15 (6.7%)		0/22 (0%)		0/9 (0%)
Surgical and medical procedures
Ear tube insertion	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		2/22 (9.1%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		2/22 (9.1%)		0/9 (0%)
Tooth extraction	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		1/7 (14.3%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		0/22 (0%)		0/9 (0%)
Vascular disorders
Hypotension	3/8 (37.5%)		4/8 (50%)		4/10 (40%)		2/9 (22.2%)		1/7 (14.3%)		1/14 (7.1%)		3/22 (13.6%)		2/8 (25%)		4/8 (50%)		5/15 (33.3%)		7/22 (31.8%)		2/9 (22.2%)
Haematoma	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Haemorrhage	0/8 (0%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		1/22 (4.5%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		1/22 (4.5%)		0/9 (0%)
Hypertension	1/8 (12.5%)		0/8 (0%)		0/10 (0%)		0/9 (0%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		1/8 (12.5%)		0/15 (0%)		0/22 (0%)		0/9 (0%)
Pallor	0/8 (0%)		0/8 (0%)		0/10 (0%)		1/9 (11.1%)		0/7 (0%)		0/14 (0%)		0/22 (0%)		0/8 (0%)		0/8 (0%)		0/15 (0%)		0/22 (0%)		1/9 (11.1%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.